Using Workflow Modeling to Identify Areas to Improve Genetic Test Processes in the University of Maryland Translational Pharmacogenomics Project.

PubMed

Cutting, Elizabeth M; Overby, Casey L; Banchero, Meghan; Pollin, Toni; Kelemen, Mark; Shuldiner, Alan R; Beitelshees, Amber L

Delivering genetic test results to clinicians is a complex process. It involves many actors and multiple steps, requiring all of these to work together in order to create an optimal course of treatment for the patient. We used information gained from focus groups in order to illustrate the current process of delivering genetic test results to clinicians. We propose a business process model and notation (BPMN) representation of this process for a Translational Pharmacogenomics Project being implemented at the University of Maryland Medical Center, so that personalized medicine program implementers can identify areas to improve genetic testing processes. We found that the current process could be improved to reduce input errors, better inform and notify clinicians about the implications of certain genetic tests, and make results more easily understood. We demonstrate our use of BPMN to improve this important clinical process for CYP2C19 genetic testing in patients undergoing invasive treatment of coronary heart disease.

Using Workflow Modeling to Identify Areas to Improve Genetic Test Processes in the University of Maryland Translational Pharmacogenomics Project

PubMed Central

Cutting, Elizabeth M.; Overby, Casey L.; Banchero, Meghan; Pollin, Toni; Kelemen, Mark; Shuldiner, Alan R.; Beitelshees, Amber L.

2015-01-01

Delivering genetic test results to clinicians is a complex process. It involves many actors and multiple steps, requiring all of these to work together in order to create an optimal course of treatment for the patient. We used information gained from focus groups in order to illustrate the current process of delivering genetic test results to clinicians. We propose a business process model and notation (BPMN) representation of this process for a Translational Pharmacogenomics Project being implemented at the University of Maryland Medical Center, so that personalized medicine program implementers can identify areas to improve genetic testing processes. We found that the current process could be improved to reduce input errors, better inform and notify clinicians about the implications of certain genetic tests, and make results more easily understood. We demonstrate our use of BPMN to improve this important clinical process for CYP2C19 genetic testing in patients undergoing invasive treatment of coronary heart disease. PMID:26958179

Genetic testing: medico-legal issues.

PubMed

Bird, Sara

2014-07-01

The availability and frequency of genetic testing is increasing. Genetic testing poses some unique ethical and legal issues for medical practitioners because of the potential to identify genetic variants that carry implications for the risk of disease in the future for the patient and their relatives. The regulatory framework within which genetic testing is provided in Australia is also changing. This article examines some medico-legal issues associated with genetic testing that general practitioners (GPs) are likely encounter in their practices. There is inevitable involvement of the GP in the long term care of a patient (and possibly their family) following genetic testing, regardless of whether or not the GP has ordered the testing. Cases are presented to illustrate some of the medico-legal issues that may arise from direct-to-consumer genetic testing, information disclosure to genetic relatives and requests for parentage testing.

Feline Genetics: Clinical Applications and Genetic Testing

PubMed Central

Lyons, Leslie A.

2010-01-01

DNA testing for domestic cat diseases and appearance traits is a rapidly growing asset for veterinary medicine. Approximately thirty-three genes contain fifty mutations that cause feline health problems or alterations in the cat’s appearance. A variety of commercial laboratories can now perform cat genetic diagnostics, allowing both the veterinary clinician and the private owner to obtain DNA test results. DNA is easily obtained from a cat via a buccal swab using a standard cotton bud or cytological brush, allowing DNA samples to be easily sent to any laboratory in the world. The DNA test results identify carriers of the traits, predict the incidence of traits from breeding programs, and influence medical prognoses and treatments. An overall goal of identifying these genetic mutations is the correction of the defect via gene therapies and designer drug therapies. Thus, genetic testing is an effective preventative medicine and a potential ultimate cure. However, genetic diagnostic tests may still be novel for many veterinary practitioners and their application in the clinical setting needs to have the same scrutiny as any other diagnostic procedure. This article will review the genetic tests for the domestic cat, potential sources of error for genetic testing, and the pros and cons of DNA results in veterinary medicine. Highlighted are genetic tests specific to the individual cat, which are a part of the cat’s internal genome. PMID:21147473

Feline genetics: clinical applications and genetic testing.

PubMed

Lyons, Leslie A

2010-11-01

DNA testing for domestic cat diseases and appearance traits is a rapidly growing asset for veterinary medicine. Approximately 33 genes contain 50 mutations that cause feline health problems or alterations in the cat's appearance. A variety of commercial laboratories can now perform cat genetic diagnostics, allowing both the veterinary clinician and the private owner to obtain DNA test results. DNA is easily obtained from a cat via a buccal swab with a standard cotton bud or cytological brush, allowing DNA samples to be easily sent to any laboratory in the world. The DNA test results identify carriers of the traits, predict the incidence of traits from breeding programs, and influence medical prognoses and treatments. An overall goal of identifying these genetic mutations is the correction of the defect via gene therapies and designer drug therapies. Thus, genetic testing is an effective preventative medicine and a potential ultimate cure. However, genetic diagnostic tests may still be novel for many veterinary practitioners and their application in the clinical setting needs to have the same scrutiny as any other diagnostic procedure. This article will review the genetic tests for the domestic cat, potential sources of error for genetic testing, and the pros and cons of DNA results in veterinary medicine. Highlighted are genetic tests specific to the individual cat, which are a part of the cat's internal genome. Copyright © 2010 Elsevier Inc. All rights reserved.

Identifying Needs: a Qualitative Study of women's Experiences Regarding Rapid Genetic Testing for Hereditary Breast and Ovarian Cancer in the DNA BONus Study.

PubMed

Augestad, Mirjam Tonheim; Høberg-Vetti, Hildegunn; Bjorvatn, Cathrine; Sekse, Ragnhild Johanne Tveit

2017-02-01

Genetic testing for hereditary breast and ovarian cancer is increasingly being offered in newly diagnosed breast and ovarian cancer patients. This genetic information may influence treatment decisions. However, there are some concerns that genetic testing offered in an already vulnerable situation might be an extra burden to these women. The aim of this study was to explore the experiences of women who had been offered and accepted genetic testing when newly diagnosed with breast or ovarian cancer. Four semi-structured focus-group interviews were conducted with 17 women recruited from a Norwegian multicenter study. The material was condensed, and conventional qualitative analysis was used to identify patterns in the participants' descriptions. Three core themes were identified: 1) being "beside oneself" 2) altruism and ethical dilemmas 3) the need for support and counselling to assist the decision process. The present study indicates that women who are offered genetic testing when newly diagnosed with breast or ovarian cancer want a consultation with a health professional. Personalized support and counselling might empower women to improve their ability to manage and comprehend this overwhelming situation, and find meaning in this experience.

Direct-to-consumer genetic testing for addiction susceptibility: a premature commercialisation of doubtful validity and value.

PubMed

Mathews, Rebecca; Hall, Wayne; Carter, Adrian

2012-12-01

Genetic research on addiction liability and pharmacogenetic research on treatments for addiction have identified some genetic variants associated with disease risk and treatment. Genetic testing for addiction liability and treatment response has not been used widely in clinical practice because most of the genes identified only modestly predict addiction risk or treatment response. However, many of these genetic tests have been commercialized prematurely and are available direct to the consumer (DTC). The easy availability of DTC tests for addiction liability and lack of regulation over their use raises a number of ethical concerns. Of paramount concern is the limited predictive power and clinical utility of these tests. Many DTC testing companies do not provide the consumer with the necessary genetic counselling to assist them in interpreting and acting on their test results. They may also engage in misleading marketing to entice consumers to purchase their products. Consumers' genetic information may be vulnerable to misuse by third parties, as there are limited standards to protect the privacy of the genetic information. Non-consensual testing and inappropriate testing of minors may also occur. The United States Food and Drug Administration plans to regulate DTC genetic tests. Based on the ethical concerns we discuss below, we believe there is a strong case for regulation of DTC genetic tests for addiction liability and treatment response. We argue that until this occurs, these tests have more potential to cause harm than to contribute to improved prevention and treatment of addiction. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.

Adults' perceptions of genetic counseling and genetic testing.

PubMed

Houfek, Julia Fisco; Soltis-Vaughan, Brigette S; Atwood, Jan R; Reiser, Gwendolyn M; Schaefer, G Bradley

2015-02-01

This study described the perceptions of genetic counseling and testing of adults (N = 116) attending a genetic education program. Understanding perceptions of genetic counseling, including the importance of counseling topics, will contribute to patient-focused care as clinical genetic applications for common, complex disorders evolve. Participants completed a survey addressing: the importance of genetic counseling topics, benefits and negative effects of genetic testing, and sharing test results. Topics addressing practical information about genetic conditions were rated most important; topics involving conceptual genetic/genomic principles were rated least important. The most frequently identified benefit and negative effect of testing were prevention/early detection/treatment and psychological distress. Participants perceived that they were more likely to share test results with first-degree than other relatives. Findings suggest providing patients with practical information about genetic testing and genetic contributions to disease, while also determining whether their self-care abilities would be enhanced by teaching genetic/genomic principles. Copyright © 2014 Elsevier Inc. All rights reserved.

How Is Wilson Disease Inherited?

MedlinePlus

... ATP7B gene have been identified thus far. Testing Methods Available Linkage analysis (Haplotype analysis) Molecular genetic testing ... genetic counselor who can carefully discuss the best method of testing to perform and the benefits, limitations, ...

Valuations of genetic test information for treatable conditions: the case of colorectal cancer screening.

PubMed

Kilambi, Vikram; Johnson, F Reed; González, Juan Marcos; Mohamed, Ateesha F

2014-12-01

The value of the information that genetic testing services provide can be questioned for insurance-based health systems. The results of genetic tests oftentimes may not lead to well-defined clinical interventions; however, Lynch syndrome, a genetic mutation for which carriers are at an increased risk for colorectal cancer, can be identified through genetic testing, and meaningful health interventions are available via increased colonoscopic surveillance. Valuations of test information for such conditions ought to account for the full impact of interventions and contingent outcomes. To conduct a discrete-choice experiment to elicit individuals' preferences for genetic test information. A Web-enabled discrete-choice experiment survey was administered to a representative sample of US residents aged 50 years and older. In addition to specifying expenditures on colonoscopies, respondents were asked to make a series of nine selections between two hypothetical genetic tests or a no-test option under the premise that a relative had Lynch syndrome. The hypothetical genetic tests were defined by the probability of developing colorectal cancer, the probability of a false-negative test result, privacy of the result, and out-of-pocket cost. A model specification identifying necessary interactions was derived from assumptions of risk behavior and the decision context and was estimated using random-parameters logit. A total of 650 respondents were contacted, and 385 completed the survey. The monetary equivalent of test information was approximately $1800. Expenditures on colonoscopies to reduce mortality risks affected valuations. Respondents with lower income or who reported being employed significantly valued genetic tests more. Genetic testing may confer benefits through the impact of subsequent interventions on private individuals. Copyright © 2014. Published by Elsevier Inc.

Genetic testing in inherited polyposis syndromes - how and why?

PubMed

Lee, G H; Payne, S J; Melville, A; Clark, S K

2014-08-01

There have been recent advances in genetic testing enabling accurate diagnosis of polyposis syndromes by identifying causative gene mutations, which is essential in the management of individuals with polyposis syndrome and predictive genetic testing of their extended families. There are some similarities in clinical presentation of various polyposis syndromes, which may pose a challenge to diagnosis. In this review, we discuss the clinical presentation of the main polyposis syndromes and the process of genetic testing, including the latest advancement and future of genetic testing. We aim to reiterate the importance of genetic testing in the management of polyposis syndromes, potential pitfalls associated with genetic testing and recommendations for healthcare professionals involved with the care of polyposis patients. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.

Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes.

PubMed

Rohde, Palle Duun; Demontis, Ditte; Cuyabano, Beatriz Castro Dias; Børglum, Anders D; Sørensen, Peter

2016-08-01

Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited power to detect genetic markers with small effects. Instead, aggregating genetic markers based on biological information might increase the power to identify sets of genetic markers of etiological significance. Several set test methods have been proposed: Here we propose a new set test derived from genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case-control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism and immunological responses, which previously have been implicated with schizophrenia based on experimental and observational studies. Copyright © 2016 by the Genetics Society of America.

Merits and pitfalls of genetic testing in a hypertrophic cardiomyopathy clinic.

PubMed

Arad, Michael; Monserrat, Lorenzo; Haron-Khun, Shiraz; Seidman, Jonathan G; Seidman, Christine E; Arbustini, Eloisa; Glikson, Michael; Freimark, Dov

2014-11-01

Hypertrophic cardiomyopathy (HCM) is a familial disease with autosomal dominant inheritance and age-dependent penetrance, caused primarily by mutations of sarcomere genes. Because the clinical variability of HCM is related to its genetic heterogeneity, genetic studies may improve the diagnosis and prognostic evaluation in HCM. To analyze the impact of genetic diagnosis on the clinical management of HCM. Genetic studies were performed for either research or clinical reasons. Once the disease-causing mutation was identified, the management plan was reevaluated. Family members were invited to receive genetic counseling and encouraged to be tested for the mutation. Ten mutations in sarcomere protein genes were identified in 9 probands: 2 novel and 8 previously described. Advanced heart failure or sudden death in a young person prompted the genetic study in 8 of the 9 families. Of 98 relatives available for genotyping, only 53 (54%) agreed to be tested. The compliance was higher in families with sudden death and lower in what appeared to be sporadic HCM or elderly-onset disease. Among the healthy we identified 9 carriers and 19 non-carriers. In 6 individuals the test result resolved an uncertainty about "possible HCM." In several cases the genetic result was also used for family planning and played a role in decisions on cardioverter-defibrillator implantation. Recurrence of a same mutation in different families created an opportunity to apply the information from the literature for risk stratification of individual patients. We suggest that the clinical context determines the indication for genetic testing and interpretation of the results.

The effect of referral for genetic counseling on genetic testing and surgical prevention in women at high risk for ovarian cancer: Results from a randomized controlled trial.

PubMed

Drescher, Charles W; Beatty, J David; Resta, Robert; Andersen, M Robyn; Watabayashi, Kate; Thorpe, Jason; Hawley, Sarah; Purkey, Hannah; Chubak, Jessica; Hanson, Nancy; Buist, Diana S M; Urban, Nicole

2016-07-22

Guidelines recommend genetic counseling and testing for women who have a pedigree suggestive of an inherited susceptibility for ovarian cancer. The authors evaluated the effect of referral to genetic counseling on genetic testing and prophylactic oophorectomy in a randomized controlled trial. Data from an electronic mammography reporting system identified 12,919 women with a pedigree that included breast cancer, of whom 625 were identified who had a high risk for inherited susceptibility to ovarian cancer using a risk-assessment questionnaire. Of these, 458 women provided informed consent and were randomized 1:1 to intervention consisting of a genetic counseling referral (n = 228) or standard clinical care (n = 230). Participants were predominantly aged 45 to 65 years, and 30% and 20% reported a personal history of breast cancer or a family history of ovarian cancer, respectively. Eighty-five percent of women in the intervention group participated in a genetic counseling session. Genetic testing was reported by 74 (33%) and 20 (9%) women in the intervention and control arms (P < .005), respectively. Five women in the intervention arm and 2 in the control arm were identified as germline mutation carriers. Ten women in the intervention arm and 3 in the control arm underwent prophylactic bilateral salpingo-oophorectomy (P < .05). Routine referral of women at high risk for ovarian cancer to genetic counseling promotes genetic testing and prophylactic surgery. The findings from the current randomized controlled trial demonstrate the value of implementing strategies that target women at high risk for ovarian cancer to ensure they are offered access to recommended care. CA Cancer J Clin 2016. © 2016 American Cancer Society, Inc. © 2016 American Cancer Society.

Breast cancer genetic testing awareness, attitudes and intentions of Latinas living along the US-Mexico border: a qualitative study.

PubMed

Chalela, Patricia; Pagán, José A; Su, Dejun; Muñoz, Edgar; Ramirez, Amelie G

2012-01-01

Genetic testing for breast cancer may facilitate better-informed decisions regarding cancer prevention, risk reduction, more effective early detection, and better determination of risk for family members. Despite these potential benefits, significant portions of the US population-particularly Latinas-lack awareness of genetic testing for breast cancer susceptibility. Among women who are tested, less than 4% are Latina. To uncover reasons for Latinas' low participation, this study explores awareness, attitudes and behavioral intentions to undergo genetic testing among average-risk Latinas along the Texas-Mexico border. Eight focus groups were conducted with 58 Latinas aged 19-69 living in Hidalgo County, a largely Latino region of South Texas. Focus group discussions were digitally recorded, transcribed and analyzed using qualitative content analysis to assess, categorize and interpret them. Two experienced study team members analyzed transcripts to identify major concepts grouped into theme categories. Participants mostly had less than a high-school education (43%), spoke primarily Spanish (52%), were of Mexican-American origin (90%) and had a family income of $30,000 or less (75%). Focus groups found that most participants had positive attitudes and strong interest in genetic testing, yet lacked general awareness and knowledge about genetic testing, its risks, benefits, and limitations. Participants also identified several key cultural-based influencers, such as family, religious beliefs and fear of testing. The delivery of culturally adapted risk information is needed to increase and ensure Latinas' understanding of breast cancer genetic testing during their decision-making processes. Key Latino values-religiosity, importance of family and the influential role of health care providers in health decisions-should also be considered when designing interventions targeting this specific group. Further research is needed to identify effective ways to communicate genetic risk susceptibility information to Latinas to help them make informed testing decisions.

Identification of multiple genetic loci in the mouse controlling immobility time in the tail suspension and forced swimming tests.

PubMed

Abou-Elnaga, Ahmed F; Torigoe, Daisuke; Fouda, Mohamed M; Darwish, Ragab A; Abou-Ismail, Usama A; Morimatsu, Masami; Agui, Takashi

2015-05-01

Depression is one of the most famous psychiatric disorders in humans in all over the countries and considered a complex neurobehavioral trait and difficult to identify causal genes. Tail suspension test (TST) and forced swimming test (FST) are widely used for assessing depression-like behavior and antidepressant activity in mice. A variety of antidepressant agents are known to reduce immobility time in both TST and FST. To identify genetic determinants of immobility duration in both tests, we analyzed 101 F2 mice from an intercross between C57BL/6 and DBA/2 strains. Quantitative trait locus (QTL) mapping using 106 microsatellite markers revealed three loci (two significant and one suggestive) and five suggestive loci controlling immobility time in the TST and FST, respectively. Results of QTL analysis suggest a broad description of the genetic architecture underlying depression, providing underpinnings for identifying novel molecular targets for antidepressants to clear the complex genetic mechanisms of depressive disorders.

Effects of Cancer Genetic Panel Testing on at-Risk Individuals.

PubMed

Frost, Anja S; Toaff, Miriam; Biagi, Tara; Stark, Elizabeth; McHenry, Allison; Kaltman, Rebecca

2018-06-01

To evaluate the role of screening patients at increased risk for hereditary cancer syndromes with an extended panel of cancer predisposition genes to identify actionable genetic mutations. A retrospective chart review was conducted of all patients presenting to a multidisciplinary cancer program for genetic counseling and testing from January 2015 to December 2016. Individuals presenting to the program were identified as at-risk by a personal or family history of cancer, by their health care provider, or by self-referral. All participants met current National Comprehensive Cancer Network criteria for genetic risk evaluation for hereditary cancer. The results of testing and its implications for management, based on National Comprehensive Cancer Network guidelines, were recorded. Of 670 at-risk patients who underwent genetic testing, 66 (9.9%) had BRCA-limited testing; of these, 26 of 670 (3.9%) had a deleterious or likely pathogenic mutation. Expanded panel testing was done for 560 of the 670 patients (83.4%), and abnormal results were found in 65 of 670 (9.7%); non-BRCA mutations (predominantly CHEK2) were found in 49 of the 65 (75%). Abnormal genetic testing was associated with increased surveillance in 96% of those with deleterious mutations, whereas negative testing for a known familial mutation in 45 patients was associated with a downgrade of their risk and reduction of subsequent surveillance and management. Guideline-based management is frequently altered by genetic testing, including panel testing, in patients at risk for cancer. We recommend that obstetrics and gynecology providers routinely refer at-risk patients for genetic counseling and testing when clinically appropriate.

Genetically distinct genogroup IV norovirus strains identified in wastewater.

PubMed

Kitajima, Masaaki; Rachmadi, Andri T; Iker, Brandon C; Haramoto, Eiji; Gerba, Charles P

2016-12-01

We investigated the prevalence and genetic diversity of genogroup IV norovirus (GIV NoV) strains in wastewater in Arizona, United States, over a 13-month period. Among 50 wastewater samples tested, GIV NoVs were identified in 13 (26 %) of the samples. A total of 47 different GIV NoV strains were identified, which were classified into two genetically distinct clusters: the GIV.1 human cluster and a unique genetic cluster closely related to strains previously identified in Japanese wastewater. The results provide additional evidence of the considerable genetic diversity among GIV NoV strains through the analysis of wastewater containing virus strains shed from all populations.

Perspectives on Genetic and Genomic Technologies in an Academic Medical Center: The Duke Experience

PubMed Central

Katsanis, Sara Huston; Minear, Mollie A.; Vorderstrasse, Allison; Yang, Nancy; Reeves, Jason W.; Rakhra-Burris, Tejinder; Cook-Deegan, Robert; Ginsburg, Geoffrey S.; Simmons, Leigh Ann

2015-01-01

In this age of personalized medicine, genetic and genomic testing is expected to become instrumental in health care delivery, but little is known about its actual implementation in clinical practice. Methods. We surveyed Duke faculty and healthcare providers to examine the extent of genetic and genomic testing adoption. We assessed providers’ use of genetic and genomic testing options and indications in clinical practice, providers’ awareness of pharmacogenetic applications, and providers’ opinions on returning research-generated genetic test results to participants. Most clinician respondents currently use family history routinely in their clinical practice, but only 18 percent of clinicians use pharmacogenetics. Only two respondents correctly identified the number of drug package inserts with pharmacogenetic indications. We also found strong support for the return of genetic research results to participants. Our results demonstrate that while Duke healthcare providers are enthusiastic about genomic technologies, use of genomic tools outside of research has been limited. Respondents favor return of research-based genetic results to participants, but clinicians lack knowledge about pharmacogenetic applications. We identified challenges faced by this institution when implementing genetic and genomic testing into patient care that should inform a policy and education agenda to improve provider support and clinician-researcher partnerships. PMID:25854543

Opportunities to integrate new approaches in genetic toxicology: an ILSI-HESI workshop report.

PubMed

Zeiger, Errol; Gollapudi, Bhaskar; Aardema, Marilyn J; Auerbach, Scott; Boverhof, Darrell; Custer, Laura; Dedon, Peter; Honma, Masamitsu; Ishida, Seiichi; Kasinski, Andrea L; Kim, James H; Manjanatha, Mugimane G; Marlowe, Jennifer; Pfuhler, Stefan; Pogribny, Igor; Slikker, William; Stankowski, Leon F; Tanir, Jennifer Y; Tice, Raymond; van Benthem, Jan; White, Paul; Witt, Kristine L; Thybaud, Véronique

2015-04-01

Genetic toxicity tests currently used to identify and characterize potential human mutagens and carcinogens rely on measurements of primary DNA damage, gene mutation, and chromosome damage in vitro and in rodents. The International Life Sciences Institute Health and Environmental Sciences Institute (ILSI-HESI) Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity Testing held an April 2012 Workshop in Washington, DC, to consider the impact of new understanding of biology and new technologies on the identification and characterization of genotoxic substances, and to identify new approaches to inform more accurate human risk assessment for genetic and carcinogenic effects. Workshop organizers and speakers were from industry, academe, and government. The Workshop focused on biological effects and technologies that would potentially yield the most useful information for evaluating human risk of genetic damage. Also addressed was the impact that improved understanding of biology and availability of new techniques might have on genetic toxicology practices. Workshop topics included (1) alternative experimental models to improve genetic toxicity testing, (2) Biomarkers of epigenetic changes and their applicability to genetic toxicology, and (3) new technologies and approaches. The ability of these new tests and technologies to be developed into tests to identify and characterize genotoxic agents; to serve as a bridge between in vitro and in vivo rodent, or preferably human, data; or to be used to provide dose response information for quantitative risk assessment was also addressed. A summary of the workshop and links to the scientific presentations are provided. © 2014 Wiley Periodicals, Inc.

Impact of presymptomatic genetic testing on young adults: a systematic review.

PubMed

Godino, Lea; Turchetti, Daniela; Jackson, Leigh; Hennessy, Catherine; Skirton, Heather

2016-04-01

Presymptomatic and predictive genetic testing should involve a considered choice, which is particularly true when testing is undertaken in early adulthood. Young adults are at a key life stage as they may be developing a career, forming partnerships and potentially becoming parents: presymptomatic testing may affect many facets of their future lives. The aim of this integrative systematic review was to assess factors that influence young adults' or adolescents' choices to have a presymptomatic genetic test and the emotional impact of those choices. Peer-reviewed papers published between January 1993 and December 2014 were searched using eight databases. Of 3373 studies identified, 29 were reviewed in full text: 11 met the inclusion criteria. Thematic analysis was used to identify five major themes: period before testing, experience of genetic counselling, parental involvement in decision-making, impact of test result communication, and living with genetic risk. Many participants grew up with little or no information concerning their genetic risk. The experience of genetic counselling was either reported as an opportunity for discussing problems or associated with feelings of disempowerment. Emotional outcomes of disclosure did not directly correlate with test results: some mutation carriers were relieved to know their status, however, the knowledge they may have passed on the mutation to their children was a common concern. Parents appeared to have exerted pressure on their children during the decision-making process about testing and risk reduction surgery. Health professionals should take into account all these issues to effectively assist young adults in making decisions about presymptomatic genetic testing.

Genetic Testing for Hereditary Breast Cancer: The Decision to Decline.

PubMed

White, V Brook; Walsh, Kendall K; Foss, Kimberly Showers; Amacker-North, Lisa; Lenarcic, Stacy; McNeely, Lindsay; White, Richard L

2018-01-01

Genetic testing is important for comprehensive cancer care. Commercial analysis of the BRCA1/2 genes has been available since 1996, and testing for hereditary breast and ovarian cancer syndrome is well established. The National Comprehensive Cancer Network (NCCN) guidelines identify individuals for whom BRCA1/2 analysis is appropriate and define management recommendations for mutation carriers. Despite recommendations, not all who meet NCCN criteria undergo genetic testing. We assess the frequency that individuals meeting NCCN criteria decline BRCA1/2 analysis, as well as factors that affect the decision-making process. A retrospective chart review was performed from September 2013 through August 2014 of individuals who received genetic counseling at the Levine Cancer Institute. A total of 1082 individuals identified through the retrospective chart review met NCCN criteria for BRCA1/2 analysis. Of these, 267 (24.7%) did not pursue genetic testing. Of the Nontested cohort, 59 (22.1%) were disinterested in testing and 108 (40.4%) were advised to gather additional genetic or medical information about their relatives before testing. The remaining 100 (37.5%) individuals were insured and desired to undergo genetic testing but were prohibited by the expense. Eighty five of these 100 patients were responsible for the total cost of the test, whereas the remaining 15 faced a prohibitive copay expense. Financial concerns are a major deterrent to the pursuit of BRCA1/2 analysis among those who meet NCNN criteria, especially in patients diagnosed with breast or ovarian cancer. These findings highlight the need to address financial concerns for genetic testing in this high-risk population.

Heritability of Nociception IV: Neuropathic pain assays are genetically distinct across methods of peripheral nerve injury

PubMed Central

Young, Erin E.; Costigan, Michael; Herbert, Teri A.; Lariviere, William R.

2013-01-01

Prior genetic correlation analysis of 22 heritable behavioral measures of nociception and hypersensitivity in the mouse identified five genetically distinct pain types. In the present study, we reanalyzed that dataset and included the results of an additional nine assays of nociception and hypersensitivity to: 1) replicate the previously identified five pain types; 2) test whether any of the newly added pain assays represent novel genetically distinct pain types; 3) test the level of genetic relatedness among nine commonly employed neuropathic pain assays. Multivariate analysis of pairwise correlations between assays shows that the newly added zymosan-induced heat hypersensitivity assay does not conform to the two previously identified groups of heat hypersensitivity assays and cyclophosphamide-induced cystitis, the first organ-specific visceral pain model examined, is genetically distinct from other inflammatory assays. The four included mechanical hypersensitivity assays are genetically distinct, and do not comprise a single pain type as previously reported. Among the nine neuropathic pain assays including autotomy, chemotherapy, nerve ligation and spared nerve injury assays, at least four genetically distinct types of neuropathic sensory abnormalities were identified, corresponding to differences in nerve injury method. In addition, two itch assays and Comt genotype were compared to the expanded set of nociception and hypersensitivity assays. Comt genotype was strongly related only to spontaneous inflammatory nociception assays. These results indicate the priority for continued investigation of genetic mechanisms in several assays newly identified to represent genetically distinct pain types. PMID:24071598

Impact of Clinical Genetics Attendance at a Gynecologic Oncology Tumor Board on Referrals for Genetic Counseling and BRCA Mutation Testing.

PubMed

Cohen, Paul A; Nichols, Cassandra B; Schofield, Lyn; Van Der Werf, Steven; Pachter, Nicholas

2016-06-01

The objectives of this work were to determine the proportion of eligible patients with ovarian cancer discussed at a gynecologic oncology tumor board who were referred for counseling and BRCA mutation testing; to compare referral rates before genetics attendance at the tumor board to referral rates after genetics attendance; and to ascertain the proportions of women with germline BRCA mutations. Eligible cases were identified from the minutes of the weekly Western Australian gynecologic oncology tumor board from July 1, 2013 to June 30, 2015.Patients with ovarian cancer who met eligibility criteria for genetics referral were identified and checked against the records of the genetic services database to ascertain whether a referral was received. Outcomes including attendance for counseling and results of mutation testing were analyzed. Two hundred sixty-one patients were eligible for referral during the 24-month study period. One hundred six patients (40.6%) were referred for counseling and germline mutation testing. Of the eligible patients, 26.7% were referred in the 12 months before genetics attendance at the tumor board compared to 51.7% of the eligible patients in the 12 months after genetics attendance (P ≤ 0.0001). Ninety-seven patients were offered BRCA mutation testing, and 73 underwent testing with 65 results reported to date. Twenty-two patients (33.8 %) tested positive for a germline BRCA mutation. Patients with ovarian cancer had a high rate of BRCA mutations. Attendance of a genetics service at a tumor board was associated with an improved rate of referral of patients for genetic counseling and BRCA mutation testing.

Direct-to-consumer genetic testing for predicting sports performance and talent identification: Consensus statement

PubMed Central

Webborn, Nick; Williams, Alun; McNamee, Mike; Bouchard, Claude; Pitsiladis, Yannis; Ahmetov, Ildus; Ashley, Euan; Byrne, Nuala; Camporesi, Silvia; Collins, Malcolm; Dijkstra, Paul; Eynon, Nir; Fuku, Noriyuki; Garton, Fleur C; Hoppe, Nils; Holm, Søren; Kaye, Jane; Klissouras, Vassilis; Lucia, Alejandro; Maase, Kamiel; Moran, Colin; North, Kathryn N; Pigozzi, Fabio; Wang, Guan

2015-01-01

The general consensus among sport and exercise genetics researchers is that genetic tests have no role to play in talent identification or the individualised prescription of training to maximise performance. Despite the lack of evidence, recent years have witnessed the rise of an emerging market of direct-to-consumer marketing (DTC) tests that claim to be able to identify children's athletic talents. Targeted consumers include mainly coaches and parents. There is concern among the scientific community that the current level of knowledge is being misrepresented for commercial purposes. There remains a lack of universally accepted guidelines and legislation for DTC testing in relation to all forms of genetic testing and not just for talent identification. There is concern over the lack of clarity of information over which specific genes or variants are being tested and the almost universal lack of appropriate genetic counselling for the interpretation of the genetic data to consumers. Furthermore independent studies have identified issues relating to quality control by DTC laboratories with different results being reported from samples from the same individual. Consequently, in the current state of knowledge, no child or young athlete should be exposed to DTC genetic testing to define or alter training or for talent identification aimed at selecting gifted children or adolescents. Large scale collaborative projects, may help to develop a stronger scientific foundation on these issues in the future. PMID:26582191

Nutrigenomics and ethics interface: direct-to-consumer services and commercial aspects.

PubMed

Ries, Nola M; Castle, David

2008-12-01

A growing variety and number of genetic tests are advertised and sold directly to consumers (DTC) via the Internet, including nutrigenomic tests and associated products and services. Consumers have more access to genetic information about themselves, but access does not entail certainty about the implications of test results. Potential personal and public health harms and benefits are associated with DTC access to genetic testing services. Early policy responses to direct-to-consumer (DTC) genetic testing often involved calls for bans, and some jurisdictions prohibited DTC genetic tests. Recent policy responses by oversight bodies acknowledge expansion in the range of DTC tests available and suggest that a "one-size-fits-all" regulatory approach is not appropriate for all genetic tests. This review discusses ethical and regulatory aspects of DTC genetic testing, focusing particularly on nutrigenomic tests. We identify policy options for regulating DTC genetic tests, including full or partial prohibitions, enforcement of existing truth-in-advertising laws, and more comprehensive information disclosure about genetic tests. We advocate the latter option as an important means to improve transparency about current evidence on the strengths and limits of gene-disease associations and allow consumers to make informed purchasing decisions in the DTC marketplace.

The Canadian Pharmacogenomics Network for Drug Safety: a model for safety pharmacology.

PubMed

Ross, Colin J D; Visscher, Henk; Sistonen, Johanna; Brunham, Liam R; Pussegoda, Kusala; Loo, Tenneille T; Rieder, Michael J; Koren, Gideon; Carleton, Bruce C; Hayden, Michael R

2010-07-01

Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death in the developed world, and the direct medical costs of ADRs exceed $100 billion annually in the United States alone. Pharmacogenomics research seeks to identify genetic factors that are responsible for individual differences in drug efficacy and susceptibility to ADRs. This has led to several genetic tests that are currently being used to provide clinical recommendations. The Canadian Pharmacogenomics Network for Drug Safety is a nation-wide effort established in Canada to identify novel predictive genomic markers of severe ADRs in children and adults. A surveillance network has been established in 17 of Canada's major hospitals to identify patients experiencing specific ADRs and to collect biological samples and relevant clinical history for genetic association studies. To identify ADR-associated genetic markers that could be incorporated into predictive tests that will reduce the occurrence of serious ADRs, high-throughput genomic analyses are conducted with samples from patients that have suffered serious ADRs and matched control patients. ADRs represent a significant unmet medical problem with significant morbidity and mortality, and Canadian Pharmacogenomics Network for Drug Safety is a nation-wide network in Canada that seeks to identify genetic factors responsible for interindividual differences in susceptibility to serious ADRs. Active ADR surveillance is necessary to identify and recruit patients who suffer from serious ADRs. National and international collaborations are required to recruit sufficient patients for these studies. Several pharmacogenomics tests are currently in clinical use to provide dosing recommendations, and the number of pharmacogenomics tests is expected to significantly increase in the future.

Factors Motivating Individuals to Consider Genetic Testing for Type 2 Diabetes Risk Prediction

PubMed Central

Wessel, Jennifer; Gupta, Jyoti; de Groot, Mary

2016-01-01

The purpose of this study was to identify attitudes and perceptions of willingness to participate in genetic testing for type 2 diabetes (T2D) risk prediction in the general population. Adults (n = 598) were surveyed on attitudes about utilizing genetic testing to predict future risk of T2D. Participants were recruited from public libraries (53%), online registry (37%) and a safety net hospital emergency department (10%). Respondents were 37±11 years old, primarily White (54%), female (69%), college educated (46%), with an annual income ≥$25,000 (56%). Half of participants were interested in genetic testing for T2D (52%) and 81% agreed/strongly agreed genetic testing should be available to the public. Only 57% of individuals knew T2D is preventable. A multivariate model to predict interest in genetic testing was adjusted for age, gender, recruitment location and BMI; significant predictors were motivation (high perceived personal risk of T2D [OR = 4.38 (1.76, 10.9)]; family history [OR = 2.56 (1.46, 4.48)]; desire to know risk prior to disease onset [OR = 3.25 (1.94, 5.42)]; and knowing T2D is preventable [OR = 2.11 (1.24, 3.60)], intention (if the cost is free [OR = 10.2 (4.27, 24.6)]; and learning T2D is preventable [OR = 5.18 (1.95, 13.7)]) and trust of genetic testing results [OR = 0.03 (0.003, 0.30)]. Individuals are interested in genetic testing for T2D risk which offers unique information that is personalized. Financial accessibility, validity of the test and availability of diabetes prevention programs were identified as predictors of interest in T2D testing. PMID:26789839

Factors Motivating Individuals to Consider Genetic Testing for Type 2 Diabetes Risk Prediction.

PubMed

Wessel, Jennifer; Gupta, Jyoti; de Groot, Mary

2016-01-01

The purpose of this study was to identify attitudes and perceptions of willingness to participate in genetic testing for type 2 diabetes (T2D) risk prediction in the general population. Adults (n = 598) were surveyed on attitudes about utilizing genetic testing to predict future risk of T2D. Participants were recruited from public libraries (53%), online registry (37%) and a safety net hospital emergency department (10%). Respondents were 37 ± 11 years old, primarily White (54%), female (69%), college educated (46%), with an annual income ≥$25,000 (56%). Half of participants were interested in genetic testing for T2D (52%) and 81% agreed/strongly agreed genetic testing should be available to the public. Only 57% of individuals knew T2D is preventable. A multivariate model to predict interest in genetic testing was adjusted for age, gender, recruitment location and BMI; significant predictors were motivation (high perceived personal risk of T2D [OR = 4.38 (1.76, 10.9)]; family history [OR = 2.56 (1.46, 4.48)]; desire to know risk prior to disease onset [OR = 3.25 (1.94, 5.42)]; and knowing T2D is preventable [OR = 2.11 (1.24, 3.60)], intention (if the cost is free [OR = 10.2 (4.27, 24.6)]; and learning T2D is preventable [OR = 5.18 (1.95, 13.7)]) and trust of genetic testing results [OR = 0.03 (0.003, 0.30)]. Individuals are interested in genetic testing for T2D risk which offers unique information that is personalized. Financial accessibility, validity of the test and availability of diabetes prevention programs were identified as predictors of interest in T2D testing.

Impact of Gene Patents and Licensing Practices on Access to Genetic Testing for Cystic Fibrosis

PubMed Central

Chandrasekharan, Subhashini; Heaney, Christopher; James, Tamara; Conover, Chris; Cook-Deegan, Robert

2010-01-01

Cystic fibrosis (CF) is one of the most commonly tested autosomal recessive disorders in the US. Clinical CF is associated with mutations in the CFTR gene, of which the most common mutation among Caucasians, ΔF508, was identified in 1989. The University of Michigan, Johns Hopkins University, and the Hospital for Sick Children, where much of the initial research occurred, hold key patents for CF genetic sequences, mutations and methods for detecting them. Several patents including the one that covers detection of the ΔF508 mutation are jointly held by the University of Michigan and the Hospital for Sick Children in Toronto, with Michigan administering patent licensing in the US. The University of Michigan broadly licenses the ΔF508 patent for genetic testing with over 60 providers of genetic testing to date. Genetic testing is now used in newborn screening, diagnosis, and reproductive decisions. Interviews with key researchers and intellectual property managers, a survey of laboratories’ prices for CF genetic testing, a review of literature on CF tests’ cost effectiveness, and a review of the developing market for CF testing provide no evidence that patents have significantly hindered access to genetic tests for CF or prevented financially cost-effective screening. Current licensing practices for cystic fibrosis (CF) genetic testing appear to facilitate both academic research and commercial testing. More than one thousand different CFTR mutations have been identified, and research continues to determine their clinical significance. Patents have been nonexclusively licensed for diagnostic use, and have been variably licensed for gene transfer and other therapeutic applications. The Cystic Fibrosis Foundation has been engaged in licensing decisions, making CF a model of collaborative and cooperative patenting and licensing practice. PMID:20393308

Ethnic differences in parental perceptions of genetic testing for deaf infants.

PubMed

Palmer, Christina G S; Martinez, Ariadna; Fox, Michelle; Sininger, Yvonne; Grody, Wayne W; Schimmenti, Lisa A

2008-02-01

As genetic testing becomes an integral part of the evaluation of deaf infants and children, it is important to understand parental views on genetic testing. The purpose of this study is to examine parental reasons for, and beliefs about, genetic testing for deafness in early-identified infants, and to determine if they differ as a function of ethnicity. We present baseline data collected from 56 Caucasian, 59 Hispanic, and 24 Asian parents of deaf children participating in a longitudinal, prospective study on genetic testing for connexin-related deafness. The overall finding is that reasons for, and beliefs about, genetic testing for deafness varied as a function of ethnicity. Virtually all parents sought genetic testing to understand why their child is deaf. However, Asian and/or Hispanic parents were more likely than Caucasian parents to view family planning, helping with their child's medical care, and helping the family as other important reasons for testing, and were more likely than Caucasian parents to perceive genetic testing to be useful for these purposes. Asian and Hispanic parents were more likely than Caucasian parents to perceive genetic testing in harmful terms. Genetic testing fulfills a cognitive need for parents to understand why their child is deaf, yet differences in responses suggest that Asian and Hispanic parents may seek testing for other purposes. Understanding different perspectives on genetic testing for deafness will enhance genetic counselors' cultural competence and facilitate the pre-test genetic counseling session.

Differences in attitudes toward genetic testing among the public, patients, and health-care professionals in Korea.

PubMed

Eum, Heesang; Lee, Mangyeong; Yoon, Junghee; Cho, Juhee; Lee, Eun Sook; Choi, Kui Son; Lee, Sangwon; Jung, So-Youn; Lim, Myong Cheol; Kong, Sun-Young; Chang, Yoon Jung

2018-06-18

With further advances in medical genetics, genetic tests to determine predisposition to disease are becoming viable for a growing number of diseases. Accordingly, it has also become important to identify various viewpoints on genetic testing. The aims of this study were to examine awareness of and attitudes toward genetic testing among the general public (public), cancer patients (patients), and health-care professionals (clinicians and researchers) in Korea. The present survey was conducted from November 2016 to February 2017. The public and patients were surveyed via face-to-face interviews conducted by trained interviewers. Health-care professionals were surveyed via self-administered questionnaires. In total, 1500 individuals from the general public, 1500 cancer patients, 113 clinicians, and 413 researchers were surveyed. Most respondents from the public and patients had previously heard about genetic testing (public, 89.4%; patients, 92.7%, p < 0.01). Differences in attitudes toward genetic testing among the public, patients, and professionals were noted, although most respondents in the present study were aware of genetic testing. Most of the cancer patients tended to overestimate the potential benefit of genetic testing, whereas clinicians expressed concerns for genetic testing. Providing correct information to people who are scheduled to undergo or order genetic testing could help in making an informed decision thereon.

Ethical Issues of Predictive Genetic Testing for Diabetes

PubMed Central

Haga, Susanne B.

2009-01-01

With the rising number of individuals affected with diabetes and the significant health care costs of treatment, the emphasis on prevention is key to controlling the health burden of this disease. Several genetic and genomic studies have identified genetic variants associated with increased risk to diabetes. As a result, commercial testing is available to predict an individual's genetic risk. Although the clinical benefits of testing have not yet been demonstrated, it is worth considering some of the ethical implications of testing for this common chronic disease. In this article, I discuss several issues that should be considered during the translation of predictive testing for diabetes, including familial implications, improvement of risk communication, implications for behavioral change and health outcomes, the Genetic Information Nondiscrimination Act, direct-to-consumer testing, and appropriate age of testing. PMID:20144329

Unleashing the power of human genetic variation knowledge: New Zealand stakeholder perspectives.

PubMed

Gu, Yulong; Warren, James Roy; Day, Karen Jean

2011-01-01

This study aimed to characterize the challenges in using genetic information in health care and to identify opportunities for improvement. Taking a grounded theory approach, semistructured interviews were conducted with 48 participants to collect multiple stakeholder perspectives on genetic services in New Zealand. Three themes emerged from the data: (1) four service delivery models were identified in operation, including both those expected models involving genetic counselors and variations that do not route through the formal genetic service program; (2) multiple barriers to sharing and using genetic information were perceived, including technological, organizational, institutional, legal, ethical, and social issues; and (3) impediments to wider use of genetic testing technology, including variable understanding of genetic test utilities among clinicians and the limited capacity of clinical genetic services. Targeting these problems, information technologies and knowledge management tools have the potential to support key tasks in genetic services delivery, improve knowledge processes, and enhance knowledge networks. Because of the effect of issues in genetic information and knowledge management, the potential of human genetic variation knowledge to enhance health care delivery has been put on a "leash."

The clinical content of preconception care: genetics and genomics.

PubMed

Solomon, Benjamin D; Jack, Brian W; Feero, W Gregory

2008-12-01

The prevalence of paternal and maternal genetic conditions that affect pregnancy varies according to many factors that include parental age, medical history, and family history. Although some genetic conditions that affect pregnancy are identified easily early in life, other conditions are not and may require additional diagnostic testing. A complete 3-generation family medical history that includes ethnicity information about both sides of the family is arguably the single best genetic "test" that is applicable to preconception care. Assessment of genetic risk by an experienced professional has been shown to improve the detection rate of identifiable risk factors. Learning about possible genetic issues in the preconception period is ideal, because knowledge permits patients to make informed reproductive decisions. Options that are available to couples before conception include adoption, surrogacy, use of donor sperm, in vitro fertilization after preimplantation genetic diagnosis, and avoidance of pregnancy. Future technologic advances will increase the choices that are available to couples.

Population genetic testing for cancer susceptibility: founder mutations to genomes.

PubMed

Foulkes, William D; Knoppers, Bartha Maria; Turnbull, Clare

2016-01-01

The current standard model for identifying carriers of high-risk mutations in cancer-susceptibility genes (CSGs) generally involves a process that is not amenable to population-based testing: access to genetic tests is typically regulated by health-care providers on the basis of a labour-intensive assessment of an individual's personal and family history of cancer, with face-to-face genetic counselling performed before mutation testing. Several studies have shown that application of these selection criteria results in a substantial proportion of mutation carriers being missed. Population-based genetic testing has been proposed as an alternative approach to determining cancer susceptibility, and aims for a more-comprehensive detection of mutation carriers. Herein, we review the existing data on population-based genetic testing, and consider some of the barriers, pitfalls, and challenges related to the possible expansion of this approach. We consider mechanisms by which population-based genetic testing for cancer susceptibility could be delivered, and suggest how such genetic testing might be integrated into existing and emerging health-care structures. The existing models of genetic testing (including issues relating to informed consent) will very likely require considerable alteration if the potential benefits of population-based genetic testing are to be fully realized.

Assessing Genetic Literacy Awareness and Knowledge Gaps in the US Population: Results from the Health Information National Trends Survey.

PubMed

Krakow, Melinda; Ratcliff, Chelsea L; Hesse, Bradford W; Greenberg-Worisek, Alexandra J

2018-05-31

Public understanding of the role of genetics in disease risk is key to appropriate disease prevention and detection. This study assessed the current extent of awareness and use of genetic testing in the US population. Additionally, the study identified characteristics of subgroups more likely to be at risk for low genetic literacy. The study used data from the National Cancer Institute's 2017 Health Information National Trends Survey, including measures of genetic testing awareness, genetic testing applications and genetic testing usage. Multivariable logistic regression models estimated associations between sociodemographics, genetic testing awareness, and genetic testing use. Fifty-seven percent of respondents were aware of genetic tests. Testing awareness differed by age, household income, and race/ethnicity. Most participants had heard of using tests to determine personal disease risk (82.58%) or inherited disease risk in children (81.41%), but less were familiar with determining treatment (38.29%) or drug efficacy (40.76%). Among those with genetic testing awareness, actual testing uptake was low. A large portion of the general public lacks genetic testing awareness and may benefit from educational campaigns. As precision medicine expands, increasing public awareness about genetic testing applications for disease prevention and treatment will be important to support population health. This is a work of the US Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. Published by S. Karger AG, Basel.

Research Issues in Genetic Testing of Adolescents for Obesity

PubMed Central

Segal, Mary E.; Sankar, Pamela; Reed, Danielle R.

2006-01-01

Obesity is often established in adolescence, and advances are being made in identifying its genetic underpinnings. We examine issues related to the eventual likelihood of genetic tests for obesity targeted to adolescents: family involvement; comprehension of the test’s meaning; how knowledge of genetic status may affect psychological adaptation; minors’ ability to control events; parental/child autonomy; ability to make informed medical decisions; self-esteem; unclear distinctions between early/late onset for this condition; and social stigmatization. The public health arena will be important in educating families about possible future genetic tests for obesity. PMID:15478685

A Prospective, Longitudinal Study of the Impact of GJB2/GJB6 Genetic Testing on the Beliefs and Attitudes of Parents of Deaf and Hard-of-Hearing Infants

PubMed Central

Palmer, Christina G.S.; Martinez, Ariadna; Fox, Michelle; Zhou, Jin; Shapiro, Nina; Sininger, Yvonne; Grody, Wayne W.; Schimmenti, Lisa A.

2010-01-01

There are limited data on the impact of incorporating genetic counseling and testing into the newborn hearing screening process. We report on results from a prospective, longitudinal study to determine the impact of genetic counseling and GJB2/GJB6 genetic testing on parental knowledge, attitudes, and beliefs about genetic testing. One hundred thirty culturally hearing parents of 93 deaf or hard-of-hearing children ages 0 – 3 years primarily identified through newborn hearing screening received pre- and post-test genetic counseling for GJB2 and GJB6. Parents completed questionnaires following pre-test counseling, and 1- and 6-months post-test result disclosure. Results indicate that following pre-test counseling all parents perceived benefits to genetic testing. While parents who received positive results continued to perceive benefits from testing, perceived benefit declined among parents who received inconclusive or negative results. Parents did not perceive genetic testing as harmful following pre-test counseling or receipt of test results. Parents who received positive test results performed better in understanding recurrence and causation of their child’s deafness and indicated greater interest in prenatal genetic testing than those who received inconclusive or negative test results. Parents felt that pediatricians and audiologists should inform parents of genetic testing availability; however, there was no consensus on timing of this discussion. Thus culturally hearing parents do not perceive genetic testing of their deaf or hard-of-hearing infants/toddlers as harmful; they feel that primary care providers should discuss genetic testing with them; and positive genetic test results with genetic counseling give rise to better understanding and perceived benefit than negative or inconclusive results. PMID:19449415

A prospective, longitudinal study of the impact of GJB2/GJB6 genetic testing on the beliefs and attitudes of parents of deaf and hard-of-hearing infants.

PubMed

Palmer, Christina G S; Martinez, Ariadna; Fox, Michelle; Zhou, Jin; Shapiro, Nina; Sininger, Yvonne; Grody, Wayne W; Schimmenti, Lisa A

2009-06-01

There are limited data on the impact of incorporating genetic counseling and testing into the newborn hearing screening process. We report on results from a prospective, longitudinal study to determine the impact of genetic counseling and GJB2/GJB6 genetic testing on parental knowledge, attitudes, and beliefs about genetic testing. One hundred thirty culturally hearing parents of 93 deaf or hard-of-hearing children ages 0-3 years primarily identified through newborn hearing screening received pre- and post-test genetic counseling for GJB2 and GJB6. Parents completed questionnaires following pre-test counseling, and 1- and 6-month post-test result disclosure. Results indicate that following pre-test counseling all parents perceived benefits to genetic testing. While parents who received positive results continued to perceive benefits from testing, perceived benefit declined among parents who received inconclusive or negative results. Parents did not perceive genetic testing as harmful following pre-test counseling or receipt of test results. Parents who received positive test results performed better in understanding recurrence and causation of their child's deafness and indicated greater interest in prenatal genetic testing than those who received inconclusive or negative test results. Parents felt that pediatricians and audiologists should inform parents of genetic testing availability; however, there was no consensus on timing of this discussion. Thus culturally hearing parents do not perceive genetic testing of their deaf or hard-of-hearing infants/toddlers as harmful; they feel that primary care providers should discuss genetic testing with them; and positive genetic test results with genetic counseling give rise to better understanding and perceived benefit than negative or inconclusive results. (c) 2009 Wiley-Liss, Inc.

Pathways from Autism Spectrum Disorder (ASD) Diagnosis to Genetic Testing

PubMed Central

Barton, Krysta S.; Tabor, Holly K.; Starks, Helene; Garrison, Nanibaa’ A.; Laurino, Mercy; Burke, Wylie

2017-01-01

Purpose This study examines challenges faced by families and health providers related to genetic testing for autism spectrum disorder (ASD). Methods This qualitative study of 14 parents and 15 health providers identified an unstandardized three-step process for families who pursue ASD genetic testing. Results Step 1 is the clinical diagnosis of ASD, confirmed by providers practicing alone or in a team. Step 2 is the offer of genetic testing to find an etiology. For those offered testing, step 3 involves the parents’ decision whether to pursue testing. Despite professional guidelines and recommendations, interviews describe considerable variability in approaches to genetic testing for ASD, a lack of consensus among providers, and questions about clinical utility. Many families in our study were unaware of the option for genetic testing; testing decisions by parents appear to be influenced by both provider recommendations and insurance coverage. Conclusion Consideration of genetic testing for ASD should take into account different views about the clinical utility of testing and variability in insurance coverage. Ideally, policy makers from the range of clinical specialties involved in ASD care should revisit policies to clarify the purpose of genetic testing for ASD and promote consensus about its appropriate use. PMID:29048417

Incorporating gene-environment interaction in testing for association with rare genetic variants.

PubMed

Chen, Han; Meigs, James B; Dupuis, Josée

2014-01-01

The incorporation of gene-environment interactions could improve the ability to detect genetic associations with complex traits. For common genetic variants, single-marker interaction tests and joint tests of genetic main effects and gene-environment interaction have been well-established and used to identify novel association loci for complex diseases and continuous traits. For rare genetic variants, however, single-marker tests are severely underpowered due to the low minor allele frequency, and only a few gene-environment interaction tests have been developed. We aimed at developing powerful and computationally efficient tests for gene-environment interaction with rare variants. In this paper, we propose interaction and joint tests for testing gene-environment interaction of rare genetic variants. Our approach is a generalization of existing gene-environment interaction tests for multiple genetic variants under certain conditions. We show in our simulation studies that our interaction and joint tests have correct type I errors, and that the joint test is a powerful approach for testing genetic association, allowing for gene-environment interaction. We also illustrate our approach in a real data example from the Framingham Heart Study. Our approach can be applied to both binary and continuous traits, it is powerful and computationally efficient.

Genetic Diagnosis and Testing in Clinical Practice

PubMed Central

McPherson, Elizabeth

2006-01-01

Genetic testing is defined as “the analysis of human DNA, RNA, chromosomes, proteins and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes or karyotypes for clinical purposes.” This article focuses on diagnostic and predictive genetic testing. The latter includes presymptomatic testing, which identifies individuals who are expected to become ill in the future and predisposition testing, which identifies those who are at increased risk of becoming ill. Decisions regarding genetic testing must be based not only on the analytic accuracy, availability and cost of the test, but on the clinical utility as well, including the sensitivity, specificity and interpretability of results. Clinical information, including the medical and family history and the findings of the physical examination, is vital for the selection of appropriate diagnostic tests, as well as the interpretation of the results. Presymptomatic genetic testing is a very personal choice that should only be made after the patient has had sufficient counseling to develop an understanding of the risks and benefits of the test and is able to make an informed decision. The same principle applies to predisposition testing; however, additional factors, such as the probability of a positive result, the likelihood that the disease will actually develop in those with positive results, the effect on the management of the index patient, the effects on family members, the risk of false reassurance if the result is negative or the potential for loss of hope if it is positive, all contribute to the assessment of risk versus benefit. Clinical evaluation and counseling of the patient who is at risk for a genetic disorder are labor intensive but essential for the selection and interpretation of genetic tests. PMID:16809405

Against Genetic Tests for Athletic Talent: The Primacy of the Phenotype.

PubMed

Loland, Sigmund

2015-09-01

New insights into the genetics of sport performance lead to new areas of application. One area is the use of genetic tests to identify athletic talent. Athletic performances involve a high number of complex phenotypical traits. Based on the ACCE model (review of Analytic and Clinical validity, Clinical utility, and Ethical, legal and social implications), a critique is offered of the lack of validity and predictive power of genetic tests for talent. Based on the ideal of children's right to an open future, a moral argument is given against such tests on children and young athletes. A possible role of genetic tests in sport is proposed in terms of identifying predisposition for injury. In meeting ACCE requirements, such tests could improve individualised injury prevention and increase athlete health. More generally, limitations of science are discussed in the identification of talent and in the understanding of complex human performance phenotypes. An alternative approach to talent identification is proposed in terms of ethically sensitive, systematic and evidence-based holistic observation over time of relevant phenotypical traits by experienced observers. Talent identification in sport should be based on the primacy of the phenotype.

Current Landscape and New Paradigms of Proficiency Testing and External Quality Assessment for Molecular Genetics

PubMed Central

Kalman, Lisa V.; Lubin, Ira M.; Barker, Shannon; du Sart, Desiree; Elles, Rob; Grody, Wayne W.; Pazzagli, Mario; Richards, Sue; Schrijver, Iris; Zehnbauer, Barbara

2015-01-01

Context Participation in proficiency testing (PT) or external quality assessment (EQA) programs allows the assessment and comparison of test performance among different clinical laboratories and technologies. In addition to the approximately 2300 tests for individual genetic disorders, recent advances in technology have enabled the development of clinical tests which quickly and economically analyze the entire human genome. New PT/EQA approaches are needed to ensure the continued quality of these complex tests. Objective To review the availability and scope of PT/EQA for molecular genetic testing for inherited conditions in Europe, Australasia and the United States; to evaluate the successes and demonstrated value of available PT/EQA programs; and to examine the challenges to the provision of comprehensive PT/EQA posed by new laboratory practices and methodologies. Data Sources The available literature on this topic was reviewed and supplemented with personal experiences of several PT/EQA providers. Conclusions PT/EQA schemes are available for common genetic disorders tested in many clinical laboratories, but are not available for most genetic tests offered by only one or a few laboratories. Provision of broad, method-based PT schemes, such as DNA sequencing, would allow assessment of a large number of tests for which formal PT is not currently available. Participation in PT/EQA improves the quality of testing by identifying inaccuracies that laboratories can trace to errors in the testing process. Areas of research and development to ensure that PT/EQA programs can meet the needs of new and evolving genetic tests and technologies are identified and discussed. PMID:23808472

Pulmonary arterial hypertension: Specialists’ knowledge, practices, and attitudes of genetic counseling and genetic testing in the USA

PubMed Central

Jacher, Joseph E.; Martin, Lisa J.; Chung, Wendy K.; Loyd, James E.; Nichols, William C.

2017-01-01

Pulmonary arterial hypertension (PAH) is characterized by obstruction of pre-capillary pulmonary arteries, which leads to sustained elevation of pulmonary arterial pressure. Identifying those at risk through early interventions, such as genetic testing, may mitigate disease course. Current practice guidelines recommend genetic counseling and offering genetic testing to individuals with heritable PAH, idiopathic PAH, and their family members. However, it is unclear if PAH specialists follow these recommendations. Thus, our research objective was to determine PAH specialists’ knowledge, utilization, and perceptions about genetic counseling and genetic testing. A survey was designed and distributed to PAH specialists who primarily work in the USA to assess their knowledge, practices, and attitudes about the genetics of PAH. Participants’ responses were analyzed using parametric and non-parametric statistics and groups were compared using the Wilcoxon rank sum test. PAH specialists had low perceived and actual knowledge of the genetics of PAH, with 13.2% perceiving themselves as knowledgeable and 27% actually being knowledgeable. Although these specialists had positive or ambivalent attitudes about genetic testing and genetic counseling, they had poor utilization of these genetic services, with almost 80% of participants never or rarely ordering genetic testing or referring their patients with PAH for genetic counseling. Physicians were more knowledgeable, but had lower perceptions of the value of genetic testing and genetic counseling compared to non-physicians (P < 0.05). The results suggest that increased education and awareness is needed about the genetics of PAH as well as the benefits of genetic testing and genetic counseling for individuals who treat patients with PAH. PMID:28597770

Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity.

PubMed

Shapiro, Lucy; Chatterjee, Sumana; Ramadan, Dina G; Davies, Kate M; Savage, Martin O; Metherell, Louise A; Storr, Helen L

2017-12-01

GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown. To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect. We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS. A genetic diagnosis was discovered 38/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19/IGF2 region or mUPD7 consistent with Silver-Russell Syndrome (total with genetic diagnosis 51/107, 48% or 41/97, 42% probands). WES also identified homozygous putative variants in FANCA and PHKB in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect. Comprehensive genetic testing confirms the genetic heterogeneity of GH/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres. © 2017 European Society of Endocrinology.

Genetic testing improves identification of transthyretin amyloid (ATTR) subtype in cardiac amyloidosis.

PubMed

Brown, Emily E; Lee, Yi Zhen Joan; Halushka, Marc K; Steenbergen, Charles; Johnson, Nicole M; Almansa, Johana; Tedford, Ryan J; Cingolani, Oscar; Russell, Stuart D; Sharma, Kavita; Judge, Daniel P

2017-06-01

Amyloidosis is a group of conditions characterized by the accumulation of amyloid deposits in various tissues. Among these disorders, ATTR amyloidosis occurs either with or without a TTR pathogenic variant. Treatment for amyloidosis depends on the subtype, which is often identified through a tissue biopsy followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Genetic testing may be done to confirm these results for patients with ATTR amyloidosis; however, the necessity of genetic testing after LC-MS/MS has not been evaluated. A retrospective review identified 153 patients diagnosed with biopsy-proven ATTR amyloidosis, and 56 of these patients underwent both genetic testing and LC-MS/MS. LC-MS/MS and proteomics correctly reported the mutant peptide and heterozygosity in 47/56 (84%) cases. It failed to identify two individuals who were homozygous for the ATTRV122I mutation and failed to detect the following mutations in six other individuals: ATTRA19D, ATTRF44L, ATTRT60A, ATTRI68L and ATTRV122I. Therefore, LC-MS/MS is not sufficient to rule out a pathogenic mutation in cases of ATTR amyloid, and genetic testing should be performed in most cases of ATTR amyloidosis. Correct recognition of hereditary ATTR amyloidosis is important for estimating prognosis, proper familial counselling and guiding use of therapies, such as liver transplantation.

Multi-gene panel testing in Korean patients with common genetic generalized epilepsy syndromes.

PubMed

Lee, Cha Gon; Lee, Jeehun; Lee, Munhyang

2018-01-01

Genetic heterogeneity of common genetic generalized epilepsy syndromes is frequently considered. The present study conducted a focused analysis of potential candidate or susceptibility genes for common genetic generalized epilepsy syndromes using multi-gene panel testing with next-generation sequencing. This study included patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We identified pathogenic variants according to the American College of Medical Genetics and Genomics guidelines and identified susceptibility variants using case-control association analyses and family analyses for familial cases. A total of 57 patients were enrolled, including 51 sporadic cases and 6 familial cases. Twenty-two pathogenic and likely pathogenic variants of 16 different genes were identified. CACNA1H was the most frequently observed single gene. Variants of voltage-gated Ca2+ channel genes, including CACNA1A, CACNA1G, and CACNA1H were observed in 32% of variants (n = 7/22). Analyses to identify susceptibility variants using case-control association analysis indicated that KCNMA1 c.400G>C was associated with common genetic generalized epilepsy syndromes. Only 1 family (family A) exhibited a candidate pathogenic variant p.(Arg788His) on CACNA1H, as determined via family analyses. This study identified candidate genetic variants in about a quarter of patients (n = 16/57) and an average of 2.8 variants was identified in each patient. The results reinforced the polygenic disorder with very high locus and allelic heterogeneity of common GGE syndromes. Further, voltage-gated Ca2+ channels are suggested as important contributors to common genetic generalized epilepsy syndromes. This study extends our comprehensive understanding of common genetic generalized epilepsy syndromes.

Genetic risks and healthy choices: creating citizen-consumers of genetic services through empowerment and facilitation.

PubMed

Harvey, Alison

2010-03-01

Genetic testing to identify susceptibility to a variety of common complex diseases is increasingly becoming available. In this article, focusing on the development of genetic susceptibility testing for diet-related disease, I examine the emergence of direct-to-the-consumer genetic testing services and the (re)configuration of healthcare provision, both within and outside the specialist genetics service, in the UK. I identify two key techniques within these practices: empowerment and facilitation. Using Foucauldian social theory, I show that empowerment and facilitation are being positioned as tools for the creation of citizen-consumers who will make appropriate dietary choices, based on the results of their genetic analysis. Through these techniques, individuals are transformed into properly entrepreneurial citizens who will, through judicious choices, act to maximise their 'vital capital' (their health) and the capital of the social body. I argue that the user of these services is not purely an economic figure, making rational choices as a consumer, but that her configuration as a citizen-consumer who avails herself of genetic information and services in a proper manner ensures that she is fit to contribute to the economic life of our present.

Barriers to genetic testing for breast cancer risk among ethnic minority women: an exploratory study.

PubMed

Glenn, Beth A; Chawla, Neetu; Bastani, Roshan

2012-01-01

To assess awareness of genetic testing for breast cancer risk and identify influences on the decision-making process regarding counseling and testing among an ethnically-diverse sample of women. Semi-structured interviews were conducted with 33 women who were breast or ovarian cancer survivors or first degree relatives of survivors. Interviews were audiotaped, translated, and transcribed. Analysis of transcripts identified relevant themes and quotes were extracted for illustration. Low levels of awareness were observed in minority women, including those with a significant family history of cancer. A number of potential influences on the decision-making process emerged including beliefs about risk factors for cancer and opinions about the options following testing. Distinct issues were identified within ethnic groups that may function as barriers such as concern about the misuse of genetic information (African Americans), unfamiliarity with Western preventive medicine (Asians), and women prioritizing family obligations over personal health needs (Latinas). Results suggest there may be a need for interventions to raise awareness about genetic counseling and testing among minorities. Our findings contribute to the literature by using in-depth interviews to uncover potential barriers and facilitators to counseling and testing and by including Asians and Latinas, groups under-represented in previous research.

Psychosocial aspects of genetic testing.

PubMed

Cameron, Linda D; Muller, Cecile

2009-03-01

With rapid advances in genetic testing for disease susceptibility, behavioral medicine faces significant challenges in identifying likely patterns of use, how individuals interpret test results, and psychosocial and health impacts of testing. We review recent research on these psychosocial aspects of genetic testing for disease risk. Individuals exhibit limited sensitivity in their perceptions of genetic risk information, and mental representations of disease risk appear to guide testing perceptions and behavioral responses. Motivations to undergo testing are complex, and efforts to develop decision aids are underway. Findings on psychological and behavioral impacts of genetic testing vary markedly, with some evidence of minimal or positive effects and other evidence indicating negative consequences that may be undetectable using common measures of general well being. Recent evidence suggests that genetic risk information can motivate health behavior change. Research demonstrates wide-ranging influences of testing on family dynamics, and use of genetic testing with children is of increasing concern. More research is needed to determine how to structure health communications and counseling to motivate informed use, promote positive responses, and optimize behavior change. Given the ramifications of genetic information for families, personalized genomics will demand a shift toward a family-based healthcare model.

Genetic Testing between Private and Public Interests: Some Legal and Ethical Reflections

PubMed Central

Sándor, Judit

2018-01-01

In Europe, there is a wide variety of genetic tests that various private companies offer to patients or to consumers. More and more people have become curious about their genetic predisposition and susceptibility. Most public health-care systems, however, are not adequately prepared for responding to these new demands and to the results of these genetic tests as, quite often, there is no available therapy for the identified genetic condition. This discrepancy between the newly emerging expectations and the insufficient responses contributes to a further rift between the public and private sectors of health care. Individual genetic test results may also trigger the need for personalized medicine and may open up a competition between the two fields in offering further genetic tests and medical exams. Pro-active patients may need a different kind of information on genetic tests and their implications. In this context, how should the public health system deal with the challenges of private testing? Will private genetic testing transform health care from a solidarity-based system to an individualistic one? In this paper, I would like to explore the emerging legal and ethical issues related to genetic testing and the relevant legal framework that has developed so far. In the conclusion, I will examine the possibilities of further legal development. PMID:29445722

Genetic Testing between Private and Public Interests: Some Legal and Ethical Reflections.

PubMed

Sándor, Judit

2018-01-01

In Europe, there is a wide variety of genetic tests that various private companies offer to patients or to consumers. More and more people have become curious about their genetic predisposition and susceptibility. Most public health-care systems, however, are not adequately prepared for responding to these new demands and to the results of these genetic tests as, quite often, there is no available therapy for the identified genetic condition. This discrepancy between the newly emerging expectations and the insufficient responses contributes to a further rift between the public and private sectors of health care. Individual genetic test results may also trigger the need for personalized medicine and may open up a competition between the two fields in offering further genetic tests and medical exams. Pro-active patients may need a different kind of information on genetic tests and their implications. In this context, how should the public health system deal with the challenges of private testing? Will private genetic testing transform health care from a solidarity-based system to an individualistic one? In this paper, I would like to explore the emerging legal and ethical issues related to genetic testing and the relevant legal framework that has developed so far. In the conclusion, I will examine the possibilities of further legal development.

Intention to Obtain Genetic Testing for Melanoma among Individuals at Low to Moderate Risk for Hereditary Melanoma

ERIC Educational Resources Information Center

Vadaparampil, Susan T.; Azzarello, Lora; Pickard, Jennifer; Jacobsen, Paul B.

2007-01-01

Background: Melanoma is a serious skin cancer that has been on the rise in the United States. Some genetic component is apparent. Purpose: The purpose of this study was to identify demographic, clinical, attitudinal, and health belief factors associated with intention to obtain genetic testing for hereditary melanoma among unaffected first-degree…

Neonatal diabetes in Ukraine: incidence, genetics, clinical phenotype and treatment

PubMed Central

Globa, Evgenia; Zelinska, Nataliya; Mackay, Deborah J.G.; Temple, Karen I.; Houghton, Jayne A.L.; Hattersley, Andrew T.; Flanagan, Sarah E.; Ellard, Sian

2016-01-01

Background Neonatal diabetes has not been previously studied in Ukraine. We investigated the genetic etiology in patients with onset of diabetes during the first 9 months of life. Methods We established a Pediatric Diabetes Register to identify patients diagnosed with diabetes before 9 months of age. Genetic testing was undertaken for 42 patients with permanent or transient diabetes diagnosed within the first 6 months of life (n=22) or permanent diabetes diagnosed between 6 and 9 months (n=20). Results We determined the genetic etiology in 23 of 42 (55%) patients; 86% of the patients diagnosed before 6 months and 20% diagnosed between 6 and 9 months. The incidence of neonatal diabetes in Ukraine was calculated to be 1 in 126,397 live births. Conclusions Genetic testing for patients identified through the Ukrainian Pediatric Diabetes Register identified KCNJ11 and ABCC8 mutations as the most common cause (52%) of neonatal diabetes. Transfer to sulfonylureas improved glycemic control in all 11 patients. PMID:26208381

Genetic Counseling in Mental Retardation.

ERIC Educational Resources Information Center

Bowen, Peter

The task of the genetic counselor who identifies genetic causes of mental retardation and assists families to understand risk of recurrence is described. Considered are chromosomal genetic disorders such as Down's syndrome, inherited disorders such as Tay-Sachs disease, identification by testing the amniotic fluid cells (amniocentresis) in time…

Genome-Wide Associations between Genetic and Epigenetic Variation Influence mRNA Expression and Insulin Secretion in Human Pancreatic Islets

PubMed Central

Olsson, Anders H.; Volkov, Petr; Bacos, Karl; Dayeh, Tasnim; Hall, Elin; Nilsson, Emma A.; Ladenvall, Claes; Rönn, Tina; Ling, Charlotte

2014-01-01

Genetic and epigenetic mechanisms may interact and together affect biological processes and disease development. However, most previous studies have investigated genetic and epigenetic mechanisms independently, and studies examining their interactions throughout the human genome are lacking. To identify genetic loci that interact with the epigenome, we performed the first genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human pancreatic islets. We related 574,553 single nucleotide polymorphisms (SNPs) with genome-wide DNA methylation data of 468,787 CpG sites targeting 99% of RefSeq genes in islets from 89 donors. We identified 67,438 SNP-CpG pairs in cis, corresponding to 36,783 SNPs (6.4% of tested SNPs) and 11,735 CpG sites (2.5% of tested CpGs), and 2,562 significant SNP-CpG pairs in trans, corresponding to 1,465 SNPs (0.3% of tested SNPs) and 383 CpG sites (0.08% of tested CpGs), showing significant associations after correction for multiple testing. These include reported diabetes loci, e.g. ADCY5, KCNJ11, HLA-DQA1, INS, PDX1 and GRB10. CpGs of significant cis-mQTLs were overrepresented in the gene body and outside of CpG islands. Follow-up analyses further identified mQTLs associated with gene expression and insulin secretion in human islets. Causal inference test (CIT) identified SNP-CpG pairs where DNA methylation in human islets is the potential mediator of the genetic association with gene expression or insulin secretion. Functional analyses further demonstrated that identified candidate genes (GPX7, GSTT1 and SNX19) directly affect key biological processes such as proliferation and apoptosis in pancreatic β-cells. Finally, we found direct correlations between DNA methylation of 22,773 (4.9%) CpGs with mRNA expression of 4,876 genes, where 90% of the correlations were negative when CpGs were located in the region surrounding transcription start site. Our study demonstrates for the first time how genome-wide genetic and epigenetic variation interacts to influence gene expression, islet function and potential diabetes risk in humans. PMID:25375650

Pathway-based discovery of genetic interactions in breast cancer

PubMed Central

Xu, Zack Z.; Boone, Charles; Lange, Carol A.

2017-01-01

Breast cancer is the second largest cause of cancer death among U.S. women and the leading cause of cancer death among women worldwide. Genome-wide association studies (GWAS) have identified several genetic variants associated with susceptibility to breast cancer, but these still explain less than half of the estimated genetic contribution to the disease. Combinations of variants (i.e. genetic interactions) may play an important role in breast cancer susceptibility. However, due to a lack of statistical power, the current tests for genetic interactions from GWAS data mainly leverage prior knowledge to focus on small sets of genes or SNPs that are known to have an association with breast cancer. Thus, many genetic interactions, particularly among novel variants, remain understudied. Reverse-genetic interaction screens in model organisms have shown that genetic interactions frequently cluster into highly structured motifs, where members of the same pathway share similar patterns of genetic interactions. Based on this key observation, we recently developed a method called BridGE to search for such structured motifs in genetic networks derived from GWAS studies and identify pathway-level genetic interactions in human populations. We applied BridGE to six independent breast cancer cohorts and identified significant pathway-level interactions in five cohorts. Joint analysis across all five cohorts revealed a high confidence consensus set of genetic interactions with support in multiple cohorts. The discovered interactions implicated the glutathione conjugation, vitamin D receptor, purine metabolism, mitotic prometaphase, and steroid hormone biosynthesis pathways as major modifiers of breast cancer risk. Notably, while many of the pathways identified by BridGE show clear relevance to breast cancer, variants in these pathways had not been previously discovered by traditional single variant association tests, or single pathway enrichment analysis that does not consider SNP-SNP interactions. PMID:28957314

Stakeholder perspectives on decision-analytic modeling frameworks to assess genetic services policy.

PubMed

Guzauskas, Gregory F; Garrison, Louis P; Stock, Jacquie; Au, Sylvia; Doyle, Debra Lochner; Veenstra, David L

2013-01-01

Genetic services policymakers and insurers often make coverage decisions in the absence of complete evidence of clinical utility and under budget constraints. We evaluated genetic services stakeholder opinions on the potential usefulness of decision-analytic modeling to inform coverage decisions, and asked them to identify genetic tests for decision-analytic modeling studies. We presented an overview of decision-analytic modeling to members of the Western States Genetic Services Collaborative Reimbursement Work Group and state Medicaid representatives and conducted directed content analysis and an anonymous survey to gauge their attitudes toward decision-analytic modeling. Participants also identified and prioritized genetic services for prospective decision-analytic evaluation. Participants expressed dissatisfaction with current processes for evaluating insurance coverage of genetic services. Some participants expressed uncertainty about their comprehension of decision-analytic modeling techniques. All stakeholders reported openness to using decision-analytic modeling for genetic services assessments. Participants were most interested in application of decision-analytic concepts to multiple-disorder testing platforms, such as next-generation sequencing and chromosomal microarray. Decision-analytic modeling approaches may provide a useful decision tool to genetic services stakeholders and Medicaid decision-makers.

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing

PubMed Central

Susswein, Lisa R.; Marshall, Megan L.; Nusbaum, Rachel; Vogel Postula, Kristen J.; Weissman, Scott M.; Yackowski, Lauren; Vaccari, Erica M.; Bissonnette, Jeffrey; Booker, Jessica K.; Cremona, M. Laura; Gibellini, Federica; Murphy, Patricia D.; Pineda-Alvarez, Daniel E.; Pollevick, Guido D.; Xu, Zhixiong; Richard, Gabi; Bale, Sherri; Klein, Rachel T.; Hruska, Kathleen S.; Chung, Wendy K.

2016-01-01

Purpose: Germ-line testing for panels of cancer genes using next-generation sequencing is becoming more common in clinical care. We report our experience as a clinical laboratory testing both well-established, high-risk cancer genes (e.g., BRCA1/2, MLH1, MSH2) as well as more recently identified cancer genes (e.g., PALB2, BRIP1), many of which have increased but less well-defined penetrance. Genet Med 18 8, 823–832. Methods: Clinical genetic testing was performed on over 10,000 consecutive cases referred for evaluation of germ-line cancer genes, and results were analyzed for frequency of pathogenic or likely pathogenic variants, and were stratified by testing panel, gene, and clinical history. Genet Med 18 8, 823–832. Results: Overall, a molecular diagnosis was made in 9.0% of patients tested, with the highest yield in the Lynch syndrome/colorectal cancer panel. In patients with breast, ovarian, or colon/stomach cancer, positive yields were 9.7, 13.4, and 14.8%, respectively. Approximately half of the pathogenic variants identified in patients with breast or ovarian cancer were in genes other than BRCA1/2. Genet Med 18 8, 823–832. Conclusion: The high frequency of positive results in a wide range of cancer genes, including those of high penetrance and with clinical care guidelines, underscores both the genetic heterogeneity of hereditary cancer and the usefulness of multigene panels over genetic tests of one or two genes. Genet Med 18 8, 823–832. PMID:26681312

Direct-to-consumer genetic testing for predicting sports performance and talent identification: Consensus statement.

PubMed

Webborn, Nick; Williams, Alun; McNamee, Mike; Bouchard, Claude; Pitsiladis, Yannis; Ahmetov, Ildus; Ashley, Euan; Byrne, Nuala; Camporesi, Silvia; Collins, Malcolm; Dijkstra, Paul; Eynon, Nir; Fuku, Noriyuki; Garton, Fleur C; Hoppe, Nils; Holm, Søren; Kaye, Jane; Klissouras, Vassilis; Lucia, Alejandro; Maase, Kamiel; Moran, Colin; North, Kathryn N; Pigozzi, Fabio; Wang, Guan

2015-12-01

The general consensus among sport and exercise genetics researchers is that genetic tests have no role to play in talent identification or the individualised prescription of training to maximise performance. Despite the lack of evidence, recent years have witnessed the rise of an emerging market of direct-to-consumer marketing (DTC) tests that claim to be able to identify children's athletic talents. Targeted consumers include mainly coaches and parents. There is concern among the scientific community that the current level of knowledge is being misrepresented for commercial purposes. There remains a lack of universally accepted guidelines and legislation for DTC testing in relation to all forms of genetic testing and not just for talent identification. There is concern over the lack of clarity of information over which specific genes or variants are being tested and the almost universal lack of appropriate genetic counselling for the interpretation of the genetic data to consumers. Furthermore independent studies have identified issues relating to quality control by DTC laboratories with different results being reported from samples from the same individual. Consequently, in the current state of knowledge, no child or young athlete should be exposed to DTC genetic testing to define or alter training or for talent identification aimed at selecting gifted children or adolescents. Large scale collaborative projects, may help to develop a stronger scientific foundation on these issues in the future. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies.

PubMed

Lee, Kristy; Garg, Seema

2015-04-01

Inherited eye disorders are a significant cause of vision loss. Genetic testing can be particularly helpful for patients with inherited retinal dystrophies because of genetic heterogeneity and overlapping phenotypes. The need to identify a molecular diagnosis for retinal dystrophies is particularly important in the era of developing novel gene therapy-based treatments, such as the RPE65 gene-based clinical trials and others on the horizon, as well as recent advances in reproductive options. The introduction of massively parallel sequencing technologies has significantly advanced the identification of novel gene candidates and has expanded the landscape of genetic testing. In a relatively short time clinical medicine has progressed from limited testing options to a plethora of choices ranging from single-gene testing to whole-exome sequencing. This article outlines currently available genetic testing and factors to consider when selecting appropriate testing for patients with inherited retinal dystrophies.

Utility of Genetic Testing in Elite Volleyball Players with Aortic Root Dilation.

PubMed

Herrick, Nicole; Davis, Christopher; Vargas, Lisa; Dietz, Hal; Grossfeld, Paul

2017-07-01

Basketball and volleyball attract individuals with a characteristic biophysical profile, mimicking features of Marfan syndrome. Consequently, identification of these abnormalities can be lifesaving. To determine how physical examination, echocardiography, and genetic screening can identify elite volleyball players with a previously undiagnosed aortopathy. We have performed cardiac screening on 90 US Volleyball National Team members and identified four individuals with dilated sinuses of Valsalva. This case series reports on three individuals who underwent a comprehensive genetics evaluation, including gene sequencing. Cardiac screening combined with genetic testing can identify previously undiagnosed tall athletes with an aortopathy, in the absence of noncardiac findings of a connective tissue disorder. Subject 1 had a revised Ghent systems (RGS) score of 2 and a normal aortopathy gene panel. Subject 2 had a RGS score of 1 and genetic testing revealed a de novo disease causing mutation in the gene encoding fibrillin-1 (FBN1). Subject 3 had an RGS score of 4.0 and had a normal aortopathy gene panel. Despite variable clinical features of Marfan syndrome, dilated sinuses of Valsalva were found in 4.9% of the athletes. A disease-causing mutation in the FBN1 gene was identified in subject 2, who had the lowest RGS but the largest aortic root measurement. Subjects 1 and 3, with the highest RGS, had a normal aortopathy gene panel. Our findings provide further evidence suggesting that a cardiac evaluation, including a screening echocardiogram, should be performed on all elite tall adult athletes independent of other physical findings. Genetic testing should be considered for athletes with dilated sinuses of Valsalva (male, >4.2 cm; female, >3.4 cm), regardless of other extracardiac findings.

Molecular Diagnosis of Thalassemias and Hemoglobinopathies: An ACLPS Critical Review.

PubMed

Sabath, Daniel E

2017-07-01

To describe the use of molecular diagnostic techniques for patients with hemoglobin disorders. A clinical scenario is presented in which molecular diagnosis is important for genetic counseling. Globin disorders, techniques for their diagnosis, and the role of molecular genetic testing in managing patients with these disorders are described in detail. Hemoglobin disorders, including thalassemias and hemoglobinopathies, are among the commonest genetic diseases, and the clinical laboratory is essential for the diagnosis of patients with these abnormalities. Most disorders can be diagnosed with protein-based techniques such as electrophoresis and chromatography. Since severe syndromes can result due to inheritance of combinations of globin genetic disorders, genetic counseling is important to prevent adverse outcomes. Protein-based methods cannot always detect potentially serious thalassemia disorders; in particular, α-thalassemia may be masked in the presence of β-thalassemia. Deletional forms of β-thalassemia are also sometimes difficult to diagnose definitively with standard methods. Molecular genetic testing serves an important role in identifying individuals carrying thalassemia traits that can cause adverse outcomes in offspring. Furthermore, prenatal genetic testing can identify fetuses with severe globin phenotypes. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Something Old, Something New: Using Family History and Genetic Testing to Diagnose and Manage Athletes with Inherited Cardiovascular Disease.

PubMed

Thomas, Matthew J; Battle, Robert W

2015-07-01

A primary objective of the preparticipation physical examination is to identify athletes at increased risk for sudden cardiac arrest (SCA). Review of an athlete's family history may identify those at risk for SCA. Genetic testing for inherited cardiovascular disease has emerged as a valuable addition to the repertoire of cardiologists facing the decision of clearing athletes with concerning clinical signs and/or family histories. Genetic testing may lead to various outcomes for an athlete including: reassurance, diagnosis in those with borderline clinical features, finding disease predisposition prior to the onset of clinical signs (ie, genotype-positive/phenotype-negative), or continued uncertainty. Copyright © 2015 Elsevier Inc. All rights reserved.

ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

PubMed

Syngal, Sapna; Brand, Randall E; Church, James M; Giardiello, Francis M; Hampel, Heather L; Burt, Randall W

2015-02-01

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

ACG Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes

PubMed Central

Syngal, Sapna; Brand, Randall E.; Church, James M.; Giardiello, Francis M.; Hampel, Heather L.; Burt, Randall W.

2015-01-01

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz–Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer. PMID:25645574

The Impact of Gene-Environment Dependence and Misclassification in Genetic Association Studies Incorporating Gene-Environment Interactions

PubMed Central

Lindström, Sara; Yen, Yu-Chun; Spiegelman, Donna; Kraft, Peter

2009-01-01

The possibility of gene-environment interaction can be exploited to identify genetic variants associated with disease using a joint test of genetic main effect and gene-environment interaction. We consider how exposure misclassification and dependence between the true exposure E and the tested genetic variant G affect this joint test in absolute terms and relative to three other tests: the marginal test (G), the standard test for multiplicative gene-environment interaction (GE), and the case-only test for interaction (GE-CO). All tests can have inflated Type I error rate when E and G are correlated in the underlying population. For the GE and G-GE tests this inflation is only noticeable when the gene-environment dependence is unusually strong; the inflation can be large for the GE-CO test even for modest correlation. The joint G-GE test has greater power than the GE test generally, and greater power than the G test when there is no genetic main effect and the measurement error is small to moderate. The joint G-GE test is an attractive test for assessing genetic association when there is limited knowledge about casual mechanisms a priori, even in the presence of misclassification in environmental exposure measurement and correlation between exposure and genetic variants. PMID:19521099

Initial Results of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome.

PubMed

Howarth, Dt R; Lum, Sharon S; Esquivel, Pamela; Garberoglio, Carlos A; Senthil, Maheswari; Solomon, Naveenraj L

2015-10-01

Multigene panel testing for hereditary cancer risk has recently become commercially available; however, the impact of its use on patient care is undefined. We sought to evaluate results from implementation of panel testing in a multidisciplinary cancer center. We performed a retrospective review of consecutive patients undergoing genetic testing after initiating use of multigene panel testing at Loma Linda University Medical Center. From February 13 to August 25, 2014, 92 patients were referred for genetic testing based on National Comprehensive Cancer Network guidelines. Testing was completed in 90 patients. Overall, nine (10%) pathogenic mutations were identified: five BRCA1/2, and four in non-BRCA loci. Single-site testing identified one BRCA1 and one BRCA2 mutation. The remaining mutations were identified by use of panel testing for hereditary breast and ovarian cancer. There were 40 variants of uncertain significance identified in 34 patients. The use of panel testing more than doubled the identification rate of clinically significant pathogenic mutations that would have been missed with BRCA testing alone. The large number of variants of uncertain significance identified will require long-term follow-up for potential reclassification. Multigene panel testing provides additional information that may improve patient outcomes.

Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from Southern Brazil.

PubMed

Palmero, Edenir Inêz; Alemar, Bárbara; Schüler-Faccini, Lavínia; Hainaut, Pierre; Moreira-Filho, Carlos Alberto; Ewald, Ingrid Petroni; Santos, Patricia Koehler Dos; Ribeiro, Patricia Lisbôa Izetti; Oliveira, Cristina Brinkmann de Netto; Calvez-Kelm, Florence Le; Tavtigian, Sean; Cossio, Silvia Liliana; Giugliani, Roberto; Caleffi, Maira; Ashton-Prolla, Patricia

2016-05-24

In Brazil, breast cancer is a public health care problem due to its high incidence and mortality rates. In this study, we investigated the prevalence of hereditary breast cancer syndromes (HBCS) in a population-based cohort in Brazils southernmost capital, Porto Alegre. All participants answered a questionnaire about family history (FH) of breast, ovarian and colorectal cancer and those with a positive FH were invited for genetic cancer risk assessment (GCRA). If pedigree analysis was suggestive of HBCS, genetic testing of the BRCA1, BRCA2, TP53, and CHEK2 genes was offered. Of 902 women submitted to GCRA, 214 had pedigrees suggestive of HBCS. Fifty of them underwent genetic testing: 18 and 40 for BRCA1/BRCA2 and TP53 mutation screening, respectively, and 7 for CHEK2 1100delC testing. A deleterious BRCA2 mutation was identified in one of the HBOC probands and the CHEK2 1100delC mutation occurred in one of the HBCC families. No deleterious germline alterations were identified in BRCA1 or TP53. Although strict inclusion criteria and a comprehensive testing approach were used, the suspected genetic risk in these families remains unexplained. Further studies in a larger cohort are necessary to better understand the genetic component of hereditary breast cancer in Southern Brazil.

An Evaluation of Factors Associated With Pathogenic PRSS1, SPINK1, CTFR, and/or CTRC Genetic Variants in Patients With Idiopathic Pancreatitis.

PubMed

Jalaly, Niloofar Y; Moran, Robert A; Fargahi, Farshid; Khashab, Mouen A; Kamal, Ayesha; Lennon, Anne Marie; Walsh, Christi; Makary, Martin A; Whitcomb, David C; Yadav, Dhiraj; Cebotaru, Liudmila; Singh, Vikesh K

2017-08-01

We evaluated factors associated with pathogenic genetic variants in patients with idiopathic pancreatitis. Genetic testing (PRSS1, CFTR, SPINK1, and CTRC) was performed in all eligible patients with idiopathic pancreatitis between 2010 to 2015. Patients were classified into the following groups based on a review of medical records: (1) acute recurrent idiopathic pancreatitis (ARIP) with or without underlying chronic pancreatitis; (2) idiopathic chronic pancreatitis (ICP) without a history of ARP; (3) an unexplained first episode of acute pancreatitis (AP)<35 years of age; and (4) family history of pancreatitis. Logistic regression analysis was used to determine the factors associated with pathogenic genetic variants. Among 197 ARIP and/or ICP patients evaluated from 2010 to 2015, 134 underwent genetic testing. A total of 88 pathogenic genetic variants were found in 64 (47.8%) patients. Pathogenic genetic variants were identified in 58, 63, and 27% of patients with ARIP, an unexplained first episode of AP <35 years of age, and ICP without ARP, respectively. ARIP (OR: 18.12; 95% CI: 2.16-151.87; P=0.008) and an unexplained first episode of AP<35 years of age (OR: 2.46; 95% CI: 1.18-5.15; P=0.017), but not ICP, were independently associated with pathogenic genetic variants in the adjusted analysis. Pathogenic genetic variants are most likely to be identified in patients with ARIP and an unexplained first episode of AP<35 years of age. Genetic testing in these patient populations may delineate an etiology and prevent unnecessary diagnostic testing and procedures.

State of play in direct-to-consumer genetic testing for lifestyle-related diseases: market, marketing content, user experiences and regulation.

PubMed

Saukko, Paula

2013-02-01

Direct-to-consumer (DTC) genetic tests have aroused controversy. Critics have argued many of the tests are not backed by scientific evidence, misguide their customers and should be regulated more stringently. Proponents suggest that finding out genetic susceptibilities for diseases could encourage healthier behaviours and makes the results of genetics research available to the public. This paper reviews the state of play in DTC genetic testing, focusing on tests identifying susceptibilities for lifestyle-related diseases. It will start with mapping the market for the tests. The paper will review (1) research on the content of the online marketing of DTC tests, (2) studies on the effects of DTC genetic tests on customers and (3) academic and policy proposals on how to regulate the tests. Current studies suggest that the marketing of DTC genetic tests often exaggerates their predictive powers, which could misguide consumers. However, research indicates that the tests do not seem to have major negative effects (worry and confusion) but neither do they engender positive effects (lifestyle change) on current users. Research on regulation of the tests has most commonly suggested regulating the marketing claims of the companies. In conclusion, the risks and benefits of DTC genetic tests are less significant than what has been predicted by critics and proponents, which will be argued reflects broader historical trends transforming health and medicine.

Frequency of five disease-causing genetic mutations in a large mixed-breed dog population (2011–2012)

PubMed Central

Zierath, Sharon; Hughes, Angela M.; Fretwell, Neale; Dibley, Mark

2017-01-01

Background A large and growing number of inherited genetic disease mutations are now known in the dog. Frequencies of these mutations are typically examined within the breed of discovery, possibly in related breeds, but nearly always in purebred dogs. No report to date has examined the frequencies of specific genetic disease mutations in a large population of mixed-breed dogs. Further, veterinarians and dog owners typically dismiss inherited/genetic diseases as possibilities for health problems in mixed-breed dogs, assuming hybrid vigor will guarantee that single-gene disease mutations are not a cause for concern. Therefore, the objective of this study was to screen a large mixed-breed canine population for the presence of mutant alleles associated with five autosomal recessive disorders: hyperuricosuria and hyperuricemia (HUU), cystinuria (CYST), factor VII deficiency (FVIID), myotonia congenita (MYC) and phosphofructokinase deficiency (PKFD). Genetic testing was performed in conjunction with breed determination via the commercially-available Wisdom PanelTM test. Results From a population of nearly 35,000 dogs, homozygous mutant dogs were identified for HUU (n = 57) and FVIID (n = 65). Homozygotes for HUU and FVIID were identified even among dogs with highly mixed breed ancestry. Carriers were identified for all disorders except MYC. HUU and FVIID were of high enough frequency to merit consideration in any mixed-breed dog, while CYST, MYC, and PKFD are vanishingly rare. Conclusions The assumption that mixed-breed dogs do not suffer from single-gene genetic disorders is shown here to be false. Within the diseases examined, HUU and FVIID should remain on any practitioner’s rule-out list, when clinically appropriate, for all mixed-breed dogs, and judicious genetic testing should be performed for diagnosis or screening. Future testing of large mixed-breed dog populations that include additional known canine genetic mutations will refine our knowledge of which genetic diseases can strike mixed-breed dogs. PMID:29166669

Frequency of five disease-causing genetic mutations in a large mixed-breed dog population (2011-2012).

PubMed

Zierath, Sharon; Hughes, Angela M; Fretwell, Neale; Dibley, Mark; Ekenstedt, Kari J

2017-01-01

A large and growing number of inherited genetic disease mutations are now known in the dog. Frequencies of these mutations are typically examined within the breed of discovery, possibly in related breeds, but nearly always in purebred dogs. No report to date has examined the frequencies of specific genetic disease mutations in a large population of mixed-breed dogs. Further, veterinarians and dog owners typically dismiss inherited/genetic diseases as possibilities for health problems in mixed-breed dogs, assuming hybrid vigor will guarantee that single-gene disease mutations are not a cause for concern. Therefore, the objective of this study was to screen a large mixed-breed canine population for the presence of mutant alleles associated with five autosomal recessive disorders: hyperuricosuria and hyperuricemia (HUU), cystinuria (CYST), factor VII deficiency (FVIID), myotonia congenita (MYC) and phosphofructokinase deficiency (PKFD). Genetic testing was performed in conjunction with breed determination via the commercially-available Wisdom PanelTM test. From a population of nearly 35,000 dogs, homozygous mutant dogs were identified for HUU (n = 57) and FVIID (n = 65). Homozygotes for HUU and FVIID were identified even among dogs with highly mixed breed ancestry. Carriers were identified for all disorders except MYC. HUU and FVIID were of high enough frequency to merit consideration in any mixed-breed dog, while CYST, MYC, and PKFD are vanishingly rare. The assumption that mixed-breed dogs do not suffer from single-gene genetic disorders is shown here to be false. Within the diseases examined, HUU and FVIID should remain on any practitioner's rule-out list, when clinically appropriate, for all mixed-breed dogs, and judicious genetic testing should be performed for diagnosis or screening. Future testing of large mixed-breed dog populations that include additional known canine genetic mutations will refine our knowledge of which genetic diseases can strike mixed-breed dogs.

Quality assessment of genetic counseling process in the context of presymptomatic testing for late-onset disorders: a thematic analysis of three review articles.

PubMed

Paneque, Milena; Sequeiros, Jorge; Skirton, Heather

2012-01-01

Presymptomatic testing (PST) is available for a range of late-onset disorders. Health practitioners generally follow guidelines regarding appropriate number of counseling sessions, involvement of multidisciplinary teams, topics for pretest discussion, and follow-up sessions; however, more understanding is needed about what helps consultands effectively and the impact of amount and quality of genetic counseling on the psychosocial sequelae of PST for late-onset disorders. We conducted a thematic analysis of three review articles on quality of the genetic counseling process, aiming at (1) exploring current evidence; (2) identifying quality assessment indicators; and (3) making recommendations for genetic counseling practice in late-onset disorders. We undertook a systematic search of 6 relevant databases: 38 articles were identified and 3 fitted our inclusion criteria; after quality appraisal, all were included in the review. The number of sessions, time spent, consultation environment, follow-up, and multidisciplinarity were identified as variables for quality assessment. Research on counseling in the context of genetic testing in familial cancer tends to be related to outcomes and indicators for quality assessment, while research concerning other late-onset diseases is mainly focused on the psychological impact of the test results. The quality and content of the overall process in noncancer late-onset diseases is insufficiently articulated. Despite the fact that PST for Huntington disease and other degenerative conditions has been offered for more than 20 years, good methodological approaches to assess quality of genetic counseling in that context remain elusive. This restricts improvement of the protocols for genetic services and, in general, healthcare for the at-risk population.

Prenatal diagnostic decision-making in adolescents.

PubMed

Plaga, Stacey L; Demarco, Kristin; Shulman, Lee P

2005-04-01

We sought to evaluate the prenatal decision-making of pregnant adolescents identified at increased risk for identifiable fetal genetic abnormalities. A retrospective review of records of gravid women 19 years old or younger undergoing genetic counseling from 2001-2003 (inclusive) was undertaken. Hospital-based academic center. Thirty-seven women were identified; four cases did not meet inclusion criteria. None. Decision to undergo or forgo invasive prenatal testing. Of the 33 women included in this study, the average age was 17.6 years (range: 15-19). Eighteen were Latinas, eight were African-Americans, and seven were Caucasians. Sixteen women had positive maternal serum screening outcomes; nine women sought counseling because of personal/family histories of genetic abnormalities, seven sought counseling after fetal structural anomalies were detected by ultrasound, and one woman sought counseling because she and her partner were positive for Mendelian disorder screening (sickle cell disease). Sixteen of the women (48.5%) chose to undergo invasive testing (15 amniocenteses, one chorionic villus sampling) whereas 17 (51.5%) chose to forgo invasive testing. Adolescents offered invasive prenatal diagnosis will chose to undergo or forgo such testing based on diagnostic and personal criteria as do adult women. Nonetheless, unique adolescent issues may make the process by which information is obtained and communicated during counseling to be different from counseling provided to adults. The development of new genetic screening and diagnostic protocols has and will increase the number of pregnant adolescent women who will be offered genetic counseling during their pregnancies. Such an increase in numbers will place considerably more pressure on an already taxed genetic counseling system; accordingly, new counseling paradigms will need to be developed to provide service to an expanded patient population seeking information for an increasing number of genetic issues.

Current perspectives on recommendations for BRCA genetic testing in ovarian cancer patients.

PubMed

Vergote, Ignace; Banerjee, Susana; Gerdes, Anne-Marie; van Asperen, Christi; Marth, Christian; Vaz, Fatima; Ray-Coquard, Isabelle; Stoppa-Lyonnet, Dominique; Gonzalez-Martin, Antonio; Sehouli, Jalid; Colombo, Nicoletta

2016-12-01

Traditionally, BRCA genetic testing has been undertaken to identify patients and family members at future risk of developing cancer and patients have been referred for testing based on family history. However, the now recognised risk of ovarian cancer (OC) patients, even those with no known family history, harbouring a mutation in BRCA1/2, together with the first poly adenosine diphosphate ribose polymerase inhibitor (PARPi; olaparib [Lynparza]) being licenced for the treatment of BRCA-mutated OC, has led to reconsideration of referral criteria for OC patients. Provided here is a review of the existing data and guidelines in the European Union, relating to recommendations, as well as considerations, for the referral of OC patients for BRCA genetic testing. Based on this review of newly updated guidance and up-to-date evidence, the following is recommended: all patients with invasive epithelial OC (excluding borderline or mucinous), including those with fallopian tube and peritoneal cancers, should be considered as candidates for referral for BRCA genetic testing, irrespective of age; genetic testing should ideally be offered at diagnosis, although patients can be referred at any stage; retrospective testing should be offered to patients in long-term follow-up because of the implications for family members and individual future breast cancer risk; and germline BRCA testing of a blood/saliva sample should initially be conducted and, if negative, tumour tissue should be tested (to identify non-germline [somatic] BRCA PARPi therapy candidates). Copyright © 2016 Elsevier Ltd. All rights reserved.

Genetic testing in cardiovascular diseases.

PubMed

Arndt, Anne-Karin; MacRae, Calum A

2014-05-01

The review is designed to outline the major developments in genetic testing in the cardiovascular arena in the past year or so. This is an exciting time in genetic testing as whole exome and whole genome approaches finally reach the clinic. These new approaches offer insight into disease causation in families in which this might previously have been inaccessible, and also bring a wide range of interpretative challenges. Among the most significant recent findings has been the extent of physiologic rare coding variation in the human genome. New disease genes have been identified through whole exome studies in neonatal arrhythmia, congenital heart disease and coronary artery disease that were simply inaccessible with other techniques. This has not only shed light on the challenges of genetic testing at this scale, but has also sharply defined the limits of prior gene-panel focused testing. As novel therapies targeting specific genetic subsets of disease become available, genetic testing will become a part of routine clinical care. The pace of change in sequencing technologies has begun to transform clinical medicine, and cardiovascular disease is no exception. The complexity of such studies emphasizes the importance of real-time communication between the genetics laboratory and genetically informed clinicians. New efforts in data and knowledge management will be central to the continued advancement of genetic testing.

A Rapid Systematic Review of Outcomes Studies in Genetic Counseling.

PubMed

Madlensky, Lisa; Trepanier, Angela M; Cragun, Deborah; Lerner, Barbara; Shannon, Kristen M; Zierhut, Heather

2017-06-01

As healthcare reimbursement is increasingly tied to value-of-service, it is critical for the genetic counselor (GC) profession to demonstrate the value added by GCs through outcomes research. We conducted a rapid systematic literature review to identify outcomes of genetic counseling. Web of Science (including PubMed) and CINAHL databases were systematically searched to identify articles meeting the following criteria: 1) measures were assessed before and after genetic counseling (pre-post design) or comparisons were made between a GC group vs. a non-GC group (comparative cohort design); 2) genetic counseling outcomes could be assessed independently of genetic testing outcomes, and 3) genetic counseling was conducted by masters-level genetic counselors, or non-physician providers. Twenty-three papers met the inclusion criteria. The majority of studies were in the cancer genetic setting and the most commonly measured outcomes included knowledge, anxiety or distress, satisfaction, perceived risk, genetic testing (intentions or receipt), health behaviors, and decisional conflict. Results suggest that genetic counseling can lead to increased knowledge, perceived personal control, positive health behaviors, and improved risk perception accuracy as well as decreases in anxiety, cancer-related worry, and decisional conflict. However, further studies are needed to evaluate a wider array of outcomes in more diverse genetic counseling settings.

Parental narratives about genetic testing for hearing loss: a one year follow up study.

PubMed

Kaimal, Girija; Steinberg, Annie G; Ennis, Sara; Harasink, Sue Moyer; Ewing, Rachel; Li, Yuelin

2007-12-01

Few studies examine whether and how parental attitudes towards genetic testing change over time. In this study we interviewed parents of 14 children with newly identified hearing loss at two time points: after referral to genetics and 1 year later. Qualitative analyses of parental narratives indicate that parental attitudes did not change significantly over this time. Parents who perceived genetic testing to be useful continued to value it after testing, while parents who did not perceive it as being useful for their child's future held the same view a year later. The only parents who changed their views regarding the usefulness of genetic testing for hearing loss were those who reported that their children underwent significant changes in their hearing loss or were faced with other life threatening conditions. Parents were also often unaware of the role of the genetic counselor and how genetic counseling could help address many of their lingering questions and concerns. These emergent themes indicate the need for geneticists and genetic counselors to be aware of and sensitized to the questions and attitudes that bring parents to a genetic evaluation, as well as the reasons why parents may not follow up with genetic testing for hearing loss when recommended.

Uncertainty in BRCA1 cancer susceptibility testing.

PubMed

Baty, Bonnie J; Dudley, William N; Musters, Adrian; Kinney, Anita Y

2006-11-15

This study investigated uncertainty in individuals undergoing genetic counseling/testing for breast/ovarian cancer susceptibility. Sixty-three individuals from a single kindred with a known BRCA1 mutation rated uncertainty about 12 items on a five-point Likert scale before and 1 month after genetic counseling/testing. Factor analysis identified a five-item total uncertainty scale that was sensitive to changes before and after testing. The items in the scale were related to uncertainty about obtaining health care, positive changes after testing, and coping well with results. The majority of participants (76%) rated reducing uncertainty as an important reason for genetic testing. The importance of reducing uncertainty was stable across time and unrelated to anxiety or demographics. Yet, at baseline, total uncertainty was low and decreased after genetic counseling/testing (P = 0.004). Analysis of individual items showed that after genetic counseling/testing, there was less uncertainty about the participant detecting cancer early (P = 0.005) and coping well with their result (P < 0.001). Our findings support the importance to clients of genetic counseling/testing as a means of reducing uncertainty. Testing may help clients to reduce the uncertainty about items they can control, and it may be important to differentiate the sources of uncertainty that are more or less controllable. Genetic counselors can help clients by providing anticipatory guidance about the role of uncertainty in genetic testing. (c) 2006 Wiley-Liss, Inc.

The Human Genome Project and Eugenics: Identifying the Impact on Individuals with Mental Retardation.

ERIC Educational Resources Information Center

Kuna, Jason

2001-01-01

This article explores the impact of the mapping work of the Human Genome Project on individuals with mental retardation and the negative effects of genetic testing. The potential to identify disabilities and the concept of eugenics are discussed, along with ethical issues surrounding potential genetic therapies. (Contains references.) (CR)

A systematic analysis of online marketing materials used by providers of expanded carrier screening.

PubMed

Chokoshvili, Davit; Borry, Pascal; Vears, Danya F

2017-12-14

PurposeExpanded carrier screening (ECS) for a large number of recessive disorders is available to prospective parents through commercial providers. This study aimed to analyze the content of marketing materials on ECS providers' websites.MethodsTo identify providers of ECS tests, we undertook a comprehensive online search, reviewed recent academic literature on commercial carrier screening, and consulted with colleagues familiar with the current ECS landscape. The identified websites were archived in April 2017, and inductive content analysis was performed on website text, brochures and educational materials, and video transcripts.ResultsWe identified 18 ECS providers, including 16 commercial genetic testing companies. Providers typically described ECS as an important family planning tool. The content differed in both the tone used to promote ECS and the accuracy and completeness of the test information provided. We found that most providers offered complimentary genetic counseling to their consumers, although this was often optional, limited to the posttest context, and, in some cases, appeared to be available only to test-positive individuals.ConclusionThe quality of ECS providers' websites could be improved by offering more complete and accurate information about ECS and their tests. Providers should also ensure that all carrier couples receive posttest genetic counseling to inform their subsequent reproductive decision making.Genet Med advance online publication, 14 December 2017; doi:10.1038/gim.2017.222.

Unravelling fears of genetic discrimination: an exploratory study of Dutch HCM families in an era of genetic non-discrimination acts.

PubMed

Geelen, Els; Horstman, Klasien; Marcelis, Carlo L M; Doevendans, Pieter A; Van Hoyweghen, Ine

2012-10-01

Since the 1990s, many countries in Europe and the United States have enacted genetic non-discrimination legislation to prevent people from deferring genetic tests for fear that insurers or employers would discriminate against them based on that information. Although evidence for genetic discrimination exists, little is known about the origins and backgrounds of fears of discrimination and how it affects decisions for uptake of genetic testing. The aim of this article is to gain a better understanding of these fears and its possible impact on the uptake of testing by studying the case of hypertrophic cardiomyopathy (HCM). In a qualitative study, we followed six Dutch extended families involved in genetic testing for HCM for three-and-a-half years. Semi-structured interviews were conducted with 57 members of these families. Based on the narratives of the families, we suggest that fears of discrimination have to be situated in the broader social and life-course context of family and kin. We describe the processes in which families developed meaningful interpretations of genetic discrimination and how these interpretations affected family members' decisions to undergo genetic testing. Our findings show that fears of genetic discrimination do not so much stem from the opportunity of genetic testing but much more from earlier experiences of discrimination of diseased family members. These results help identify the possible limitations of genetic non-discrimination regulations and provide direction to clinicians supporting their clients as they confront issues of genetic testing and genetic discrimination.

Unravelling fears of genetic discrimination: an exploratory study of Dutch HCM families in an era of genetic non-discrimination acts

PubMed Central

Geelen, Els; Horstman, Klasien; Marcelis, Carlo LM; Doevendans, Pieter A; Van Hoyweghen, Ine

2012-01-01

Since the 1990s, many countries in Europe and the United States have enacted genetic non-discrimination legislation to prevent people from deferring genetic tests for fear that insurers or employers would discriminate against them based on that information. Although evidence for genetic discrimination exists, little is known about the origins and backgrounds of fears of discrimination and how it affects decisions for uptake of genetic testing. The aim of this article is to gain a better understanding of these fears and its possible impact on the uptake of testing by studying the case of hypertrophic cardiomyopathy (HCM). In a qualitative study, we followed six Dutch extended families involved in genetic testing for HCM for three-and-a-half years. Semi-structured interviews were conducted with 57 members of these families. Based on the narratives of the families, we suggest that fears of discrimination have to be situated in the broader social and life-course context of family and kin. We describe the processes in which families developed meaningful interpretations of genetic discrimination and how these interpretations affected family members' decisions to undergo genetic testing. Our findings show that fears of genetic discrimination do not so much stem from the opportunity of genetic testing but much more from earlier experiences of discrimination of diseased family members. These results help identify the possible limitations of genetic non-discrimination regulations and provide direction to clinicians supporting their clients as they confront issues of genetic testing and genetic discrimination. PMID:22453290

Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from Southern Brazil

PubMed Central

Palmero, Edenir Inêz; Alemar, Bárbara; Schüler-Faccini, Lavínia; Hainaut, Pierre; Moreira-Filho, Carlos Alberto; Ewald, Ingrid Petroni; dos Santos, Patricia Koehler; Ribeiro, Patricia Lisbôa Izetti; de Oliveira, Cristina Brinkmann; Kelm, Florence Le Calvez; Tavtigian, Sean; Cossio, Silvia Liliana; Giugliani, Roberto; Caleffi, Maira; Ashton-Prolla, Patricia

2016-01-01

Abstract In Brazil, breast cancer is a public health care problem due to its high incidence and mortality rates. In this study, we investigated the prevalence of hereditary breast cancer syndromes (HBCS) in a population-based cohort in Brazils southernmost capital, Porto Alegre. All participants answered a questionnaire about family history (FH) of breast, ovarian and colorectal cancer and those with a positive FH were invited for genetic cancer risk assessment (GCRA). If pedigree analysis was suggestive of HBCS, genetic testing of the BRCA1, BRCA2, TP53, and CHEK2 genes was offered. Of 902 women submitted to GCRA, 214 had pedigrees suggestive of HBCS. Fifty of them underwent genetic testing: 18 and 40 for BRCA1/BRCA2 and TP53 mutation screening, respectively, and 7 for CHEK2 1100delC testing. A deleterious BRCA2 mutation was identified in one of the HBOC probands and the CHEK2 1100delC mutation occurred in one of the HBCC families. No deleterious germline alterations were identified in BRCA1 or TP53. Although strict inclusion criteria and a comprehensive testing approach were used, the suspected genetic risk in these families remains unexplained. Further studies in a larger cohort are necessary to better understand the genetic component of hereditary breast cancer in Southern Brazil. PMID:27223485

Next-generation sequencing to solve complex inherited retinal dystrophy: A case series of multiple genes contributing to disease in extended families.

PubMed

Jones, Kaylie D; Wheaton, Dianna K; Bowne, Sara J; Sullivan, Lori S; Birch, David G; Chen, Rui; Daiger, Stephen P

2017-01-01

With recent availability of next-generation sequencing (NGS), it is becoming more common to pursue disease-targeted panel testing rather than traditional sequential gene-by-gene dideoxy sequencing. In this report, we describe using NGS to identify multiple disease-causing mutations that contribute concurrently or independently to retinal dystrophy in three relatively small families. Family members underwent comprehensive visual function evaluations, and genetic counseling including a detailed family history. A preliminary genetic inheritance pattern was assigned and updated as additional family members were tested. Family 1 (FAM1) and Family 2 (FAM2) were clinically diagnosed with retinitis pigmentosa (RP) and had a suspected autosomal dominant pedigree with non-penetrance (n.p.). Family 3 (FAM3) consisted of a large family with a diagnosis of RP and an overall dominant pedigree, but the proband had phenotypically cone-rod dystrophy. Initial genetic analysis was performed on one family member with traditional Sanger single gene sequencing and/or panel-based testing, and ultimately, retinal gene-targeted NGS was required to identify the underlying cause of disease for individuals within the three families. Results obtained in these families necessitated further genetic and clinical testing of additional family members to determine the complex genetic and phenotypic etiology of each family. Genetic testing of FAM1 (n = 4 affected; 1 n.p.) identified a dominant mutation in RP1 (p.Arg677Ter) that was present for two of the four affected individuals but absent in the proband and the presumed non-penetrant individual. Retinal gene-targeted NGS in the fourth affected family member revealed compound heterozygous mutations in USH2A (p. Cys419Phe, p.Glu767Serfs*21). Genetic testing of FAM2 (n = 3 affected; 1 n.p.) identified three retinal dystrophy genes ( PRPH2 , PRPF8 , and USH2A ) with disease-causing mutations in varying combinations among the affected family members. Genetic testing of FAM3 (n = 7 affected) identified a mutation in PRPH2 (p.Pro216Leu) tracking with disease in six of the seven affected individuals. Additional retinal gene-targeted NGS testing determined that the proband also harbored a multiple exon deletion in the CRX gene likely accounting for her cone-rod phenotype; her son harbored only the mutation in CRX , not the familial mutation in PRPH2 . Multiple genes contributing to the retinal dystrophy genotypes within a family were discovered using retinal gene-targeted NGS. Families with noted examples of phenotypic variation or apparent non-penetrant individuals may offer a clue to suspect complex inheritance. Furthermore, this finding underscores that caution should be taken when attributing a single gene disease-causing mutation (or inheritance pattern) to a family as a whole. Identification of a disease-causing mutation in a proband, even with a clear inheritance pattern in hand, may not be sufficient for targeted, known mutation analysis in other family members.

Barriers and Strategies Related to Qualitative Research on Genetic Ancestry Testing in Indigenous Communities.

PubMed

Blanchard, Jessica W; Tallbull, Gloria; Wolpert, Chantelle; Powell, Jill; Foster, Morris W; Royal, Charmaine

2017-07-01

Conducting genetics-related research with populations that have historically experienced considerable harm and little benefit from genetics research poses unique challenges for understanding community-based perceptions of new genetic technologies. This article identifies challenges and strategies for collecting qualitative data on the perceptions of direct-to-consumer (DTC) Genetic Ancestry tests (GAT) among diverse Indigenous communities. Based on a 3-year project related to perceptions, attitudes, and values associated with genetic ancestry testing among diverse Indigenous communities in Oklahoma, the engagement process revealed specific opportunities to improve the process of qualitative data collection related to GAT, and more broadly, to conduct genetics-related research with Indigenous communities in culturally and methodologically appropriate ways. Priority areas include issues related to participant recruitment and tribal advisory boards, challenges of self-identification as a recruitment mechanism, and the necessity of including Indigenous researchers in all aspects of the research process.

Public Awareness of Direct-to-Consumer Genetic Tests: Findings from the 2013 U.S. Health Information National Trends Survey.

PubMed

Agurs-Collins, Tanya; Ferrer, Rebecca; Ottenbacher, Allison; Waters, Erika A; O'Connell, Mary E; Hamilton, Jada G

2015-12-01

Although the availability of direct-to-consumer (DTC) genetic testing has increased in recent years, the general public's awareness of this testing is not well understood. This study examined levels of public awareness of DTC genetic testing, sources of information about testing, and psychosocial factors associated with awareness of testing in the USA. Data were obtained from the nationally representative 2013 U.S. Health Information National Trends Survey. Guided by a social-cognitive conceptual framework, univariable and multivariable logistic regressions were conducted to identify factors associated with awareness of DTC genetic tests. Of 3185 participants, 35.6% were aware of DTC genetic tests, with the majority learning about these tests through radio, television, and the Internet. In the final adjusted model, participants with annual incomes of $99,999 or less had lower odds of being aware of DTC genetic testing (ORs ranging from 0.46-0.61) than did those participants with incomes of $100,000 or more. The odds of awareness of DTC genetic tests were significantly higher for those who actively seek cancer information (OR=1.91, 95% CI=1.36-2.69), use the Internet (OR=1.81, 95% CI=1.05-3.13), and have high numeracy skills (OR=1.67, 95% CI=1.17-2.38). It will be critical for healthcare researchers and practitioners to understand predictors and consequences of the public's awareness of DTC genetic tests, as well as how such awareness may translate into DTC genetic testing uptake, health behavior change, and ultimately disease prevention.

iGWAS: Integrative Genome-Wide Association Studies of Genetic and Genomic Data for Disease Susceptibility Using Mediation Analysis.

PubMed

Huang, Yen-Tsung; Liang, Liming; Moffatt, Miriam F; Cookson, William O C M; Lin, Xihong

2015-07-01

Genome-wide association studies (GWAS) have been a standard practice in identifying single nucleotide polymorphisms (SNPs) for disease susceptibility. We propose a new approach, termed integrative GWAS (iGWAS) that exploits the information of gene expressions to investigate the mechanisms of the association of SNPs with a disease phenotype, and to incorporate the family-based design for genetic association studies. Specifically, the relations among SNPs, gene expression, and disease are modeled within the mediation analysis framework, which allows us to disentangle the genetic effect on a disease phenotype into two parts: an effect mediated through a gene expression (mediation effect, ME) and an effect through other biological mechanisms or environment-mediated mechanisms (alternative effect, AE). We develop omnibus tests for the ME and AE that are robust to underlying true disease models. Numerical studies show that the iGWAS approach is able to facilitate discovering genetic association mechanisms, and outperforms the SNP-only method for testing genetic associations. We conduct a family-based iGWAS of childhood asthma that integrates genetic and genomic data. The iGWAS approach identifies six novel susceptibility genes (MANEA, MRPL53, LYCAT, ST8SIA4, NDFIP1, and PTCH1) using the omnibus test with false discovery rate less than 1%, whereas no gene using SNP-only analyses survives with the same cut-off. The iGWAS analyses further characterize that genetic effects of these genes are mostly mediated through their gene expressions. In summary, the iGWAS approach provides a new analytic framework to investigate the mechanism of genetic etiology, and identifies novel susceptibility genes of childhood asthma that were biologically meaningful. © 2015 WILEY PERIODICALS, INC.

A collaborative approach to cancer risk assessment services using genetic counselor extenders in a multi-system community hospital.

PubMed

Cohen, Stephanie A; Nixon, Dawn M

2016-10-01

This study aimed to evaluate a unique approach to cancer risk assessment for improved access by smaller rural communities. Local, on-site nurse navigators were trained and utilized as genetic counselor extenders (GCEs) to provide basic risk assessment and offer BRCA1/2 genetic testing to select patients based on a triaging process in collaboration with board-certified genetic counselors (CGCs). From August 2012 to July 2014, 12,477 family history questionnaires representing 8937 unique patients presenting for a screening mammogram or new oncology appointment were triaged. Of these, 8.2 % patients were identified at increased risk for hereditary breast cancer, and 4.2 % were identified at increased risk for other hereditary causes of cancer. A total of 75 of 1130 at-risk patients identified (6.6 %) completed a genetic risk assessment appointment; 23 with a GCE and 52 with a CGC. A review of the completed genetic test requisition forms from a 9-year pre-collaboration time period found that 16 % (20/125) did not appear to meet genetic testing criteria. Overall, there was a fourfold increase in patients accessing genetic services in this study period compared to the pre-collaboration time period. Efficiency of this model was assessed by determining time spent by the CGC in all activities related to the collaboration, which amounted to approximately 16 h/month. Adjustments have been made and the program continues to be monitored for opportunities to improve efficiency. This study demonstrates the feasibility of CGCs and GCEs collaborating to improve access to quality services in an efficient manner.

Genetic enhancement in sport: just another form of doping?

PubMed

Mehlman, Maxwell J

2012-12-01

Patented genetic technologies such as the ACTN3 genetic test are adding a new dimension to the types of performance enhancement available to elite athletes. Organized sports organizations and governments are seeking to prevent athletes' use of biomedical enhancements. This paper discusses how these interdiction efforts will affect the use and availability of genetic technologies that can enhance athletic performance. The paper provides a working definition of enhancement, and in light of that definition and the concerns of the sports community, reviews genetic enhancement as a result of varied technologies, including, genetic testing to identify innate athletic ability, performance-enhancing drugs developed with genetic science and technology, pharmacogenetics, enhancement through reproductive technologies, somatic gene transfer, and germ line gene transfer.

Population structure and genetic diversity of black redhorse (Moxostoma duquesnei) in a highly fragmented watershed

USGS Publications Warehouse

Reid, S.M.; Wilson, C.C.; Mandrak, N.E.; Carl, L.M.

2008-01-01

Dams have the potential to affect population size and connectivity, reduce genetic diversity, and increase genetic differences among isolated riverine fish populations. Previous research has reported adverse effects on the distribution and demographics of black redhorse (Moxostoma duquesnei), a threatened fish species in Canada. However, effects on genetic diversity and population structure are unknown. We used microsatellite DNA markers to assess the number of genetic populations in the Grand River (Ontario) and to test whether dams have resulted in a loss of genetic diversity and increased genetic differentiation among populations. Three hundred and seventy-seven individuals from eight Grand River sites were genotyped at eight microsatellite loci. Measures of genetic diversity were moderately high and not significantly different among populations; strong evidence of recent population bottlenecks was not detected. Pairwise FST and exact tests identified weak (global FST = 0.011) but statistically significant population structure, although little population structuring was detected using either genetic distances or an individual-based clustering method. Neither geographic distance nor the number of intervening dams were correlated with pairwise differences among populations. Tests for regional equilibrium indicate that Grand River populations were either in equilibrium between gene flow and genetic drift or that gene flow is more influential than drift. While studies on other species have identified strong dam-related effects on genetic diversity and population structure, this study suggests that barrier permeability, river fragment length and the ecological characteristics of affected species can counterbalance dam-related effects. ?? 2007 Springer Science+Business Media B.V.

Individual and family characteristics associated with BRCA1/2 genetic testing in high-risk families.

PubMed

Katapodi, Maria C; Northouse, Laurel L; Milliron, Kara J; Liu, Guipeng; Merajver, Sofia D

2013-06-01

Little is known about family members' interrelated decisions to seek genetic testing for breast cancer susceptibility. The specific aims of this cross-sectional, descriptive, cohort study were (i) to examine whether individual and family characteristics have a direct effect on women's decisions to use genetic testing for hereditary susceptibility to breast cancer and (ii) to explore whether family characteristics moderate the relationships between individual characteristics and the decision to use genetic testing. Participants were women (>18 years old) who (i) received genetic testing for hereditary breast cancer and who agreed to invite one of their female relatives into the study and (ii) female relatives who had NOT obtained genetic testing and were identified by pedigree analysis as having >10% chances of hereditary susceptibility to breast cancer. The final sample consisted of 168 English-speaking, family dyads who completed self-administered, mailed surveys with validated instruments. Multivariate conditional logistic regression analyses showed that the proposed model explained 62% of the variance in genetic testing. The factors most significantly associated with genetic testing were having a personal history of cancer; perceiving genetic testing to have more benefits than barriers; having greater family hardiness; and perceiving fewer negative consequences associated with a breast cancer diagnosis. No significant interaction effects were observed. Findings suggest that both individual and family characteristics are associated with the decision to obtain genetic testing for hereditary breast cancer; hence, there is a need for interventions that foster a supportive family environment for patients and their high-risk relatives. Copyright © 2012 John Wiley & Sons, Ltd.

Impact of Genetics on the Clinical Management of Channelopathies

PubMed Central

Schwartz, Peter J.; Ackerman, Michael J.; George, Alfred L.; Wilde, Arthur A.M.

2013-01-01

There are few areas in cardiology where the impact of genetics and of genetic testing on clinical management has been as great as in cardiac channelopathies, arrhythmic disorders of genetic origin related to the ionic control of the cardiac action potential. Among the growing number of diseases identified as channelopathies, three are sufficiently prevalent to represent significant clinical and societal problems and to warrant adequate understanding by practicing cardiologists: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome. This review will focus selectively on the impact of genetic discoveries on clinical management of these three diseases. For each disorder, we will discuss to what extent genetic knowledge and clinical genetic test results modify the way cardiologists should approach and manage affected patients. We will also address the optimal use of genetic testing including its potential limitations and the potential medico-legal implications when such testing is not performed. We will highlight how important can be to understand the ways by which genotype can impact clinical manifestations, risk stratification, and responses to the therapy. We will also illustrate the close bridge between molecular biology and clinical medicine, and will emphasize that consideration of the genetic basis for these hereditable arrhythmia syndromes, as well as the proper use and interpretation of clinical genetic testing, should remain the standard-of-care. PMID:23684683

Genetic testing in congenital heart disease: A clinical approach

PubMed Central

Chaix, Marie A; Andelfinger, Gregor; Khairy, Paul

2016-01-01

Congenital heart disease (CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient follow-up. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel. PMID:26981213

Breast cancer genetic testing: more than a medical management tool.

PubMed

Schroeder, Dawn; Conroy, Sherrill A

2015-10-01

Knowing whether a harmful hereditary mutation exists in BRCA1 and BRCA2 can enable women to make informed decisions regarding surveillance and surgery options to manage risk. Given the attention in the media about BRCA genetic testing, nurses need to revisit how this knowledge may affect a woman's sense of self and the forces that may influence this decision. This article aims to understand how complex the decision to undergo genetic testing may be for some women by exploring the impact of genetic knowledge on the self, changes to customary definitions for health and illness, and ethical issues and social forces that may influence genetic testing decisions. A review of the literature was undertaken to understand how genetic knowledge may alter meanings attached to the breast and how health is defined, and to identify ethical concerns and social forces that may affect a woman's decision to undergo or decline an offer for genetic testing. An understanding and awareness of the potential benefits and harms of BRCA1 and BRCA2 genetic testing, as well as the social forces that may influence a woman's decision to undergo or decline an offer for genetic testing and the commitment to remain open to the uniqueness of each woman's situation, may enhance the nurse-patient relationship and result in a decision that is ethically in the best interest of the patient.

Whole-genome sequencing expands diagnostic utility and improves clinical management in paediatric medicine

PubMed Central

Stavropoulos, Dimitri J; Merico, Daniele; Jobling, Rebekah; Bowdin, Sarah; Monfared, Nasim; Thiruvahindrapuram, Bhooma; Nalpathamkalam, Thomas; Pellecchia, Giovanna; Yuen, Ryan K C; Szego, Michael J; Hayeems, Robin Z; Shaul, Randi Zlotnik; Brudno, Michael; Girdea, Marta; Frey, Brendan; Alipanahi, Babak; Ahmed, Sohnee; Babul-Hirji, Riyana; Porras, Ramses Badilla; Carter, Melissa T; Chad, Lauren; Chaudhry, Ayeshah; Chitayat, David; Doust, Soghra Jougheh; Cytrynbaum, Cheryl; Dupuis, Lucie; Ejaz, Resham; Fishman, Leona; Guerin, Andrea; Hashemi, Bita; Helal, Mayada; Hewson, Stacy; Inbar-Feigenberg, Michal; Kannu, Peter; Karp, Natalya; Kim, Raymond H; Kronick, Jonathan; Liston, Eriskay; MacDonald, Heather; Mercimek-Mahmutoglu, Saadet; Mendoza-Londono, Roberto; Nasr, Enas; Nimmo, Graeme; Parkinson, Nicole; Quercia, Nada; Raiman, Julian; Roifman, Maian; Schulze, Andreas; Shugar, Andrea; Shuman, Cheryl; Sinajon, Pierre; Siriwardena, Komudi; Weksberg, Rosanna; Yoon, Grace; Carew, Chris; Erickson, Raith; Leach, Richard A; Klein, Robert; Ray, Peter N; Meyn, M Stephen; Scherer, Stephen W; Cohn, Ronald D; Marshall, Christian R

2016-01-01

The standard of care for first-tier clinical investigation of the aetiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy-number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion–deletions (indels) and single-nucleotide variant (SNV) mutations. Whole-genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilised WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a fourfold increase in diagnostic rate over CMA (8%; P value=1.42E−05) alone and more than twofold increase in CMA plus targeted gene sequencing (13%; P value=0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harbouring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis. PMID:28567303

Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine.

PubMed

Stavropoulos, Dimitri J; Merico, Daniele; Jobling, Rebekah; Bowdin, Sarah; Monfared, Nasim; Thiruvahindrapuram, Bhooma; Nalpathamkalam, Thomas; Pellecchia, Giovanna; Yuen, Ryan K C; Szego, Michael J; Hayeems, Robin Z; Shaul, Randi Zlotnik; Brudno, Michael; Girdea, Marta; Frey, Brendan; Alipanahi, Babak; Ahmed, Sohnee; Babul-Hirji, Riyana; Porras, Ramses Badilla; Carter, Melissa T; Chad, Lauren; Chaudhry, Ayeshah; Chitayat, David; Doust, Soghra Jougheh; Cytrynbaum, Cheryl; Dupuis, Lucie; Ejaz, Resham; Fishman, Leona; Guerin, Andrea; Hashemi, Bita; Helal, Mayada; Hewson, Stacy; Inbar-Feigenberg, Michal; Kannu, Peter; Karp, Natalya; Kim, Raymond; Kronick, Jonathan; Liston, Eriskay; MacDonald, Heather; Mercimek-Mahmutoglu, Saadet; Mendoza-Londono, Roberto; Nasr, Enas; Nimmo, Graeme; Parkinson, Nicole; Quercia, Nada; Raiman, Julian; Roifman, Maian; Schulze, Andreas; Shugar, Andrea; Shuman, Cheryl; Sinajon, Pierre; Siriwardena, Komudi; Weksberg, Rosanna; Yoon, Grace; Carew, Chris; Erickson, Raith; Leach, Richard A; Klein, Robert; Ray, Peter N; Meyn, M Stephen; Scherer, Stephen W; Cohn, Ronald D; Marshall, Christian R

2016-01-13

The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. Whole genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilized WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counseling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.

Genetic susceptibility testing for neurodegenerative diseases: Ethical and practice issues

PubMed Central

Roberts, J. Scott; Uhlmann, Wendy R.

2013-01-01

As the genetics of neurodegenerative disease become better understood, opportunities for genetic susceptibility testing for at-risk individuals will increase. Such testing raises important ethical and practice issues related to test access, informed consent, risk estimation and communication, return of results, and policies to prevent genetic discrimination. The advent of direct-to-consumer genetic susceptibility testing for various neurodegenerative disorders (including Alzheimer’s disease, Parkinson’s disease, and certain prion diseases) means that ethical and practical challenges must be faced not only in traditional research and clinical settings, but also in broader society. This review addresses several topics relevant to the development and implementation of genetic susceptibility tests across research, clinical, and consumer settings; these include appropriate indications for testing, the implications of different methods for disclosing test results, clinical versus personal utility of risk information, psychological and behavioral responses to test results, testing of minors, genetic discrimination, and ethical dilemmas posed by whole-genome sequencing. We also identify future areas of likely growth in the field, including pharmacogenomics and genetic screening for individuals considering or engaged in activities that pose elevated risk of brain injury (e.g., football players, military personnel). APOE gene testing for risk of Alzheimer’s disease is used throughout as an instructive case example, drawing upon the authors’ experience as investigators in a series of multisite randomized clinical trials that have examined the impact of disclosing APOE genotype status to interested individuals (e.g., first-degree relatives, persons with mild cognitive impairment). PMID:23583530

Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors.

PubMed

Goldman, Jill S; Hahn, Susan E; Catania, Jennifer Williamson; LaRusse-Eckert, Susan; Butson, Melissa Barber; Rumbaugh, Malia; Strecker, Michelle N; Roberts, J Scott; Burke, Wylie; Mayeux, Richard; Bird, Thomas

2011-06-01

Alzheimer disease is the most common cause of dementia. It occurs worldwide and affects all ethnic groups. The incidence of Alzheimer disease is increasing due, in part, to increased life expectancy and the aging baby boomer generation. The average lifetime risk of developing Alzheimer disease is 10-12%. This risk at least doubles with the presence of a first-degree relative with the disorder. Despite its limited utility, patients express concern over their risk and, in some instances, request testing. Furthermore, research has demonstrated that testing individuals for apolipoprotein E can be valuable and safe in certain contexts. However, because of the complicated genetic nature of the disorder, few clinicians are prepared to address the genetic risks of Alzheimer disease with their patients. Given the increased awareness in family history thanks to family history campaigns, the increasing incidence of Alzheimer disease, and the availability of direct to consumer testing, patient requests for information is increasing. This practice guideline provides clinicians with a framework for assessing their patients' genetic risk for Alzheimer disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for AD.

Using Zebrafish to Test the Genetic Basis of Human Craniofacial Diseases.

PubMed

Machado, R Grecco; Eames, B Frank

2017-10-01

Genome-wide association studies (GWASs) opened an innovative and productive avenue to investigate the molecular basis of human craniofacial disease. However, GWASs identify candidate genes only; they do not prove that any particular one is the functional villain underlying disease or just an unlucky genomic bystander. Genetic manipulation of animal models is the best approach to reveal which genetic loci identified from human GWASs are functionally related to specific diseases. The purpose of this review is to discuss the potential of zebrafish to resolve which candidate genetic loci are mechanistic drivers of craniofacial diseases. Many anatomic, embryonic, and genetic features of craniofacial development are conserved among zebrafish and mammals, making zebrafish a good model of craniofacial diseases. Also, the ability to manipulate gene function in zebrafish was greatly expanded over the past 20 y, enabling systems such as Gateway Tol2 and CRISPR-Cas9 to test gain- and loss-of-function alleles identified from human GWASs in coding and noncoding regions of DNA. With the optimization of genetic editing methods, large numbers of candidate genes can be efficiently interrogated. Finding the functional villains that underlie diseases will permit new treatments and prevention strategies and will increase understanding of how gene pathways operate during normal development.

Unique genetic loci identified for emotional behavior in control and chronic stress conditions.

PubMed

Carhuatanta, Kimberly A K; Shea, Chloe J A; Herman, James P; Jankord, Ryan

2014-01-01

An individual's genetic background affects their emotional behavior and response to stress. Although studies have been conducted to identify genetic predictors for emotional behavior or stress response, it remains unknown how prior stress history alters the interaction between an individual's genome and their emotional behavior. Therefore, the purpose of this study is to identify chromosomal regions that affect emotional behavior and are sensitive to stress exposure. We utilized the BXD behavioral genetics mouse model to identify chromosomal regions that predict fear learning and emotional behavior following exposure to a control or chronic stress environment. 62 BXD recombinant inbred strains and C57BL/6 and DBA/2 parental strains underwent behavioral testing including a classical fear conditioning paradigm and the elevated plus maze. Distinct quantitative trait loci (QTLs) were identified for emotional learning, anxiety and locomotion in control and chronic stress populations. Candidate genes, including those with already known functions in learning and stress were found to reside within the identified QTLs. Our data suggest that chronic stress history reveals novel genetic predictors of emotional behavior.

Unique genetic loci identified for emotional behavior in control and chronic stress conditions

PubMed Central

Carhuatanta, Kimberly A. K.; Shea, Chloe J. A.; Herman, James P.; Jankord, Ryan

2014-01-01

An individual's genetic background affects their emotional behavior and response to stress. Although studies have been conducted to identify genetic predictors for emotional behavior or stress response, it remains unknown how prior stress history alters the interaction between an individual's genome and their emotional behavior. Therefore, the purpose of this study is to identify chromosomal regions that affect emotional behavior and are sensitive to stress exposure. We utilized the BXD behavioral genetics mouse model to identify chromosomal regions that predict fear learning and emotional behavior following exposure to a control or chronic stress environment. 62 BXD recombinant inbred strains and C57BL/6 and DBA/2 parental strains underwent behavioral testing including a classical fear conditioning paradigm and the elevated plus maze. Distinct quantitative trait loci (QTLs) were identified for emotional learning, anxiety and locomotion in control and chronic stress populations. Candidate genes, including those with already known functions in learning and stress were found to reside within the identified QTLs. Our data suggest that chronic stress history reveals novel genetic predictors of emotional behavior. PMID:25374516

Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation.

PubMed

Kapplinger, Jamie D; Pundi, Krishna N; Larson, Nicholas B; Callis, Thomas E; Tester, David J; Bikker, Hennie; Wilde, Arthur A M; Ackerman, Michael J

2018-02-01

Pathogenic RYR2 variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign RYR2 variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of the RYR2 genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability. Frequency and location comparisons were made for RYR2 variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield of RYR2 variants was examined. Six in silico tools were assessed using patient- and control-derived variants. A total of 18.2% (218/1200) of patients referred for commercial testing hosted rare RYR2 variants, statistically less than the 59% (46/78) yield among clinically definite cases, resulting in a much higher potential genetic false discovery rate among referrals considering the 3.2% background rate of rare, benign RYR2 variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novel RYR2 variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation. Current expert recommendations have resulted in increased use of RYR2 genetic testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2% background rate that confounds RYR2 variant interpretation. © 2018 American Heart Association, Inc.

Genetics and Personal Insurance: the Perspectives of Canadian Cancer Genetic Counselors.

PubMed

Lane, Michelle; Ngueng Feze, Ida; Joly, Yann

2015-12-01

Genetic discrimination in the context of genetic testing has been identified as a concern for symptomatic and asymptomatic individuals for more than three decades. Genetic counselors are often the health care professionals who discuss risks and benefits of genetic testing with patients, thereby making them most appropriate to address patient concerns about genetics and personal insurance (i.e., life, life as related to mortgage or group insurance, disability, critical illness and travel). A pilot study was conducted to ascertain the current practices of Canadian cancer genetic counselors in regard to their discussions with patients about genetic testing and access to personal insurance. Among the 36 counselors surveyed, 100 % reported discussing the issue of genetic testing and personal insurance with their patients. Several factors influenced the content, depth and length of these discussions including age, cancer status, family members, and patients' current and future insurance needs. Counselors reported discussing with patients the possible impact of genetic test results on access to personal insurance, possible access and use of patient genetic information by insurance companies, and whom patients should contact if they have additional questions. The most commonly reported inquiries from patients included questions about the possible impact of genetic testing on their ability to obtain insurance, and the insurability of family members. While 28 % of counselors reported having been contacted by an insurer requesting access to patient information, only one counselor was aware of or could recall the outcome of such a request. This pilot study revealed that issues concerning genetics and personal insurance are commonly discussed in Canadian cancer genetic counseling sessions. Counselors furthermore expressed a need for additional educational resources on the topic of genetics and personal insurance for themselves and their patients.

Improving nurse practitioners' competence with genetics: Effectiveness of an online course.

PubMed

Whitt, Karen J; Macri, Charles; O'Brien, Travis J; Wright, Stephanie

2016-03-01

The purpose of this study was to assess the effectiveness of an online genetics course for improving nurse practitioners' knowledge, competence, and comfort with genetic principles and their application to clinical practice. A genetics knowledge test and survey were administered to 232 nurse practitioner students, between 2011 and 2013, before and after completing a 15-week online genetics course taught by a multidisciplinary team of instructors at a private east coast U.S. university. The 65-item survey allowed participants to rate competence regarding genetic principles, diseases, and terminology, as well as comfort performing various clinical tasks related to genetics. The 21-item knowledge test contained multiple choice questions regarding core competencies in genetics. Paired t-tests were used to compare mean pre- and postscores. Participants significantly increased postcourse knowledge (p < .001) and comfort with genetic core competencies and clinical skills related to genetics (p < .001). This study demonstrates the effectiveness of an online genetics course for increasing nurse practitioners' knowledge, competence, and confidence with genetics and identifies specific topics educators should consider when designing curricula for nurse practitioners. Findings from this study can improve genetics education for nurse practitioners, which will in turn improve patient health. ©2015 American Association of Nurse Practitioners.

Genetic tests obtainable through pharmacies: the good, the bad, and the ugly.

PubMed

Patrinos, George P; Baker, Darrol J; Al-Mulla, Fahd; Vasiliou, Vasilis; Cooper, David N

2013-07-08

Genomic medicine seeks to exploit an individual's genomic information in the context of guiding the clinical decision-making process. In the post-genomic era, a range of novel molecular genetic testing methodologies have emerged, allowing the genetic testing industry to grow at a very rapid pace. As a consequence, a considerable number of different private diagnostic testing laboratories now provide a wide variety of genetic testing services, often employing a direct-to-consumer (DTC) business model to identify mutations underlying (or associated with) common Mendelian disorders, to individualize drug response, to attempt to determine an individual's risk of a multitude of complex (multifactorial) diseases, or even to determine a person's identity. Recently, we have noted a novel trend in the provision of private molecular genetic testing services, namely saliva and buccal swab collection kits (for deoxyribonucleic acid (DNA) isolation) being offered for sale over the counter by pharmacies. This situation is somewhat different from the standard DTC genetic testing model, since pharmacists are healthcare professionals who are supposedly qualified to give appropriate advice to their clients. There are, however, a number of issues to be addressed in relation to the marketing of DNA collection kits for genetic testing through pharmacies, namely a requirement for regulatory clearance, the comparative lack of appropriate genetics education of the healthcare professionals involved, and most importantly, the lack of awareness on the part of both the patients and the general public with respect to the potential benefits or otherwise of the various types of genetic test offered, which may result in confusion as to which test could be beneficial in their own particular case. We believe that some form of genetic counseling should ideally be integrated into, and made inseparable from, the genetic testing process, while pharmacists should be obliged to receive some basic training about the genetic tests that they offer for sale.

Influence of race/ethnicity on genetic counseling and testing for hereditary breast and ovarian cancer.

PubMed

Forman, Andrea D; Hall, Michael J

2009-01-01

Risk assessment coupled with genetic counseling and testing for the cancer predisposition genes BRCA1 and BRCA2 (BRCA1/2) has become an integral element of comprehensive patient evaluation and cancer risk management in the United States for individuals meeting high-risk criteria for hereditary breast and ovarian cancer (HBOC). For mutation carriers, several options for risk modification have achieved substantial reductions in future cancer risk. However, several recent studies have shown lower rates of BRCA1/2 counseling and testing among minority populations. Here, we explore the role of race/ethnicity in cancer risk assessment, genetic counseling and genetic testing for HBOC and the BRCA1/2 cancer predisposition genes. Barriers to genetic services related to race/ethnicity and underserved populations, including socioeconomic barriers (e.g., time, access, geographic, language/cultural, awareness, cost) and psychosocial barriers (e.g., medical mistrust, perceived disadvantages to genetic services), as well as additional barriers to care once mutation carriers are identified, will be reviewed.

Should we genetically test everyone for haemochromatosis?

PubMed

Allen, K; Williamson, R

1999-04-01

The increasing availability of DNA-based diagnostic tests has raised issues about whether these should be applied to the population at large in order to identify, treat or prevent a range of diseases. DNA tests raise concerns in the community for several reasons. There is the possibility of stigmatisation and discrimination between those who test positive and those who don't. High-risk individuals may be identified for whom no proven effective intervention is possible, or conversely may test "positive" for a disease that does not eventuate. Controversy concerning prenatal diagnosis and termination of affected pregnancies may arise. Haemochromatosis, however, is a disease that is not only treatable but also preventable if those at high risk are identified presymptomatically. This paper will identify and discuss key issues regarding DNA-based population screening for haemochromatosis, and argue that population-based genetic screening for haemochromatosis should be supported when a number of contentious issues are addressed. In the context of a health system with limited resources haemochromatosis is the paradigm of a disorder where there is an ethical and clinical imperative to encourage presymptomatic DNA testing for all in ethnically relevant communities.

Creation and Implementation of an Environmental Scan to Assess Cancer Genetics Services at Three Oncology Care Settings.

PubMed

Bednar, Erica M; Walsh, Michael T; Baker, Ellen; Muse, Kimberly I; Oakley, Holly D; Krukenberg, Rebekah C; Dresbold, Cara S; Jenkinson, Sandra B; Eppolito, Amanda L; Teed, Kelly B; Klein, Molly H; Morman, Nichole A; Bowdish, Elizabeth C; Russ, Pauline; Wise, Emaline E; Cooper, Julia N; Method, Michael W; Henson, John W; Grainger, Andrew V; Arun, Banu K; Lu, Karen H

2018-05-16

An environmental scan (ES) is an efficient mixed-methods approach to collect and interpret relevant data for strategic planning and project design. To date, the ES has not been used nor evaluated in the clinical cancer genetics setting. We created and implemented an ES to inform the design of a quality improvement (QI) project to increase the rates of adherence to national guidelines for cancer genetic counseling and genetic testing at three unique oncology care settings (OCS). The ES collected qualitative and quantitative data from reviews of internal processes, past QI efforts, the literature, and each OCS. The ES used a data collection form and semi-structured interviews to aid in data collection. The ES was completed within 6 months, and sufficient data were captured to identify opportunities and threats to the QI project's success, as well as potential barriers to, and facilitators of guideline-based cancer genetics services at each OCS. Previously unreported barriers were identified, including inefficient genetic counseling appointment scheduling processes and the inability to track referrals, genetics appointments, and genetic test results within electronic medical record systems. The ES was a valuable process for QI project planning at three OCS and may be used to evaluate genetics services in other settings.

Familial Hypercholesterolemia: A Systematic Review of Guidelines on Genetic Testing and Patient Management.

PubMed

Migliara, Giuseppe; Baccolini, Valentina; Rosso, Annalisa; D'Andrea, Elvira; Massimi, Azzurra; Villari, Paolo; De Vito, Corrado

2017-01-01

Familial hypercholesterolemia (FH) is an autosomal-dominant hereditary disorder of lipid metabolism that causes lifelong exposure to increased LDL levels resulting in premature coronary heart disease and, if untreated, death. Recent studies have shown its prevalence to be higher than previously considered, which has important implications for the mortality and morbidity of associated cardiovascular disease (CVD). Several clinical tools are used worldwide to help physicians diagnose FH, but nevertheless most patients remain undetected. This systematic review of guidelines aims to assess the role of genetic testing in the screening, diagnosis, and management of patients affected by heterozygous or homozygous FH and to identify related health-care pathways. We performed a systematic review of the literature; inclusion criteria were English or Italian guidelines focusing on genetic testing. The guidelines were included and evaluated for their content and development process using the Appraisal of Guidelines for Research and Evaluation II instrument. Ten guidelines were considered eligible, and all were judged to be of good quality, with slight differences among them. The most common indications for performing genetic tests were high levels of cholesterol, or physical findings consistent with lipid disorder, in the subject or in the family history. Subsequent screening of family members was indicated when a mutation had been identified in the index patient. Regarding patient management, the various guidelines agreed that intensive treatment with lipid-lowering medications should begin as quickly as possible and that lifestyle modifications should be an integral part of the therapy. Since the early detection of affected patients is beneficial for effective prevention of CVD, genetic testing is particularly useful for identifying family members via cascade screening and for distinguishing between heterozygous and homozygous individuals, the latter of which require more extreme therapeutic intervention.

Wolcott-Rallison Syndrome Is the Most Common Genetic Cause of Permanent Neonatal Diabetes in Consanguineous Families

PubMed Central

Rubio-Cabezas, Oscar; Patch, Ann-Marie; Minton, Jayne A. L.; Flanagan, Sarah E.; Edghill, Emma L.; Hussain, Khalid; Balafrej, Amina; Deeb, Asma; Buchanan, Charles R.; Jefferson, Ian G.; Mutair, Angham; Hattersley, Andrew T.; Ellard, Sian

2009-01-01

Context and Objective: Mutations in EIF2AK3 cause Wolcott-Rallison syndrome (WRS), a rare recessive disorder characterized by early-onset diabetes, skeletal abnormalities, and liver dysfunction. Although early diagnosis is important for clinical management, genetic testing is generally performed after the full clinical picture develops. We aimed to identify patients with WRS before any other abnormalities apart from diabetes are present and study the overall frequency of WRS among patients with permanent neonatal diabetes. Research Design and Methods: The coding regions of EIF2AK3 were sequenced in 34 probands with infancy-onset diabetes with a clinical phenotype suggestive of WRS (n = 28) or homozygosity at the WRS locus (n = 6). Results: Twenty-five probands (73.5%) were homozygous or compound heterozygous for mutations in EIF2AK3. Twenty of the 26 mutations identified were novel. Whereas a diagnosis of WRS was suspected before genetic testing in 22 probands, three patients with apparently isolated diabetes were diagnosed after identifying a large homozygous region encompassing EIF2AK3. In contrast to nonconsanguineous pedigrees, mutations in EIF2AK3 are the most common known genetic cause of diabetes among patients born to consanguineous parents (24 vs. < 2%). Age at diabetes onset and birth weight might be used to prioritize genetic testing in the latter group. Conclusions: WRS is the most common cause of permanent neonatal diabetes mellitus in consanguineous pedigrees. In addition to testing patients with a definite clinical diagnosis, EIF2AK3 should be tested in patients with isolated neonatal diabetes diagnosed after 3 wk of age from known consanguineous families, isolated populations, or countries in which inbreeding is frequent. PMID:19837917

Functional DNA: Teaching Infinite Series through Genetic Analogy

ERIC Educational Resources Information Center

Kowalski, R. Travis

2011-01-01

This article presents an extended analogy that connects infinite sequences and series to the science of genetics, by identifying power series as "DNA for a function." This analogy allows standard topics such as convergence tests or Taylor approximations to be recast in a "forensic" light as mathematical analogs of genetic concepts such as DNA…

Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects.

PubMed

Busch, Robert; Hobbs, Brian D; Zhou, Jin; Castaldi, Peter J; McGeachie, Michael J; Hardin, Megan E; Hawrylkiewicz, Iwona; Sliwinski, Pawel; Yim, Jae-Joon; Kim, Woo Jin; Kim, Deog K; Agusti, Alvar; Make, Barry J; Crapo, James D; Calverley, Peter M; Donner, Claudio F; Lomas, David A; Wouters, Emiel F; Vestbo, Jørgen; Tal-Singer, Ruth; Bakke, Per; Gulsvik, Amund; Litonjua, Augusto A; Sparrow, David; Paré, Peter D; Levy, Robert D; Rennard, Stephen I; Beaty, Terri H; Hokanson, John; Silverman, Edwin K; Cho, Michael H

2017-07-01

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 × 10 -8 ) and PPP4R4/SERPINA1 (P = 1.01 × 10 -8 ) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, ∼0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.

What factors may influence psychological well being at three months and one year post BRCA genetic result disclosure?

PubMed

Bosch, Nina; Junyent, Núria; Gadea, Neus; Brunet, Joan; Ramon y Cajal, Teresa; Torres, Asunción; Graña, Begoña; Velasco, Angela; Darder, Esther; Mensa, Irene; Balmaña, Judith

2012-12-01

Genetic testing for breast cancer predisposition has been available in the clinical practice for more than a decade. How the result of genetic testing affects the psychological well-being of the individuals is an under-researched area in many populations. Follow-up analysis of psychological well-being via HADS scale was performed in 364 individuals at 3 months and 1 year after the disclosure of BRCA1/2 genetic result. We analyzed potential predictors for pathological anxiety and variables associated to the variation of HADS scores over time. At pre-test only 16% and 4% of individuals presented symptoms of anxiety and depression, respectively. Having a prior diagnosis of cancer and presenting a pathological HADS-A score at the baseline were associated with clinically significant anxiety scores at one year, but the genetic test result was not. Thus, BRCA genetic testing does not influence short and long term anxiety and depression levels among those identified as mutation carriers. It is our task to demystify the allegedly negative impact of BRCA testing on psychological well being to increase the uptake of genetic testing and benefit those who are at high risk of developing breast, ovarian and prostate cancer. Copyright © 2012 Elsevier Ltd. All rights reserved.

Testing the Structure of Hydrological Models using Genetic Programming

NASA Astrophysics Data System (ADS)

Selle, B.; Muttil, N.

2009-04-01

Genetic Programming is able to systematically explore many alternative model structures of different complexity from available input and response data. We hypothesised that genetic programming can be used to test the structure hydrological models and to identify dominant processes in hydrological systems. To test this, genetic programming was used to analyse a data set from a lysimeter experiment in southeastern Australia. The lysimeter experiment was conducted to quantify the deep percolation response under surface irrigated pasture to different soil types, water table depths and water ponding times during surface irrigation. Using genetic programming, a simple model of deep percolation was consistently evolved in multiple model runs. This simple and interpretable model confirmed the dominant process contributing to deep percolation represented in a conceptual model that was published earlier. Thus, this study shows that genetic programming can be used to evaluate the structure of hydrological models and to gain insight about the dominant processes in hydrological systems.

Dilated Cardiomyopathy: Genetic Determinants and Mechanisms.

PubMed

McNally, Elizabeth M; Mestroni, Luisa

2017-09-15

Nonischemic dilated cardiomyopathy (DCM) often has a genetic pathogenesis. Because of the large number of genes and alleles attributed to DCM, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of DCM, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to DCM and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of DCM, especially where arrhythmia risk is increased, and ultimately contribute to clinical management. © 2017 American Heart Association, Inc.

The changing landscape of genetic testing and its impact on clinical and laboratory services and research in Europe.

PubMed

Hastings, Ros; de Wert, Guido; Fowler, Brian; Krawczak, Michael; Vermeulen, Eric; Bakker, Egbert; Borry, Pascal; Dondorp, Wybo; Nijsingh, Niels; Barton, David; Schmidtke, Jörg; van El, Carla G; Vermeesch, Joris; Stol, Yrrah; Carmen Howard, Heidi; Cornel, Martina C

2012-09-01

The arrival of new genetic technologies that allow efficient examination of the whole human genome (microarray, next-generation sequencing) will impact upon both laboratories (cytogenetic and molecular genetics in the first instance) and clinical/medical genetic services. The interpretation of analytical results in terms of their clinical relevance and the predicted health status poses a challenge to both laboratory and clinical geneticists, due to the wealth and complexity of the information obtained. There is a need to discuss how to best restructure the genetic services logistically and to determine the clinical utility of genetic testing so that patients can receive appropriate advice and genetic testing. To weigh up the questions and challenges of the new genetic technologies, the European Society of Human Genetics (ESHG) held a series of workshops on 10 June 2010 in Gothenburg. This was part of an ESHG satellite symposium on the 'Changing landscape of genetic testing', co-organized by the ESHG Genetic Services Quality and Public and Professional Policy Committees. The audience consisted of a mix of geneticists, ethicists, social scientists and lawyers. In this paper, we summarize the discussions during the workshops and present some of the identified ways forward to improve and adapt the genetic services so that patients receive accurate and relevant information. This paper covers ethics, clinical utility, primary care, genetic services and the blurring boundaries between healthcare and research.

Towards a systematic nationwide screening strategy for MODY.

PubMed

Shields, Beverley; Colclough, Kevin

2017-04-01

MODY is an early-onset monogenic form of diabetes. Correctly identifying MODY is of considerable importance as diagnosing the specific genetic subtype can inform the optimal treatment, with many patients being able to discontinue unnecessary insulin treatment. Diagnostic molecular genetic testing to confirm MODY is expensive, so screening strategies are required to identify the most appropriate patients for testing. In this issue of Diabetologia, Johansson and colleagues (DOI 10.1007/s00125-016-4167-1 ) describe a nationwide systematic screening approach to identify individuals with MODY in the paediatric age range. They focused testing on patients negative for both GAD and islet antigen 2 (IA-2) islet autoantibodies, thereby ruling out those with markers of type 1 diabetes, the most common form of diabetes in this age group. This commentary discusses the advantages and limitations of the approach, and the caution required when interpreting variants of uncertain pathogenicity identified from testing whole populations rather than targeting only patients with a strong MODY phenotype.

Randomized trial of proactive rapid genetic counseling versus usual care for newly diagnosed breast cancer patients.

PubMed

Schwartz, Marc D; Peshkin, Beth N; Isaacs, Claudine; Willey, Shawna; Valdimarsdottir, Heiddis B; Nusbaum, Rachel; Hooker, Gillian; O'Neill, Suzanne; Jandorf, Lina; Kelly, Scott P; Heinzmann, Jessica; Zidell, Aliza; Khoury, Katia

2018-08-01

Breast cancer patients who carry BRCA1/BRCA2 gene mutations may consider bilateral mastectomy. Having bilateral mastectomy at the time of diagnosis not only reduces risk of a contralateral breast cancer, but can eliminate the need for radiation therapy and yield improved reconstruction options. However, most patients do not receive genetic counseling or testing at the time of their diagnosis. In this trial, we tested proactive rapid genetic counseling and testing (RGCT) in newly diagnosed breast cancer patients in order to facilitate pre-surgical genetic counseling and testing. We recruited newly diagnosed breast cancer patients at increased risk for carrying a BRCA1/2 mutation. Of 379 eligible patients who completed a baseline survey, 330 agreed to randomization in a 2:1 ratio to RGCT (n = 220) versus UC (n = 108). Primary outcomes were genetic counseling and testing uptake and breast cancer surgical decisions. RGCT led to higher overall (83.8% vs. 54.6%; p < 0.0001) and pre-surgical (57.8% vs. 38.7%; p = 0.001) genetic counseling uptake compared to UC. Despite higher rates of genetic counseling, RGCT did not differ from UC in overall (54.1% vs. 49.1%, p > 0.10) or pre-surgical (30.6% vs. 27.4%, p > 0.10) receipt of genetic test results nor did they differ in uptake of bilateral mastectomy (26.6% vs. 21.8%, p > 0.10). Although RGCT yielded increased genetic counseling participation, this did not result in increased rates of pre-surgical genetic testing or impact surgical decisions. These data suggest that those patients most likely to opt for genetic testing at the time of diagnosis are being effectively identified by their surgeons.

Genetic susceptibility testing for neurodegenerative diseases: ethical and practice issues.

PubMed

Roberts, J Scott; Uhlmann, Wendy R

2013-11-01

As the genetics of neurodegenerative disease become better understood, opportunities for genetic susceptibility testing for at-risk individuals will increase. Such testing raises important ethical and practice issues related to test access, informed consent, risk estimation and communication, return of results, and policies to prevent genetic discrimination. The advent of direct-to-consumer genetic susceptibility testing for various neurodegenerative disorders (including Alzheimer's disease (AD), Parkinson's disease, and certain prion diseases) means that ethical and practical challenges must be faced not only in traditional research and clinical settings, but also in broader society. This review addresses several topics relevant to the development and implementation of genetic susceptibility tests across research, clinical, and consumer settings; these include appropriate indications for testing, the implications of different methods for disclosing test results, clinical versus personal utility of risk information, psychological and behavioral responses to test results, testing of minors, genetic discrimination, and ethical dilemmas posed by whole-genome sequencing. We also identify future areas of likely growth in the field, including pharmacogenomics and genetic screening for individuals considering or engaged in activities that pose elevated risk of brain injury (e.g., football players, military personnel). APOE gene testing for risk of Alzheimer's disease is used throughout as an instructive case example, drawing upon the authors' experience as investigators in a series of multisite randomized clinical trials that have examined the impact of disclosing APOE genotype status to interested individuals (e.g., first-degree relatives of AD patients, persons with mild cognitive impairment). Copyright © 2013 Elsevier Ltd. All rights reserved.

Gaps in Incorporating Germline Genetic Testing Into Treatment Decision-Making for Early-Stage Breast Cancer.

PubMed

Kurian, Allison W; Li, Yun; Hamilton, Ann S; Ward, Kevin C; Hawley, Sarah T; Morrow, Monica; McLeod, M Chandler; Jagsi, Reshma; Katz, Steven J

2017-07-10

Purpose Genetic testing for breast cancer risk is evolving rapidly, with growing use of multiple-gene panels that can yield uncertain results. However, little is known about the context of such testing or its impact on treatment. Methods A population-based sample of patients with breast cancer diagnosed in 2014 to 2015 and identified by two SEER registries (Georgia and Los Angeles) were surveyed about genetic testing experiences (N = 3,672; response rate, 68%). Responses were merged with SEER data. A patient subgroup at higher pretest risk of pathogenic mutation carriage was defined according to genetic testing guidelines. Patients' attending surgeons were surveyed about genetic testing and results management. We examined patterns and correlates of genetic counseling and testing and the impact of results on bilateral mastectomy (BLM) use. Results Six hundred sixty-six patients reported genetic testing. Although two thirds of patients were tested before surgical treatment, patients without private insurance more often experienced delays. Approximately half of patients (57% at higher pretest risk, 42% at average risk) discussed results with a genetic counselor. Patients with pathogenic mutations in BRCA1/2 or another gene had the highest rates of BLM (higher risk, 80%; average risk, 85%); however, BLM was also common among patients with genetic variants of uncertain significance (VUS; higher risk, 43%; average risk, 51%). Surgeons' confidence in discussing testing increased with volume of patients with breast cancer, but many surgeons (higher volume, 24%; lower volume, 50%) managed patients with BRCA1/2 VUS the same as patients with BRCA1/2 pathogenic mutations. Conclusion Many patients with breast cancer are tested without ever seeing a genetic counselor. Half of average-risk patients with VUS undergo BLM, suggesting a limited understanding of results that some surgeons share. These findings emphasize the need to address challenges in personalized communication about genetic testing.

Variation in healthcare services for specialist genetic testing and implications for planning genetic services: the example of inherited retinal dystrophy in the English NHS.

PubMed

Harrison, Mark; Birch, Stephen; Eden, Martin; Ramsden, Simon; Farragher, Tracey; Payne, Katherine; Hall, Georgina; Black, Graeme Cm

2015-04-01

This study aims to identify and quantify the extent of current variation in service provision of a genetic testing service for dominant and X-linked retinal dystrophies in the English National Health Service (NHS). National audit data (all test requests and results (n = 1839) issued between 2003 and 2011) and survey of English regional genetic testing services were used. Age- and gender-adjusted standardised testing rates were calculated using indirect standardisation, and survey responses were transcribed verbatim and data collated and summarised. The cumulative incidence rate of testing in England was 4.5 per 100,000 population for males and 2.6 per 100,000 population for females. The standardised testing rate (STR) varied widely between regions of England, being particularly low in the North-east (STR 0.485), with half as many tests as expected based on the size and demographic distribution of the population and high in the South-east (STR 1.355), with 36 % more tests than expected. Substantial and significantly different rates of testing were found between regional populations. Specific policy mechanisms to promote, monitor and evaluate the regional distribution of access to genetic and genomic testing are required. However, commissioners will require information on the scope and role of genetic services and the population at risk of the conditions for which patients are tested.

Adaptive transmission disequilibrium test for family trio design.

PubMed

Yuan, Min; Tian, Xin; Zheng, Gang; Yang, Yaning

2009-01-01

The transmission disequilibrium test (TDT) is a standard method to detect association using family trio design. It is optimal for an additive genetic model. Other TDT-type tests optimal for recessive and dominant models have also been developed. Association tests using family data, including the TDT-type statistics, have been unified to a class of more comprehensive and flexable family-based association tests (FBAT). TDT-type tests have high efficiency when the genetic model is known or correctly specified, but may lose power if the model is mis-specified. Hence tests that are robust to genetic model mis-specification yet efficient are preferred. Constrained likelihood ratio test (CLRT) and MAX-type test have been shown to be efficiency robust. In this paper we propose a new efficiency robust procedure, referred to as adaptive TDT (aTDT). It uses the Hardy-Weinberg disequilibrium coefficient to identify the potential genetic model underlying the data and then applies the TDT-type test (or FBAT for general applications) corresponding to the selected model. Simulation demonstrates that aTDT is efficiency robust to model mis-specifications and generally outperforms the MAX test and CLRT in terms of power. We also show that aTDT has power close to, but much more robust, than the optimal TDT-type test based on a single genetic model. Applications to real and simulated data from Genetic Analysis Workshop (GAW) illustrate the use of our adaptive TDT.

How is genetic testing evaluated? A systematic review of the literature.

PubMed

Pitini, Erica; De Vito, Corrado; Marzuillo, Carolina; D'Andrea, Elvira; Rosso, Annalisa; Federici, Antonio; Di Maria, Emilio; Villari, Paolo

2018-05-01

Given the rapid development of genetic tests, an assessment of their benefits, risks, and limitations is crucial for public health practice. We performed a systematic review aimed at identifying and comparing the existing evaluation frameworks for genetic tests. We searched PUBMED, SCOPUS, ISI Web of Knowledge, Google Scholar, Google, and gray literature sources for any documents describing such frameworks. We identified 29 evaluation frameworks published between 2000 and 2017, mostly based on the ACCE Framework (n = 13 models), or on the HTA process (n = 6), or both (n = 2). Others refer to the Wilson and Jungner screening criteria (n = 3) or to a mixture of different criteria (n = 5). Due to the widespread use of the ACCE Framework, the most frequently used evaluation criteria are analytic and clinical validity, clinical utility and ethical, legal and social implications. Less attention is given to the context of implementation. An economic dimension is always considered, but not in great detail. Consideration of delivery models, organizational aspects, and consumer viewpoint is often lacking. A deeper analysis of such context-related evaluation dimensions may strengthen a comprehensive evaluation of genetic tests and support the decision-making process.

Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy

DOE PAGES

Golbus, Jessica R.; Puckelwartz, Megan J.; Dellefave-Castillo, Lisa; ...

2014-09-01

Background—Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of more than 50 genes. New genes are routinely added to panels to improve the diagnostic yield. With the anticipated $1000 genome, it is expected that genetic testing will shift towards comprehensive genome sequencing accompanied by targeted gene analysis. Therefore, we assessed the reliability of whole genome sequencing and targeted analysis to identify cardiomyopathy variants in 11 subjects with cardiomyopathy. Methods and Results—Whole genome sequencing with an average of 37× coverage was combined with targeted analysis focused onmore » 204 genes linked to cardiomyopathy. Genetic variants were scored using multiple prediction algorithms combined with frequency data from public databases. This pipeline yielded 1-14 potentially pathogenic variants per individual. Variants were further analyzed using clinical criteria and/or segregation analysis. Three of three previously identified primary mutations were detected by this analysis. In six subjects for whom the primary mutation was previously unknown, we identified mutations that segregated with disease, had clinical correlates, and/or had additional pathological correlation to provide evidence for causality. For two subjects with previously known primary mutations, we identified additional variants that may act as modifiers of disease severity. In total, we identified the likely pathological mutation in 9 of 11 (82%) subjects. We conclude that these pilot data demonstrate that ~30-40× coverage whole genome sequencing combined with targeted analysis is feasible and sensitive to identify rare variants in cardiomyopathy-associated genes.« less

Insurance and genetic testing: where are we now?

PubMed Central

Ostrer, H; Allen, W; Crandall, L A; Moseley, R E; Dewar, M A; Nye, D; McCrary, S V

1993-01-01

Basic research will spur development of genetic tests that are capable of presymptomatic prediction of disease, disability, and premature death in presently asymptomatic individuals. Concerns have been expressed about potential harms related to the use of genetic test results, especially loss of confidentiality, eugenics, and discrimination. Existing laws and administrative policies may not be sufficient to assure that genetic information is used fairly. To provide factual information and conceptual principles upon which sound social policy can be based, the Human Genome Initiative established an Ethical, Legal, and Social Issues Program. Among the first areas to be identified as a priority for study was insurance. This paper provides a review of life, health, and disability insurance systems, including basic principles, risk classification, and market and regulatory issues, and examines the potential impact of genetic information on the insurance industry. PMID:8447322

Testing the structure of a hydrological model using Genetic Programming

NASA Astrophysics Data System (ADS)

Selle, Benny; Muttil, Nitin

2011-01-01

SummaryGenetic Programming is able to systematically explore many alternative model structures of different complexity from available input and response data. We hypothesised that Genetic Programming can be used to test the structure of hydrological models and to identify dominant processes in hydrological systems. To test this, Genetic Programming was used to analyse a data set from a lysimeter experiment in southeastern Australia. The lysimeter experiment was conducted to quantify the deep percolation response under surface irrigated pasture to different soil types, watertable depths and water ponding times during surface irrigation. Using Genetic Programming, a simple model of deep percolation was recurrently evolved in multiple Genetic Programming runs. This simple and interpretable model supported the dominant process contributing to deep percolation represented in a conceptual model that was published earlier. Thus, this study shows that Genetic Programming can be used to evaluate the structure of hydrological models and to gain insight about the dominant processes in hydrological systems.

Development of carrier testing for common inborn errors of metabolism in the Wisconsin Plain population.

PubMed

Kuhl, Ashley; van Calcar, Sandra; Baker, Mei; Seroogy, Christine M; Rice, Gregory; Scott Schwoerer, Jessica

2017-03-01

This community project is an initiative through the University of Wisconsin Biochemical Genetics Clinic and the Wisconsin Newborn Screening Program to identify members of the Plain population who are at risk for having children with maple syrup urine disease (MSUD) or propionic acidemia (PA) or who have PA. Because of the high prevalence of metabolic conditions in the Plain population and the importance of early intervention, a statewide outreach project was developed to provide targeted variant analysis of the common MSUD and PA pathogenic variants in this population through health-care provider distribution of blood spot testing kits. Awareness was achieved through outreach efforts with the state midwives guild and Plain population meetings. Eighty individuals were tested; diagnosis was confirmed for three adults with PA and one couple was identified as being at risk for having a child with PA. Genetic counseling was provided to those identified. Follow-up diagnostic testing was completed for the at-risk couple's children; none were found to be affected. This initiative successfully provided accessible clinical testing for MSUD and PA for a high-risk population. Early identification of at-risk couples sets the foundation for early care of at-risk neonates, thereby improving future clinical outcomes.Genet Med 19 3, 352-356.

Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors

PubMed Central

Goldman, Jill S.; Hahn, Susan E.; Catania, Jennifer Williamson; LaRusse-Eckert, Susan; Butson, Melissa Barber; Rumbaugh, Malia; Strecker, Michelle N.; Roberts, J. Scott; Burke, Wylie; Mayeux, Richard; Bird, Thomas

2012-01-01

Alzheimer disease is the most common cause of dementia. It occurs worldwide and affects all ethnic groups. The incidence of Alzheimer disease is increasing due, in part, to increased life expectancy and the aging baby boomer generation. The average lifetime risk of developing Alzheimer disease is 10–12%. This risk at least doubles with the presence of a first-degree relative with the disorder. Despite its limited utility, patients express concern over their risk and, in some instances, request testing. Furthermore, research has demonstrated that testing individuals for apoli-poprotein E can be valuable and safe in certain contexts. However, because of the complicated genetic nature of the disorder, few clinicians are prepared to address the genetic risks of Alzheimer disease with their patients. Given the increased awareness in family history thanks to family history campaigns, the increasing incidence of Alzheimer disease, and the availability of direct to consumer testing, patient requests for information is increasing. This practice guideline provides clinicians with a framework for assessing their patients’ genetic risk for Alzheimer disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for AD. PMID:21577118

Modeling the Transition from a Phenotypic to Genotypic Conceptualization of Genetics in a University-Level Introductory Biology Context

NASA Astrophysics Data System (ADS)

Todd, Amber; Romine, William L.; Correa-Menendez, Josefina

2017-07-01

Identifying contingencies between constructs in a multi-faceted learning progression (LP) is a challenging task. Often, there is not enough evidence in the literature to support connections, and once identified, they are difficult to empirically test. Here, we use causal model search to evaluate how connections between ideas in a genetics LP change over time in the context of an introductory biology course. We identify primary and secondary hub ideas and connections between concepts before and after instruction to illustrate how students moved from a phenotypic grounding of genetics knowledge to a more genotypic grounding of their genetics knowledge after instruction. We discuss our results in light of conceptual change and illustrate the importance of understanding students' idea structures within a domain.

Interest in Genetic Testing in Ashkenazi Jewish Parkinson’s Disease Patients and Their Unaffected Relatives

PubMed Central

Gupte, Manisha; Alcalay, Roy N.; Mejia-Santana, Helen; Raymond, Deborah; Saunders-Pullman, Rachel; Roos, Ernest; Orbe-Reily, Martha; Tang, Ming-X; Mirelman, Anat; Ozelius, Laurie; Orr-Urtreger, Avi; Clark, Lorraine; Giladi, Nir; Bressman, Susan

2014-01-01

Our objective was to explore interest in genetic testing among Ashkenazi Jewish (AJ) Parkinson’s Disease (PD) cases and first-degree relatives, as genetic testing for LRRK2 G2019S is widely available. Approximately 18 % of AJ PD cases carry G2019S mutations; penetrance estimations vary between 24 and 100 % by age 80. A Genetic Attitude Questionnaire (GAQ) was administered at two New York sites to PD families unaware of LRRK2 G2019S mutation status. The association of G2019S, age, education, gender and family history of PD with desire for genetic testing (outcome) was modeled using logistic regression. One-hundred eleven PD cases and 77 relatives completed the GAQ. Both PD cases and relatives had excellent PD-specific genetic knowledge. Among PD, 32.6 % “definitely” and 41.1 % “probably” wanted testing, if offered “now.” Among relatives, 23.6 % “definitely” and 36.1 % “probably” wanted testing “now.” Desire for testing in relatives increased incrementally based on hypothetical risk of PD. The most important reasons for testing in probands and relatives were: if it influenced medication response, identifying no mutation, and early prevention and treatment. In logistic regression, older age was associated with less desire for testing in probands OR=0.921 95%CI 0.868–0.977, p=0.009. Both probands and relatives express interest in genetic testing, despite no link to current treatment or prevention. PMID:25127731

Field of Genes: An Investigation of Sports-Related Genetic Testing

PubMed Central

Wagner, Jennifer K.; Royal, Charmaine D.

2012-01-01

Sports-related genetic testing is a sector of the diverse direct-to-consumer (DTC) industry that has not yet been examined thoroughly by academic scholars. A systematic search was used to identify companies in this sector and content analysis of online information was performed. More than a dozen companies were identified. Marketing practices observed generally did not target parents for child testing, and marketing images were mild compared to images used in popular media. Information was provided at a high reading level (industry-wide Flesh-Kincaid Grade Levels > 11). While ~75% of companies provide privacy policies and terms of service prior to purchase and ~40% provide scientific citations for their tests, <25% reported using American Association of Blood Banks (AABB) accredited or the Clinical Laboratory Improvement Amendments of 1988 (CLIA) certified laboratories. Tests ranged considerably in price (~$100–$1,100) and were substantively diverse. These findings highlight the need to appreciate nuances and avoid broad generalizations of this and other DTC sectors. Utilization of consumer protections available for e-commerce generally may adequately protect DTC genetics consumers without new federal legislation or regulation. PMID:25562204

Genetic determinants of heart failure: facts and numbers.

PubMed

Czepluch, Frauke S; Wollnik, Bernd; Hasenfuß, Gerd

2018-06-01

The relevance of gene mutations leading to heart diseases and hence heart failure has become evident. The risk for and the course of heart failure depends on genomic variants and mutations underlying the so-called genetic predisposition. Genetic contribution to heart failure is highly heterogenous and complex. For any patient with a likely inherited heart failure syndrome, genetic counselling is recommended and important. In the last few years, novel sequencing technologies (named next-generation sequencing - NGS) have dramatically improved the availability of molecular testing, the efficiency of genetic analyses, and moreover reduced the cost for genetic testing. Due to this development, genetic testing has become increasingly accessible and NGS-based sequencing is now applied in clinical routine diagnostics. One of the most common reasons of heart failure are cardiomyopathies such as the dilated or the hypertrophic cardiomyopathy. Nearly 100 disease-associated genes have been identified for cardiomyopathies. The knowledge of a pathogenic mutation can be used for genetic counselling, risk and prognosis determination, therapy guidance and hence for a more effective treatment. Besides, family cascade screening for a known familial, pathogenic mutation can lead to an early diagnosis in affected individuals. At that timepoint, a preventative intervention could be used to avoid or delay disease onset or delay disease progression. Understanding the cellular basis of genetic heart failure syndromes in more detail may provide new insights into the molecular biology of physiological and impaired cardiac (cell) function. As our understanding of the molecular and genetic pathophysiology of heart failure will increase, this might help to identify novel therapeutic targets and may lead to the development of new and specific treatment options in patients with heart failure. © 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

QTLs associated with dry matter intake, metabolic mid-test weight, growth and feed efficiency have little overlap across 4 beef cattle studies.

PubMed

Saatchi, Mahdi; Beever, Jonathan E; Decker, Jared E; Faulkner, Dan B; Freetly, Harvey C; Hansen, Stephanie L; Yampara-Iquise, Helen; Johnson, Kristen A; Kachman, Stephen D; Kerley, Monty S; Kim, JaeWoo; Loy, Daniel D; Marques, Elisa; Neibergs, Holly L; Pollak, E John; Schnabel, Robert D; Seabury, Christopher M; Shike, Daniel W; Snelling, Warren M; Spangler, Matthew L; Weaber, Robert L; Garrick, Dorian J; Taylor, Jeremy F

2014-11-20

The identification of genetic markers associated with complex traits that are expensive to record such as feed intake or feed efficiency would allow these traits to be included in selection programs. To identify large-effect QTL, we performed a series of genome-wide association studies and functional analyses using 50 K and 770 K SNP genotypes scored in 5,133 animals from 4 independent beef cattle populations (Cycle VII, Angus, Hereford and Simmental×Angus) with phenotypes for average daily gain, dry matter intake, metabolic mid-test body weight and residual feed intake. A total of 5, 6, 11 and 10 significant QTL (defined as 1-Mb genome windows with Bonferroni-corrected P-value<0.05) were identified for average daily gain, dry matter intake, metabolic mid-test body weight and residual feed intake, respectively. The identified QTL were population-specific and had little overlap across the 4 populations. The pleiotropic or closely linked QTL on BTA 7 at 23 Mb identified in the Angus population harbours a promising candidate gene ACSL6 (acyl-CoA synthetase long-chain family member 6), and was the largest effect QTL associated with dry matter intake and mid-test body weight explaining 10.39% and 14.25% of the additive genetic variance, respectively. Pleiotropic or closely linked QTL associated with average daily gain and mid-test body weight were detected on BTA 6 at 38 Mb and BTA 7 at 93 Mb confirming previous reports. No QTL for residual feed intake explained more than 2.5% of the additive genetic variance in any population. Marker-based estimates of heritability ranged from 0.21 to 0.49 for residual feed intake across the 4 populations. This GWAS study, which is the largest performed for feed efficiency and its component traits in beef cattle to date, identified several large-effect QTL that cumulatively explained a significant percentage of additive genetic variance within each population. Differences in the QTL identified among the different populations may be due to differences in power to detect QTL, environmental variation, or differences in the genetic architecture of trait variation among breeds. These results enhance our understanding of the biology of growth, feed intake and utilisation in beef cattle.

Factors influencing organizational adoption and implementation of clinical genetic services.

PubMed

Hamilton, Alison B; Oishi, Sabine; Yano, Elizabeth M; Gammage, Cynthia E; Marshall, Nell J; Scheuner, Maren T

2014-03-01

We sought to identify characteristics of genetic services that facilitate or hinder adoption. We conducted semi-structured key informant interviews in five clinical specialties (primary care, medical oncology, neurology, cardiology, pathology/laboratory medicine) within 13 Veterans Administration facilities. Genetic services (defined as genetic testing and consultation) were not typically characterized by informants (n = 64) as advantageous for their facilities or their patients; compatible with organizational norms of low cost and high clinical impact; or applicable to patient populations or norms of clinical care. Furthermore, genetic services had not been systematically adopted in most facilities because of their complexity: knowledge of and expertise on genetic testing was limited, and organizational barriers to utilization of genetic services were formidable. The few facilities that had some success with implementation of genetic services had knowledgeable clinicians interested in developing services and organizational-level facilitators such as accessible genetic test-ordering processes. Adoption and implementation of genetic services will require a multilevel effort that includes education of providers and administrators, opportunities for observing the benefits of genetic medicine, strategies for reducing the complexity of genomic medicine, expanded strategies for accessing genetics expertise and streamlining utilization, and resources dedicated to assessing the value of genetic information for the outcomes that matter to health-care organizations.

Exploring Genetic Numeracy Skills in a Sample of U.S. University Students

PubMed Central

Bergman, Margo W.; Goodson, Patricia; Goltz, Heather Honoré

2017-01-01

Misconceptions concerning numerical genetic risk exist even within educated populations. To more fully characterize and understand the extent of these risk misunderstandings, which have large potential impact on clinical care, we analyzed the responses from 2,576 students enrolled at 2 Southwestern universities using the PGRID tool, a 138-item web-based survey comprising measures of understanding of genetics, genetic disease, and genetic risk. The primary purpose of this study was to characterize the intersection of risk perception and knowledge, termed genetic numeracy (GN). Additionally, we identify sociodemographic factors that might shape varying levels of GN skills within the study sample and explore the impact of GN on genetic testing intentions using both the Marascuilo procedure and logistic regression analysis. Despite having some college coursework or at least one college degree, most respondents lacked high-level aptitude in understanding genetic inheritance risk, especially with respect to recessive disorders. Prior education about genetics and biology, as well as exposure to biomedical models of genetics, was associated with higher GN levels; exposure to popular media models of genetics was inversely associated with higher GN levels. Differing GN levels affects genetic testing intentions. GN will become more relevant as genetic testing is increasingly incorporated into general clinical care. PMID:28900615

Exploring Genetic Numeracy Skills in a Sample of U.S. University Students.

PubMed

Bergman, Margo W; Goodson, Patricia; Goltz, Heather Honoré

2017-01-01

Misconceptions concerning numerical genetic risk exist even within educated populations. To more fully characterize and understand the extent of these risk misunderstandings, which have large potential impact on clinical care, we analyzed the responses from 2,576 students enrolled at 2 Southwestern universities using the PGRID tool, a 138-item web-based survey comprising measures of understanding of genetics, genetic disease, and genetic risk. The primary purpose of this study was to characterize the intersection of risk perception and knowledge, termed genetic numeracy (GN). Additionally, we identify sociodemographic factors that might shape varying levels of GN skills within the study sample and explore the impact of GN on genetic testing intentions using both the Marascuilo procedure and logistic regression analysis. Despite having some college coursework or at least one college degree, most respondents lacked high-level aptitude in understanding genetic inheritance risk, especially with respect to recessive disorders. Prior education about genetics and biology, as well as exposure to biomedical models of genetics, was associated with higher GN levels; exposure to popular media models of genetics was inversely associated with higher GN levels. Differing GN levels affects genetic testing intentions. GN will become more relevant as genetic testing is increasingly incorporated into general clinical care.

Multiple Phenotype Association Tests Using Summary Statistics in Genome-Wide Association Studies

PubMed Central

Liu, Zhonghua; Lin, Xihong

2017-01-01

Summary We study in this paper jointly testing the associations of a genetic variant with correlated multiple phenotypes using the summary statistics of individual phenotype analysis from Genome-Wide Association Studies (GWASs). We estimated the between-phenotype correlation matrix using the summary statistics of individual phenotype GWAS analyses, and developed genetic association tests for multiple phenotypes by accounting for between-phenotype correlation without the need to access individual-level data. Since genetic variants often affect multiple phenotypes differently across the genome and the between-phenotype correlation can be arbitrary, we proposed robust and powerful multiple phenotype testing procedures by jointly testing a common mean and a variance component in linear mixed models for summary statistics. We computed the p-values of the proposed tests analytically. This computational advantage makes our methods practically appealing in large-scale GWASs. We performed simulation studies to show that the proposed tests maintained correct type I error rates, and to compare their powers in various settings with the existing methods. We applied the proposed tests to a GWAS Global Lipids Genetics Consortium summary statistics data set and identified additional genetic variants that were missed by the original single-trait analysis. PMID:28653391

Multiple phenotype association tests using summary statistics in genome-wide association studies.

PubMed

Liu, Zhonghua; Lin, Xihong

2018-03-01

We study in this article jointly testing the associations of a genetic variant with correlated multiple phenotypes using the summary statistics of individual phenotype analysis from Genome-Wide Association Studies (GWASs). We estimated the between-phenotype correlation matrix using the summary statistics of individual phenotype GWAS analyses, and developed genetic association tests for multiple phenotypes by accounting for between-phenotype correlation without the need to access individual-level data. Since genetic variants often affect multiple phenotypes differently across the genome and the between-phenotype correlation can be arbitrary, we proposed robust and powerful multiple phenotype testing procedures by jointly testing a common mean and a variance component in linear mixed models for summary statistics. We computed the p-values of the proposed tests analytically. This computational advantage makes our methods practically appealing in large-scale GWASs. We performed simulation studies to show that the proposed tests maintained correct type I error rates, and to compare their powers in various settings with the existing methods. We applied the proposed tests to a GWAS Global Lipids Genetics Consortium summary statistics data set and identified additional genetic variants that were missed by the original single-trait analysis. © 2017, The International Biometric Society.

Concerns about cancer risk and experiences with genetic testing in a diverse population of patients with breast cancer.

PubMed

Jagsi, Reshma; Griffith, Kent A; Kurian, Allison W; Morrow, Monica; Hamilton, Ann S; Graff, John J; Katz, Steven J; Hawley, Sarah T

2015-05-10

To evaluate preferences for and experiences with genetic testing in a diverse cohort of patients with breast cancer identified through population-based registries, with attention to differences by race/ethnicity. We surveyed women diagnosed with nonmetastatic breast cancer from 2005 to 2007, as reported to the SEER registries of metropolitan Los Angeles and Detroit, about experiences with hereditary risk evaluation. Multivariable models evaluated correlates of a strong desire for genetic testing, unmet need for discussion with a health care professional, and receipt of testing. Among 1,536 patients who completed the survey, 35% expressed strong desire for genetic testing, 28% reported discussing testing with a health care professional, and 19% reported test receipt. Strong desire for testing was more common in younger women, Latinas, and those with family history. Minority patients were significantly more likely to have unmet need for discussion (failure to discuss genetic testing with a health professional when they had a strong desire for testing): odds ratios of 1.68, 2.44, and 7.39 for blacks, English-speaking Latinas, and Spanish-speaking Latinas compared with whites, respectively. Worry in the long-term survivorship period was higher among those with unmet need for discussion (48.7% v 24.9%; P <.001). Patients who received genetic testing were younger, less likely to be black, and more likely to have a family cancer history. Many patients, especially minorities, express a strong desire for genetic testing and may benefit from discussion to clarify risks. Clinicians should discuss genetic risk even with patients they perceive to be at low risk, as this may reduce worry. © 2015 by American Society of Clinical Oncology.

Great influence of geographic isolation on the genetic differentiation of Myriophyllum spicatum under a steep environmental gradient

PubMed Central

Wu, Zhigang; Yu, Dan; Wang, Zhong; Li, Xing; Xu, Xinwei

2015-01-01

Understanding how natural processes affect population genetic structures is an important issue in evolutionary biology. One effective method is to assess the relative importance of environmental and geographical factors in the genetic structure of populations. In this study, we examined the spatial genetic variation of thirteen Myriophyllum spicatum populations from the Qinghai-Tibetan Plateau (QTP) and adjacent highlands (Yunnan-Guizhou Plateau, YGP) by using microsatellite loci and environmental and geographical factors. Bioclim layers, hydrological properties and elevation were considered as environmental variables and reduced by principal component analysis. The genetic isolation by geographic distance (IBD) was tested by Mantel tests and the relative importance of environmental variables on population genetic differentiation was determined by a partial Mantel test and multiple matrix regression with randomization (MMRR). Two genetic clusters corresponding to the QTP and YGP were identified. Both tests and MMRR revealed a significant and strong correlation between genetic divergence and geographic isolation under the influence of environmental heterogeneity at the overall and finer spatial scales. Our findings suggested the dominant role of geography on the evolution of M. spicatum under a steep environmental gradient in the alpine landscape as a result of dispersal limitation and genetic drift. PMID:26494202

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test

PubMed Central

Lionel, Anath C; Costain, Gregory; Monfared, Nasim; Walker, Susan; Reuter, Miriam S; Hosseini, S Mohsen; Thiruvahindrapuram, Bhooma; Merico, Daniele; Jobling, Rebekah; Nalpathamkalam, Thomas; Pellecchia, Giovanna; Sung, Wilson W L; Wang, Zhuozhi; Bikangaga, Peter; Boelman, Cyrus; Carter, Melissa T; Cordeiro, Dawn; Cytrynbaum, Cheryl; Dell, Sharon D; Dhir, Priya; Dowling, James J; Heon, Elise; Hewson, Stacy; Hiraki, Linda; Inbar-Feigenberg, Michal; Klatt, Regan; Kronick, Jonathan; Laxer, Ronald M; Licht, Christoph; MacDonald, Heather; Mercimek-Andrews, Saadet; Mendoza-Londono, Roberto; Piscione, Tino; Schneider, Rayfel; Schulze, Andreas; Silverman, Earl; Siriwardena, Komudi; Snead, O Carter; Sondheimer, Neal; Sutherland, Joanne; Vincent, Ajoy; Wasserman, Jonathan D; Weksberg, Rosanna; Shuman, Cheryl; Carew, Chris; Szego, Michael J; Hayeems, Robin Z; Basran, Raveen; Stavropoulos, Dimitri J; Ray, Peter N; Bowdin, Sarah; Meyn, M Stephen; Cohn, Ronald D; Scherer, Stephen W; Marshall, Christian R

2018-01-01

Purpose Genetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use. Methods We prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing. Results WGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24% P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A. Conclusion WGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort. PMID:28771251

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

PubMed

Lionel, Anath C; Costain, Gregory; Monfared, Nasim; Walker, Susan; Reuter, Miriam S; Hosseini, S Mohsen; Thiruvahindrapuram, Bhooma; Merico, Daniele; Jobling, Rebekah; Nalpathamkalam, Thomas; Pellecchia, Giovanna; Sung, Wilson W L; Wang, Zhuozhi; Bikangaga, Peter; Boelman, Cyrus; Carter, Melissa T; Cordeiro, Dawn; Cytrynbaum, Cheryl; Dell, Sharon D; Dhir, Priya; Dowling, James J; Heon, Elise; Hewson, Stacy; Hiraki, Linda; Inbar-Feigenberg, Michal; Klatt, Regan; Kronick, Jonathan; Laxer, Ronald M; Licht, Christoph; MacDonald, Heather; Mercimek-Andrews, Saadet; Mendoza-Londono, Roberto; Piscione, Tino; Schneider, Rayfel; Schulze, Andreas; Silverman, Earl; Siriwardena, Komudi; Snead, O Carter; Sondheimer, Neal; Sutherland, Joanne; Vincent, Ajoy; Wasserman, Jonathan D; Weksberg, Rosanna; Shuman, Cheryl; Carew, Chris; Szego, Michael J; Hayeems, Robin Z; Basran, Raveen; Stavropoulos, Dimitri J; Ray, Peter N; Bowdin, Sarah; Meyn, M Stephen; Cohn, Ronald D; Scherer, Stephen W; Marshall, Christian R

2018-04-01

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

Cost-effectiveness analysis of carrier and prenatal genetic testing for X-linked hemophilia.

PubMed

Tsai, Meng-Che; Cheng, Chao-Neng; Wang, Ru-Jay; Chen, Kow-Tong; Kuo, Mei-Chin; Lin, Shio-Jean

2015-08-01

Hemophilia involves a lifelong burden from the perspective of the patient and the entire healthcare system. Advances in genetic testing provide valuable information to hemophilia-affected families for family planning. The aim of this study was to analyze the cost-effectiveness of carrier and prenatal genetic testing in the health-economic framework in Taiwan. A questionnaire was developed to assess the attitudes towards genetic testing for hemophilia. We modeled clinical outcomes of the proposed testing scheme by using the decision tree method. Incremental cost-effectiveness analysis was conducted, based on data from the National Health Insurance (NHI) database and a questionnaire survey. From the NHI database, 1111 hemophilic patients were identified and required an average medical expenditure of approximately New Taiwan (NT) $2.1 million per patient-year in 2009. By using the decision tree model, we estimated that 26 potential carriers need to be tested to prevent one case of hemophilia. At a screening rate of 79%, carrier and prenatal genetic testing would cost NT $85.9 million, which would be offset by an incremental saving of NT $203 million per year by preventing 96 cases of hemophilia. Assuming that the life expectancy for hemophilic patients is 70 years, genetic testing could further save NT $14.2 billion. Higher screening rates would increase the savings for healthcare resources. Carrier and prenatal genetic testing for hemophilia is a cost-effective investment in healthcare allocation. A case management system should be integrated in the current practice to facilitate patient care (e.g., collecting family pedigrees and providing genetic counseling). Copyright © 2013. Published by Elsevier B.V.

Early developmental gene enhancers affect subcortical volumes in the adult human brain.

PubMed

Becker, Martin; Guadalupe, Tulio; Franke, Barbara; Hibar, Derrek P; Renteria, Miguel E; Stein, Jason L; Thompson, Paul M; Francks, Clyde; Vernes, Sonja C; Fisher, Simon E

2016-05-01

Genome-wide association screens aim to identify common genetic variants contributing to the phenotypic variability of complex traits, such as human height or brain morphology. The identified genetic variants are mostly within noncoding genomic regions and the biology of the genotype-phenotype association typically remains unclear. In this article, we propose a complementary targeted strategy to reveal the genetic underpinnings of variability in subcortical brain volumes, by specifically selecting genomic loci that are experimentally validated forebrain enhancers, active in early embryonic development. We hypothesized that genetic variation within these enhancers may affect the development and ultimately the structure of subcortical brain regions in adults. We tested whether variants in forebrain enhancer regions showed an overall enrichment of association with volumetric variation in subcortical structures of >13,000 healthy adults. We observed significant enrichment of genomic loci that affect the volume of the hippocampus within forebrain enhancers (empirical P = 0.0015), a finding which robustly passed the adjusted threshold for testing of multiple brain phenotypes (cutoff of P < 0.0083 at an alpha of 0.05). In analyses of individual single nucleotide polymorphisms (SNPs), we identified an association upstream of the ID2 gene with rs7588305 and variation in hippocampal volume. This SNP-based association survived multiple-testing correction for the number of SNPs analyzed but not for the number of subcortical structures. Targeting known regulatory regions offers a way to understand the underlying biology that connects genotypes to phenotypes, particularly in the context of neuroimaging genetics. This biology-driven approach generates testable hypotheses regarding the functional biology of identified associations. Hum Brain Mapp 37:1788-1800, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The Clinical Content of Preconception Care: Genetics and Genomics

PubMed Central

SOLOMON, Benjamin D.; JACK, Brian; FEERO, W. Gregory

2008-01-01

The prevalence of paternal and maternal genetic conditions that affect pregnancy varies according to many factors, including parental age, medical history, and family history. While some genetic conditions that affect pregnancy are easily identified early in life, others are not and may require additional diagnostic testing. A complete three-generation family medical history that includes ethnicity information about both sides of the family is arguably the single best genetic “test” applicable to preconception care. Assessment of genetic risk by an experienced professional has been shown to improve the detection rate of identifiable risk factors. Learning about possible genetic issues in the pre-conception period is ideal, as knowledge permits patients to make informed reproductive decisions. Options available to couples before conception include adoption, surrogacy, use of donor sperm, in vitro fertilization after pre-implantation genetic diagnosis, and avoidance of pregnancy. Future technological advances will increase the choices available to couples. PMID:19081428

Attitudes towards cannabis use and genetic testing for schizophrenia.

PubMed

Schiffman, Jason; Lawrence, Ryan E; Demro, Caroline; Appelbaum, Paul S; Dixon, Lisa B

2016-06-01

Within schizophrenia, genetic factors contribute greatly to risk, yet genetic testing for the disorder is not available. For some individuals with specific genotypes, cannabis use may increase risk of schizophrenia. It is possible that genetic tests could be offered in the future to inform individuals of the risk of schizophrenia if they use cannabis. Previous research, however, provides little guidance on how young adults might respond to such tests. We assessed a group of young adults (n = 83) to determine how the perceived magnitude of increased risk for schizophrenia in the presence of cannabis use influences decisions to undergo genetic testing, as well as subsequent attitudes and intentions towards cannabis use. Participants were significantly more likely to indicate willingness to get tested if the results identified a 10% risk versus a 2% risk of schizophrenia. Participants also indicated that if the results of their test reflected increased risk due to cannabis use, it would be more important to avoid cannabis in the 10% risk scenario as compared to the 2% risk scenario. These findings remained consistent among a subset of participants who indicated cannabis use. Results suggest that cannabis users and non-users were positively influenced in terms of intentions to change behaviour based on the magnitude of risk conveyed by genetic testing. These findings provide an initial step towards understanding young people's attitudes towards genetic testing and may help prepare interventions specifically tailored around cannabis use reduction for people at risk for schizophrenia. © 2014 Wiley Publishing Asia Pty Ltd.

Attitudes towards cannabis use and genetic testing for schizophrenia

PubMed Central

Schiffman, Jason; Lawrence, Ryan E.; Demro, Caroline; Appelbaum, Paul S.; Dixon, Lisa

2014-01-01

Aim Within schizophrenia, genetic factors contribute greatly to risk, yet genetic testing for the disorder is not available. For some individuals with specific genotypes, cannabis use may increase risk of schizophrenia. It is possible that genetic tests could be offered in the future to inform individuals of the risk of schizophrenia if they use cannabis. Previous research, however, provides little guidance on how young adults might respond to such tests. Methods We assessed a group of young adults (n = 83) to determine how the perceived magnitude of increased risk for schizophrenia in the presence of cannabis use influences decisions to undergo genetic testing, as well as subsequent attitudes and intentions towards cannabis use. Results Participants were significantly more likely to indicate willingness to get tested if the results identified a 10% risk versus a 2% risk of schizophrenia. Participants also indicated that if the results of their test reflected increased risk due to cannabis use, it would be more important to avoid cannabis in the 10% risk scenario as compared to the 2% risk scenario. These findings remained consistent among a subset of participants who indicated cannabis use. Conclusions Results suggest that cannabis users and non-users were positively influenced in terms of intentions to change behavior based on the magnitude of risk conveyed by genetic testing. These findings provide an initial step towards understanding young people’s attitudes towards genetic testing and may help prepare interventions specifically tailored around cannabis use reduction for people at risk for schizophrenia. PMID:24957110

The changing landscape of genetic testing and its impact on clinical and laboratory services and research in Europe

PubMed Central

Hastings, Ros; de Wert, Guido; Fowler, Brian; Krawczak, Michael; Vermeulen, Eric; Bakker, Egbert; Borry, Pascal; Dondorp, Wybo; Nijsingh, Niels; Barton, David; Schmidtke, Jörg; van El, Carla G; Vermeesch, Joris; Stol, Yrrah; Carmen Howard, Heidi; Cornel, Martina C

2012-01-01

The arrival of new genetic technologies that allow efficient examination of the whole human genome (microarray, next-generation sequencing) will impact upon both laboratories (cytogenetic and molecular genetics in the first instance) and clinical/medical genetic services. The interpretation of analytical results in terms of their clinical relevance and the predicted health status poses a challenge to both laboratory and clinical geneticists, due to the wealth and complexity of the information obtained. There is a need to discuss how to best restructure the genetic services logistically and to determine the clinical utility of genetic testing so that patients can receive appropriate advice and genetic testing. To weigh up the questions and challenges of the new genetic technologies, the European Society of Human Genetics (ESHG) held a series of workshops on 10 June 2010 in Gothenburg. This was part of an ESHG satellite symposium on the ‘Changing landscape of genetic testing', co-organized by the ESHG Genetic Services Quality and Public and Professional Policy Committees. The audience consisted of a mix of geneticists, ethicists, social scientists and lawyers. In this paper, we summarize the discussions during the workshops and present some of the identified ways forward to improve and adapt the genetic services so that patients receive accurate and relevant information. This paper covers ethics, clinical utility, primary care, genetic services and the blurring boundaries between healthcare and research. PMID:22453292

Race, Genomics and Chronic Disease: What Patients with African Ancestry Have to Say

PubMed Central

Horowitz, Carol R.; Ferryman, Kadija; Negron, Rennie; Sabin, Tatiana; Rodriguez, Mayra; Zinberg, Randi F.; Böttinger, Erwin; Robinson, Mimsie

2017-01-01

Background Variants of the APOL1 gene increase risk for kidney failure 10- fold, and are nearly exclusively found in people with African ancestry. To translate genomic discoveries into practice, we gathered information about effects and challenges incorporating genetic risk in clinical care. Methods An academic- community- clinical team tested 26 adults with self- reported African ancestry for APOL1 variants, conducting in- depth interviews about patients' beliefs and attitudes toward genetic testing- before, immediately, and 30 days after receiving test results. We used constant comparative analysis of interview transcripts to identify themes. Results Themes included: Knowledge of genetic risk for kidney failure may motivate providers and patients to take hypertension more seriously, rather than inspiring fatalism or anxiety. Having genetic risk for a disease may counter stereotypes of Blacks as non- adherent or low- literate, rather than exacerbate stereotypes. Conclusion Populations most likely to benefit from genomic research can inform strategies for genetic testing and future research. PMID:28238999

Cost sharing and hereditary cancer risk: predictors of willingness-to-pay for genetic testing.

PubMed

Matro, Jennifer M; Ruth, Karen J; Wong, Yu-Ning; McCully, Katen C; Rybak, Christina M; Meropol, Neal J; Hall, Michael J

2014-12-01

Increasing use of predictive genetic testing to gauge hereditary cancer risk has been paralleled by rising cost-sharing practices. Little is known about how demographic and psychosocial factors may influence individuals' willingness-to-pay for genetic testing. The Gastrointestinal Tumor Risk Assessment Program Registry includes individuals presenting for genetic risk assessment based on personal/family cancer history. Participants complete a baseline survey assessing cancer history and psychosocial items. Willingness-to-pay items include intention for: genetic testing only if paid by insurance; testing with self-pay; and amount willing-to-pay ($25-$2,000). Multivariable models examined predictors of willingness-to-pay out-of-pocket (versus only if paid by insurance) and willingness-to-pay a smaller versus larger sum (≤$200 vs. ≥$500). All statistical tests are two-sided (α = 0.05). Of 385 evaluable participants, a minority (42%) had a personal cancer history, while 56% had ≥1 first-degree relative with colorectal cancer. Overall, 21.3% were willing to have testing only if paid by insurance, and 78.7% were willing-to-pay. Predictors of willingness-to-pay were: 1) concern for positive result; 2) confidence to control cancer risk; 3) fewer perceived barriers to colorectal cancer screening; 4) benefit of testing to guide screening (all p < 0.05). Subjects willing-to-pay a higher amount were male, more educated, had greater cancer worry, fewer relatives with colorectal cancer, and more positive attitudes toward genetic testing (all p < 0.05). Individuals seeking risk assessment are willing-to-pay out-of-pocket for genetic testing, and anticipate benefits to reducing cancer risk. Identifying factors associated with willingness-to-pay for genetic services is increasingly important as testing is integrated into routine cancer care.

Cost sharing and hereditary cancer risk: Predictors of willingness-to-pay for genetic testing

PubMed Central

Matro, Jennifer M.; Ruth, Karen J.; Wong, Yu-Ning; McCully, Katen C.; Rybak, Christina M.; Meropol, Neal J.; Hall, Michael J.

2015-01-01

Increasing use of predictive genetic testing to gauge hereditary cancer risk has been paralleled by rising cost-sharing practices. Little is known about how demographic and psychosocial factors may influence individuals’ willingness-to-pay for genetic testing. The Gastrointestinal Tumor Risk Assessment Program Registry includes individuals presenting for genetic risk assessment based on personal/family cancer history. Participants complete a baseline survey assessing cancer history and psychosocial items. Willingness-to-pay items include intention for: genetic testing only if paid by insurance; testing with self-pay; and amount willing-to-pay ($25–$2000). Multivariable models examined predictors of willingness-to-pay out-of-pocket (versus only if paid by insurance) and willingness-to-pay a smaller versus larger sum (≤200 vs. ≥$500). All statistical tests are two-sided (α=0.05). Of 385 evaluable participants, a minority (42%) had a personal cancer history, while 56% had ≥1 first-degree relative with colorectal cancer. Overall, 21.3% were willing to have testing only if paid by insurance, and 78.7% were willing-to-pay. Predictors of willingness-to-pay were: 1) concern for positive result; 2) confidence to control cancer risk; 3) fewer perceived barriers to colorectal cancer screening; 4) benefit of testing to guide screening (all p<0.05). Subjects willing-to-pay a higher amount were male, more educated, had greater cancer worry, fewer relatives with colorectal cancer, and more positive attitudes toward genetic testing (all p<0.05). Individuals seeking risk assessment are willing-to-pay out-of-pocket for genetic testing, and anticipate benefits to reducing cancer risk. Identifying factors associated with willingness-to-pay for genetic services is increasingly important as testing is integrated into routine cancer care. PMID:24794065

Scope for more genetic testing in learning disability. Case report of an inherited duplication on the X-chromosome.

PubMed

Robertshaw, B A; MacPherson, J

2006-08-01

There have been major advances in the past few years in our understanding of the X-linked learning disabilities. The most common of these is the fragile-X syndrome, but the number of other gene defects that are now recognised to be linked with learning disability is increasing year on year. We describe one family displaying a family displaying a rare X-linked abnormality. Repeat genetic testing was requested for a family member with mild learning disability when, following chromosomal analysis for her brother, it became known that he had a genetic defect. The genetic defect 46, Xdup(X) (p22.13 p22.31) was identified. To our knowledge this is the first time this precise configuration has been demonstrated. We conclude that genetic testing for individuals with learning disability is worthwhile, even when there may be only a low index of suspicion.

Participation of Korean families at high risk for hereditary breast and ovarian cancer in BRCA1/2 genetic testing.

PubMed

Sun, Young; Kang, Eunyoung; Baek, Hyunnam; Jung, Jaehag; Hwang, Euijun; Koo, Jauk; Kim, Eun-Kyu; Kim, Sung-Won

2015-06-01

The aim of our study was to determine the rate of participation in genetic testing, to determine the reasons for non-participation and to identify the factors affecting participation in BRCA genetic testing for high-risk patients. This study was performed through a retrospective review of 804 individuals who underwent genetic counseling for BRCA1/2 gene mutations at Seoul National University Bundang Hospital between July 2003 and September 2012. In total, 728 (90.5%) individuals underwent BRCA1/2 mutation screening after the initial genetic counseling; 88.2% of 647 probands and 100% of 157 family members were screened. In multivariate analysis, family history of breast cancer and younger age were independent variables affecting participation in genetic testing. Of the 132 people who initially declined genetic testing, 58 (43.9%) postponed the decision, 30 (22.7%) needed time to discuss the issue with family members, 22 (16.7%) did not want to know if they had a BRCA1/2 mutation, and 22 (16.7%) declined the test because of financial problems. When analyzing refusal of testing according to the time period before and after the implementation of national health insurance coverage for BRCA1/2 genetic testing, the critical reason given for refusal was different. After insurance coverage, refusal for financial reason was decreased from 61.1 to 9.6%. A family history of breast cancer and a younger age were important factors associated with participation in genetic testing. National health insurance decreased the proportion of individuals who did not participate in testing owing to a financial reason. In genetic counseling, we have to understand these issues and consider several factors that may influence an individual's decision to be tested. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Assessing the readiness of precision medicine interoperabilty: An exploratory study of the National Institutes of Health genetic testing registry.

PubMed

Ronquillo, Jay G; Weng, Chunhua; Lester, William T

2017-11-17

  Precision medicine involves three major innovations currently taking place in healthcare:  electronic health records, genomics, and big data.  A major challenge for healthcare providers, however, is understanding the readiness for practical application of initiatives like precision medicine.   To better understand the current state and challenges of precision medicine interoperability using a national genetic testing registry as a starting point, placed in the context of established interoperability formats.   We performed an exploratory analysis of the National Institutes of Health Genetic Testing Registry.  Relevant standards included Health Level Seven International Version 3 Implementation Guide for Family History, the Human Genome Organization Gene Nomenclature Committee (HGNC) database, and Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT).  We analyzed the distribution of genetic testing laboratories, genetic test characteristics, and standardized genome/clinical code mappings, stratified by laboratory setting. There were a total of 25472 genetic tests from 240 laboratories testing for approximately 3632 distinct genes.  Most tests focused on diagnosis, mutation confirmation, and/or risk assessment of germline mutations that could be passed to offspring.  Genes were successfully mapped to all HGNC identifiers, but less than half of tests mapped to SNOMED CT codes, highlighting significant gaps when linking genetic tests to standardized clinical codes that explain the medical motivations behind test ordering.  Conclusion:  While precision medicine could potentially transform healthcare, successful practical and clinical application will first require the comprehensive and responsible adoption of interoperable standards, terminologies, and formats across all aspects of the precision medicine pipeline.

Promises, pitfalls and practicalities of prenatal whole exome sequencing.

PubMed

Best, Sunayna; Wou, Karen; Vora, Neeta; Van der Veyver, Ignatia B; Wapner, Ronald; Chitty, Lyn S

2018-01-01

Prenatal genetic diagnosis provides information for pregnancy and perinatal decision-making and management. In several small series, prenatal whole exome sequencing (WES) approaches have identified genetic diagnoses when conventional tests (karyotype and microarray) were not diagnostic. Here, we review published prenatal WES studies and recent conference abstracts. Thirty-one studies were identified, with diagnostic rates in series of five or more fetuses varying between 6.2% and 80%. Differences in inclusion criteria and trio versus singleton approaches to sequencing largely account for the wide range of diagnostic rates. The data suggest that diagnostic yields will be greater in fetuses with multiple anomalies or in cases preselected following genetic review. Beyond its ability to improve diagnostic rates, we explore the potential of WES to improve understanding of prenatal presentations of genetic disorders and lethal fetal syndromes. We discuss prenatal phenotyping limitations, counselling challenges regarding variants of uncertain significance, incidental and secondary findings, and technical problems in WES. We review the practical, ethical, social and economic issues that must be considered before prenatal WES could become part of routine testing. Finally, we reflect upon the potential future of prenatal genetic diagnosis, including a move towards whole genome sequencing and non-invasive whole exome and whole genome testing. © 2017 John Wiley & Sons, Ltd. © 2017 John Wiley & Sons, Ltd.

A Report on Molecular Diagnostic Testing for Inherited Retinal Dystrophies by Targeted Genetic Analyses.

PubMed

Ramkumar, Hema L; Gudiseva, Harini V; Kishaba, Kameron T; Suk, John J; Verma, Rohan; Tadimeti, Keerti; Thorson, John A; Ayyagari, Radha

2017-02-01

To test the utility of targeted sequencing as a method of clinical molecular testing in patients diagnosed with inherited retinal degeneration (IRD). After genetic counseling, peripheral blood was drawn from 188 probands and 36 carriers of IRD. Single gene testing was performed on each patient in a Clinical Laboratory Improvement Amendment (CLIA) certified laboratory. DNA was isolated, and all exons in the gene of interest were analyzed along with 20 base pairs of flanking intronic sequence. Genetic testing was most often performed on ABCA4, CTRP5, ELOV4, BEST1, CRB1, and PRPH2. Pathogenicity of novel sequence changes was predicted by PolyPhen2 and sorting intolerant from tolerant (SIFT). Of the 225 genetic tests performed, 150 were for recessive IRD, and 75 were for dominant IRD. A positive molecular diagnosis was made in 70 (59%) of probands with recessive IRD and 19 (26%) probands with dominant IRD. Analysis confirmed 12 (34%) of individuals as carriers of familial mutations associated with IRD. Thirty-two novel variants were identified; among these, 17 sequence changes in four genes were predicted to be possibly or probably damaging including: ABCA4 (14), BEST1 (2), PRPH2 (1), and TIMP3 (1). Targeted analysis of clinically suspected genes in 225 subjects resulted in a positive molecular diagnosis in 26% of patients with dominant IRD and 59% of patients with recessive IRD. Novel damaging mutations were identified in four genes. Single gene screening is not an ideal method for diagnostic testing given the phenotypic and genetic heterogeneity among IRD cases. High-throughput sequencing of all genes associated with retinal degeneration may be more efficient for molecular diagnosis.

Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline.

PubMed

Weissman, Scott M; Burt, Randall; Church, James; Erdman, Steve; Hampel, Heather; Holter, Spring; Jasperson, Kory; Kalady, Matt F; Haidle, Joy Larsen; Lynch, Henry T; Palaniappan, Selvi; Wise, Paul E; Senter, Leigha

2012-08-01

Identifying individuals who have Lynch syndrome (LS) involves a complex diagnostic work up that includes taking a detailed family history and a combination of various genetic and immunohistochemical tests. The National Society of Genetic Counselors (NSGC) and the Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA-ICC) have come together to publish this clinical practice testing guideline for the evaluation of LS. The purpose of this practice guideline is to provide guidance and a testing algorithm for LS as well as recommendations on when to offer testing. This guideline does not replace a consultation with a genetics professional. This guideline includes explanations in support of this and a summary of background data. While this guideline is not intended to serve as a review of LS, it includes a discussion of background information on LS, and cites a number of key publications which should be reviewed for a more in-depth understanding of LS. These guidelines are intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses and other healthcare providers who evaluate patients for LS.

A Population Genetic Signal of Polygenic Adaptation

PubMed Central

Berg, Jeremy J.; Coop, Graham

2014-01-01

Adaptation in response to selection on polygenic phenotypes may occur via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from genome-wide association studies (GWAS). Here we combine this knowledge from GWAS with robust population genetic modeling to identify traits that may have been influenced by local adaptation. We exploit the fact that GWAS provide an estimate of the additive effect size of many loci to estimate the mean additive genetic value for a given phenotype across many populations as simple weighted sums of allele frequencies. We use a general model of neutral genetic value drift for an arbitrary number of populations with an arbitrary relatedness structure. Based on this model, we develop methods for detecting unusually strong correlations between genetic values and specific environmental variables, as well as a generalization of comparisons to test for over-dispersion of genetic values among populations. Finally we lay out a framework to identify the individual populations or groups of populations that contribute to the signal of overdispersion. These tests have considerably greater power than their single locus equivalents due to the fact that they look for positive covariance between like effect alleles, and also significantly outperform methods that do not account for population structure. We apply our tests to the Human Genome Diversity Panel (HGDP) dataset using GWAS data for height, skin pigmentation, type 2 diabetes, body mass index, and two inflammatory bowel disease datasets. This analysis uncovers a number of putative signals of local adaptation, and we discuss the biological interpretation and caveats of these results. PMID:25102153

Association Study of Common Genetic Variants and HIV-1 Acquisition in 6,300 Infected Cases and 7,200 Controls

PubMed Central

Ripke, Stephan; van den Berg, Leonard; Buchbinder, Susan; Carrington, Mary; Cossarizza, Andrea; Dalmau, Judith; Deeks, Steven G.; Delaneau, Olivier; De Luca, Andrea; Goedert, James J.; Haas, David; Herbeck, Joshua T.; Kathiresan, Sekar; Kirk, Gregory D.; Lambotte, Olivier; Luo, Ma; Mallal, Simon; van Manen, Daniëlle; Martinez-Picado, Javier; Meyer, Laurence; Miro, José M.; Mullins, James I.; Obel, Niels; O'Brien, Stephen J.; Pereyra, Florencia; Plummer, Francis A.; Poli, Guido; Qi, Ying; Rucart, Pierre; Sandhu, Manj S.; Shea, Patrick R.; Schuitemaker, Hanneke; Theodorou, Ioannis; Vannberg, Fredrik; Veldink, Jan; Walker, Bruce D.; Weintrob, Amy; Winkler, Cheryl A.; Wolinsky, Steven; Telenti, Amalio; Goldstein, David B.; de Bakker, Paul I. W.; Zagury, Jean-François; Fellay, Jacques

2013-01-01

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size. PMID:23935489

Key messages for communicating information about BRCA1 and BRCA2 to women with breast or ovarian cancer: Consensus across health professionals and service users.

PubMed

Jacobs, Chris; Pichert, Gabriella; Harris, Jackie; Tucker, Kathy; Michie, Susan

2017-11-01

Genetic testing of cancer predisposing genes will increasingly be needed in oncology clinics to target cancer treatment. This Delphi study aimed to identify areas of agreement and disagreement between genetics and oncology health professionals and service users about the key messages required by women with breast/ovarian cancer who undergo BRCA1/BRCA2 genetic testing and the optimal timing of communicating key messages. Participants were 16 expert health professionals specialising in oncology/genetics and 16 service users with breast/ovarian cancer and a pathogenic BRCA1/BRCA2 variant. Online questionnaires containing 53 inductively developed information messages were circulated to the groups separately. Participants rated each message as key/not key on a Likert scale and suggested additional messages. Questionnaires were modified according to the feedback and up to 3 rounds were circulated. Consensus was reached when there was ≥75% agreement. Thirty key messages were agreed by both groups with 7 of the key messages agreed by ≥95% of participants: dominant inheritance, the availability of predictive testing, the importance of pretest discussion, increased risk of breast and ovarian cancer, and the option of risk-reducing mastectomy and bilateral salpingo-oophorectomy. Both groups agreed that key messages should be communicated before genetic testing and once a pathogenic variant has been identified. There was a high level of agreement within and between the groups about the information requirements of women with breast/ovarian cancer about BRCA1/BRCA2. These key messages will be helpful in developing new approaches to the delivery of information as genetic testing becomes further integrated into mainstream oncology services. Copyright © 2017 John Wiley & Sons, Ltd.

Splice site mutations in GH1 detected in previously (Genetically) undiagnosed families with congenital isolated growth hormone deficiency type II.

PubMed

Kempers, M J E; van der Crabben, S N; de Vroede, M; Alfen-van der Velden, J; Netea-Maier, R T; Duim, R A J; Otten, B J; Losekoot, M; Wit, J M

2013-01-01

Congenital isolated growth hormone deficiency (IGHD) is a rare endocrine disorder that presents with severe proportionate growth failure. Dominant (type II) IGHD is usually caused by heterozygous mutations of GH1. The presentation of newly affected family members in 3 families with dominant IGHD in whom previous genetic testing had not demonstrated a GH1 mutation or had not been performed, prompted us to identify the underlying genetic cause. GH1 was sequenced in 3 Caucasian families with a clinical autosomal dominant IGHD. All affected family members had severe growth hormone (GH) deficiency that became apparent in the first 2 years of life. GH treatment led to a marked increase in height SDS. So far, no other pituitary dysfunctions have become apparent. In the first family a novel splice site mutation in GH1 was identified (c.172-1G>C, IVS2-1G>C). In two other families a previously reported splice site mutation (c.291+1G>A, IVS3+1G>A) was found. These data show that several years after negative genetic testing it was now possible to make a genetic diagnosis in these families with a well-defined, clearly heritable, autosomal dominant IGHD. This underscores the importance of clinical and genetic follow-up in a multidisciplinary setting. It also shows that even without a positive family history, genetic testing should be considered if the phenotype is strongly suggestive for a genetic syndrome. Identification of pathogenic mutations, like these GH1 mutations, has important clinical implications for the surveillance and genetic counseling of patients and expands our knowledge on the genotype-phenotype correlation. © 2013 S. Karger AG, Basel.

Men in the women's world of hereditary breast and ovarian cancer--a systematic review.

PubMed

Strømsvik, Nina; Råheim, Målfrid; Oyen, Nina; Gjengedal, Eva

2009-01-01

Little is known about men seeking genetic counseling for hereditary breast and ovarian cancer (HBOC). We review the sparse literature on men attending such genetic consultations. Two main themes are identified: the women's influence on the genetic counseling process, and the psychological impact on men. The women in the HBOC families have an influence on the men's decision to request genetic testing, and they take the leading role in communicating genetic information. With respect to psychological impact, the men suffer from grief and fear of developing cancer, and they seem to use avoidance as a coping strategy. Carrier males experience feelings of guilt because they might have passed on a mutation to their children. Non-carriers experience test-related stress if their siblings tested positive. Mutation status may have an impact on reproductive issues. These findings are discussed in light of gender issues and literature concerning men's health behavior. Further studies are needed to provide optimal care for men seeking genetic counseling for hereditary breast and ovarian cancer.

Role of genetic testing in patients undergoing percutaneous coronary intervention.

PubMed

Moon, Jae Youn; Franchi, Francesco; Rollini, Fabiana; Rivas Rios, Jose R; Kureti, Megha; Cavallari, Larisa H; Angiolillo, Dominick J

2018-02-01

Variability in individual response profiles to antiplatelet therapy, in particular clopidogrel, is a well-established phenomenon. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been associated with clopidogrel response profiles. Moreover, the presence of a CYP2C19 loss-of-function allele is associated with an increased risk of atherothrombotic events among clopidogrel-treated patients undergoing percutaneous coronary interventions (PCI), prompting studies evaluating the use of genetic tests to identify patients who may be potential candidates for alternative platelet P2Y 12 receptor inhibiting therapies (prasugrel or ticagrelor). Areas covered: The present manuscript provides an overview of genetic factors associated with response profiles to platelet P2Y 12 receptor inhibitors and their clinical implications, as well as the most recent developments and future considerations on the role of genetic testing in patients undergoing PCI. Expert commentary: The availability of more user-friendly genetic tests has contributed towards the development of many ongoing clinical trials and personalized medicine programs for patients undergoing PCI. Results of pilot investigations have shown promising results, which however need to be confirmed in larger-scale studies to support the routine use of genetic testing as a strategy to personalize antiplatelet therapy and improve clinical outcomes.

"They Just Want to Know" - Genetic Health Professionals' Beliefs About Why Parents Want to Know their Child's Carrier Status.

PubMed

Vears, Danya F; Delany, Clare; Massie, John; Gillam, Lynn

2017-12-01

In the context of a child being diagnosed with a genetic condition, reports from both parents and health professionals suggest many genetic health professionals are reluctant to provide carrier testing for unaffected siblings, despite the lack of evidence of harm. We propose that genetic health professionals' understandings of why parents want to have their children tested may contribute to their reluctance to test. We draw on interviews with 17 genetic health professionals, reporting their beliefs about parents' motivations for testing and their intentions to communicate results to their children. Data were analyzed using inductive content analysis. Genetic health professionals reported attributions that contrasted with reasons parents actually report. These disparities fall into two categories: 1) attributing reasons that parents do not themselves report (i.e. for reassurance about their child's health), and 2) not recognizing the reasons that parents actually do report for wanting testing (i.e. to communicate the information to their child). By identifying that genetic health professionals may be misattributing reasons to parents for desiring their child"s carrier status, they may be missing an opportunity to assist parents to make decisions that are in line with their values and the best interests of the family.

Role of Genetic Testing in Patients undergoing Percutaneous Coronary Intervention

PubMed Central

Moon, Jae Youn; Franchi, Francesco; Rollini, Fabiana; Rios, Jose R. Rivas; Kureti, Megha; Cavallari, Larisa H.; Angiolillo, Dominick J.

2017-01-01

Introduction Variability in individual response profiles to antiplatelet therapy, in particular clopidogrel, is a well-established phenomenon. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been associated with clopidogrel response profiles. Moreover, the presence of a CYP2C19 loss-of-function allele is associated with an increased risk of atherothrombotic events among clopidogrel-treated patients undergoing percutaneous coronary interventions (PCI), prompting studies evaluating the use of genetic tests to identify patients who may be potential candidates for alternative platelet P2Y12 receptor inhibiting therapies (prasugrel or ticagrelor). Areas covered The present manuscript provides an overview of genetic factors associated with response profiles to platelet P2Y12 receptor inhibitors and their clinical implications, as well as the most recent developments and future considerations on the role of genetic testing in patients undergoing PCI. Expert Commentary The availability of more user-friendly genetic tests has contributed towards the development of many ongoing clinical trials and personalized medicine programs for patients undergoing PCI. Results of pilot investigations have shown promising results, which however need to be confirmed in larger-scale studies to support the routine use of genetic testing as a strategy to personalize antiplatelet therapy and improve clinical outcomes. PMID:28689434

DOE Office of Scientific and Technical Information (OSTI.GOV)

Golbus, Jessica R.; Puckelwartz, Megan J.; Dellefave-Castillo, Lisa

Background—Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of more than 50 genes. New genes are routinely added to panels to improve the diagnostic yield. With the anticipated $1000 genome, it is expected that genetic testing will shift towards comprehensive genome sequencing accompanied by targeted gene analysis. Therefore, we assessed the reliability of whole genome sequencing and targeted analysis to identify cardiomyopathy variants in 11 subjects with cardiomyopathy. Methods and Results—Whole genome sequencing with an average of 37× coverage was combined with targeted analysis focused onmore » 204 genes linked to cardiomyopathy. Genetic variants were scored using multiple prediction algorithms combined with frequency data from public databases. This pipeline yielded 1-14 potentially pathogenic variants per individual. Variants were further analyzed using clinical criteria and/or segregation analysis. Three of three previously identified primary mutations were detected by this analysis. In six subjects for whom the primary mutation was previously unknown, we identified mutations that segregated with disease, had clinical correlates, and/or had additional pathological correlation to provide evidence for causality. For two subjects with previously known primary mutations, we identified additional variants that may act as modifiers of disease severity. In total, we identified the likely pathological mutation in 9 of 11 (82%) subjects. We conclude that these pilot data demonstrate that ~30-40× coverage whole genome sequencing combined with targeted analysis is feasible and sensitive to identify rare variants in cardiomyopathy-associated genes.« less

Inherited epilepsy in dogs.

PubMed

Ekenstedt, Kari J; Oberbauer, Anita M

2013-05-01

Epilepsy is the most common neurologic disease in dogs and many forms are considered to have a genetic basis. In contrast, some seizure disorders are also heritable, but are not technically defined as epilepsy. Investigation of true canine epilepsies has uncovered genetic associations in some cases, however, many remain unexplained. Gene mutations have been described for 2 forms of canine epilepsy: primary epilepsy (PE) and progressive myoclonic epilepsies. To date, 9 genes have been described to underlie progressive myoclonic epilepsies in several dog breeds. Investigations into genetic PE have been less successful, with only 1 causative gene described. Genetic testing as an aid to diagnosis, prognosis, and breeding decisions is available for these 10 forms. Additional studies utilizing genome-wide tools have identified PE loci of interest; however, specific genetic tests are not yet developed. Many studies of dog breeds with PE have failed to identify genes or loci of interest, suggesting that, similar to what is seen in many human genetic epilepsies, inheritance is likely complex, involving several or many genes, and reflective of environmental interactions. An individual dog's response to therapeutic intervention for epilepsy may also be genetically complex. Although the field of inherited epilepsy has faced challenges, particularly with PE, newer technologies contribute to further advances. © 2013 Elsevier Inc. All rights reserved.

Inferring Causalities in Landscape Genetics: An Extension of Wright's Causal Modeling to Distance Matrices.

PubMed

Fourtune, Lisa; Prunier, Jérôme G; Paz-Vinas, Ivan; Loot, Géraldine; Veyssière, Charlotte; Blanchet, Simon

2018-04-01

Identifying landscape features that affect functional connectivity among populations is a major challenge in fundamental and applied sciences. Landscape genetics combines landscape and genetic data to address this issue, with the main objective of disentangling direct and indirect relationships among an intricate set of variables. Causal modeling has strong potential to address the complex nature of landscape genetic data sets. However, this statistical approach was not initially developed to address the pairwise distance matrices commonly used in landscape genetics. Here, we aimed to extend the applicability of two causal modeling methods-that is, maximum-likelihood path analysis and the directional separation test-by developing statistical approaches aimed at handling distance matrices and improving functional connectivity inference. Using simulations, we showed that these approaches greatly improved the robustness of the absolute (using a frequentist approach) and relative (using an information-theoretic approach) fits of the tested models. We used an empirical data set combining genetic information on a freshwater fish species (Gobio occitaniae) and detailed landscape descriptors to demonstrate the usefulness of causal modeling to identify functional connectivity in wild populations. Specifically, we demonstrated how direct and indirect relationships involving altitude, temperature, and oxygen concentration influenced within- and between-population genetic diversity of G. occitaniae.

Polygenic risk predicts obesity in both white and black young adults.

PubMed

Domingue, Benjamin W; Belsky, Daniel W; Harris, Kathleen Mullan; Smolen, Andrew; McQueen, Matthew B; Boardman, Jason D

2014-01-01

To test transethnic replication of a genetic risk score for obesity in white and black young adults using a national sample with longitudinal data. A prospective longitudinal study using the National Longitudinal Study of Adolescent Health Sibling Pairs (n = 1,303). Obesity phenotypes were measured from anthropometric assessments when study members were aged 18-26 and again when they were 24-32. Genetic risk scores were computed based on published genome-wide association study discoveries for obesity. Analyses tested genetic associations with body-mass index (BMI), waist-height ratio, obesity, and change in BMI over time. White and black young adults with higher genetic risk scores had higher BMI and waist-height ratio and were more likely to be obese compared to lower genetic risk age-peers. Sibling analyses revealed that the genetic risk score was predictive of BMI net of risk factors shared by siblings. In white young adults only, higher genetic risk predicted increased risk of becoming obese during the study period. In black young adults, genetic risk scores constructed using loci identified in European and African American samples had similar predictive power. Cumulative information across the human genome can be used to characterize individual level risk for obesity. Measured genetic risk accounts for only a small amount of total variation in BMI among white and black young adults. Future research is needed to identify modifiable environmental exposures that amplify or mitigate genetic risk for elevated BMI.

Genetic Evaluation of Short Stature

PubMed Central

Rosenfeld, Ron G.

2014-01-01

Context: Genetics plays a major role in determining an individual's height. Although there are many monogenic disorders that lead to perturbations in growth and result in short stature, there is still no consensus as to the role that genetic diagnostics should play in the evaluation of a child with short stature. Evidence Acquisition: A search of PubMed was performed, focusing on the genetic diagnosis of short stature as well as on specific diagnostic subgroups included in this article. Consensus guidelines were reviewed. Evidence Synthesis: There are a multitude of rare genetic causes of severe short stature. There is no high-quality evidence to define the optimal approach to the genetic evaluation of short stature. We review genetic etiologies of a number of diagnostic subgroups and propose an algorithm for genetic testing based on these subgroups. Conclusion: Advances in genomic technologies are revolutionizing the diagnostic approach to short stature. Endocrinologists must become facile with the use of genetic testing in order to identify the various monogenic disorders that present with short stature. PMID:24915122

Implementation of personalized medicine in Central-Eastern Europe: pitfalls and potentials based on citizen's attitude.

PubMed

Balicza, Peter; Terebessy, Andras; Grosz, Zoltan; Varga, Noemi Agnes; Gal, Aniko; Fekete, Balint Andras; Molnar, Maria Judit

2018-03-01

Next-generation sequencing is increasingly utilized worldwide as a research and diagnostic tool and is anticipated to be implemented into everyday clinical practice. Since Central-Eastern European attitude toward genetic testing, especially broad genetic testing, is not well known, we performed a survey on this issue among Hungarian participants. A self-administered questionnaire was distributed among patients and patient relatives at our neurogenetic outpatient clinic. Members of the general population were also recruited via public media. We used chi-square testing and binary logistic regression to examine factors influencing attitude. We identified a mixed attitude toward genetic testing. Access to physician consultation positively influenced attitude. A higher self-determined genetic familiarity score associated with higher perceived genetic influence score, which in turn associated with greater willingness to participate in genetic testing. Medical professionals constituted a skeptical group. We think that given the controversies and complexities of the next-generation sequencing field, the optimal clinical translation of NGS data should be performed in institutions which have the unique capability to provide interprofessional health education, transformative biomedical research, and crucial patient care. With optimization of the clinical translational process, improvement of genetic literacy may increase patient engagement and empowerment. The paper highlights that in countries with relatively low-genetic literacy, a special strategy is needed to enhance the implementation of personalized medicine.

Are we ready for genetic testing for primary open-angle glaucoma?

PubMed

Khawaja, Anthony P; Viswanathan, Ananth C

2018-05-01

Following a dramatic reduction in the cost of genotyping technology in recent years, there have been significant advances in the understanding of the genetic basis of glaucoma. Glaucoma patients represent around a quarter of all outpatient activity in the UK hospital eye service and are a huge burden for the National Health Service. A potential benefit of genetic testing is personalised glaucoma management, allowing direction of our limited healthcare resources to the glaucoma patients who most need it. Our review aims to summarise recent discoveries in the field of glaucoma genetics and to discuss their potential clinical utility. While genome-wide association studies have now identified over ten genes associated with primary open-angle glaucoma (POAG), individually, variants in these genes are not predictive of POAG in populations. There are data suggesting some of these POAG variants are associated with conversion from ocular hypertension to POAG and visual field progression among POAG patients. However, these studies have not been replicated yet and such genetic testing is not currently justified in clinical care. In contrast, genetic testing for inherited early-onset disease in relatives of POAG patients with a known genetic mutation is of clear benefit; this can support either regular review to commence early treatment when the disease develops, or discharge from ophthalmology services of relatives who do not carry the mutation. Genetic testing for POAG at a population level is not currently justified.

Aligning policy to promote cascade genetic screening for prevention and early diagnosis of heritable diseases.

PubMed

George, Rani; Kovak, Karen; Cox, Summer L

2015-06-01

Cascade genetic screening is a methodology for identifying and testing close blood relatives of individuals at increased risk for heritable conditions and follows a sequential process, minimizing testing costs and the number of family members who need to be tested. It offers considerable potential for cost savings and increased awareness of heritable conditions within families. CDC-classified Tier 1 genomic applications for hereditary breast and ovarian cancer syndrome (HBOC), Lynch Syndrome (LS), and familial hypercholesterolemia (FH) are recommended for clinical use and support the use of cascade genetic screening. Most individuals are unaware of their increased risk for heritable conditions such as HBOC, LS, and FH. Consistent implementation of cascade genetic screening could significantly increase awareness and prevention of heritable conditions. Limitations to effective implementation of cascade genetic screening include: insufficient genetic risk assessment and knowledge by a majority of healthcare providers without genetics credentials; a shortage of genetic specialists, especially in rural areas; a low rate of reimbursement for comprehensive genetic counseling services; and an individual focus on prevention by clinical guidelines and insurance coverage. The family-centric approach of cascade genetic screening improves prevention and early diagnosis of heritable diseases on a population health level. Cascade genetic screening could be better supported and augmented through changes in health policy.

Attitudes Towards Prenatal Genetic Counseling, Prenatal Genetic Testing, and Termination of Pregnancy among Southeast and East Asian Women in the United States.

PubMed

Tsai, Ginger J; Cameron, Carrie A; Czerwinski, Jennifer L; Mendez-Figueroa, Hector; Peterson, Susan K; Noblin, Sarah Jane

2017-10-01

Recognizing the heterogeneity of the Asian population with regards to acculturation, education, health awareness, and cultural values is vital for tailoring culturally sensitive and appropriate care. Prior studies show that cultural values influence perceptions of genetics within Asian populations. The reputation of the family unit factors into decisions such as pregnancy termination and disclosure of family medical history, and the nondirective model of American genetic counseling may conflict with the historical Asian model of paternalistic health care. Previous studies also provide conflicting evidence regarding correlations between education, acculturation, age, and awareness and perceptions of genetic testing. The aims of this study were to describe attitudes towards prenatal genetics among Southeast and East Asian women living in the United States for varying amounts of time and to explore sociocultural factors influencing those attitudes. Twenty-three Asian women who were members of Asian cultural organizations in the United States were interviewed via telephone about their attitudes towards prenatal genetic counseling, prenatal genetic testing, and termination of pregnancy. Responses were transcribed and coded for common themes using a thematic analysis approach. Four major themes emerged. In general, participants: (1) had diverse expectations for genetic counselors; (2) tended to weigh risks and benefits with regards to genetic testing decisions; (3) had mixed views on termination for lethal and non-lethal genetic conditions; and (4) identified cultural factors which influenced testing and termination such as lack of available resources, societal shame and stigma, and family pressure. These findings may allow prenatal genetic counselors to gain a richer, more nuanced understanding of their Asian patients and to offer culturally tailored prenatal genetic counseling.

The impact of patents on the development of genome-based clinical diagnostics: an analysis of case studies

PubMed Central

Pierce, Brandon L.; Carlson, Christopher S.; Kuszler, Patricia C.; Stanford, Janet L.; Austin, Melissa A.

2010-01-01

Purpose Fragmented ownership of diagnostic gene patents has the potential to create an ‘anticommons’ in the area of genomic diagnostics, making it difficult and expensive to assemble the patent rights necessary to develop a panel of genetic tests. The objectives of this study were to identify U.S. patents that protect existing panels of genetic tests, describe how (or if) test providers acquired rights to these patents, and determine if fragmented patent ownership has inhibited the commercialization of these panels. Methods As case studies, we selected four clinical applications of genetic testing (cystic fibrosis, maturity-onset diabetes of the young, long QT syndrome, and hereditary breast cancer) that utilize tests protected by ≥3 U.S. patents. We summarized publically available information on relevant patents, test providers, licenses, and litigation. Results For each case study, all tests of major genes/mutations were patented, and at least one party held the collective rights to conduct all relevant tests, often as a result of licensing agreements. Conclusions We did not find evidence that fragmentation of patent rights has inhibited commercialization of genetic testing services. However, as knowledge of genetic susceptibility increases, it will be important to consider the potential consequences of fragmented ownership of diagnostic gene patents. PMID:19367193

Socioeconomic influences on the effects of a genetic testing direct-to-consumer marketing campaign.

PubMed

Bowen, D J; Harris, J; Jorgensen, C M; Myers, M F; Kuniyuki, A

2010-01-01

Direct-to-consumer marketing of genetic tests is beginning to appear in select markets, and little independent evaluation has been conducted on the effects of this marketing on consumer attitudes or behavior. The purpose of this paper is to identify the effects of socioeconomic status on women's reactions to such a campaign, including knowledge of the test, perceptions of personal risk, communications with others about the test, and interest in pursuing the test. The only United States provider of genetic testing for breast and ovarian cancer susceptibility (BRCA1/2 testing) conducted a pilot marketing campaign that targeted women aged 25-54 and their health care providers in 2 cities, Atlanta, Ga., and Denver, Colo. The design for the evaluation was a post campaign consumer survey, based on a cross-sectional stratified random sample of women in the 2 intervention sites and 2 comparison sites. The campaign had no differential impact by socioeconomic status. However, there was a consistent relationship between socioeconomic status and several outcome variables, including knowledge of the test, beliefs about the test, and desire to know about genetic risk. These data indicate that socioeconomic status may play a role in uptake of genetic services, regardless of response to a media campaign. Copyright 2009 S. Karger AG, Basel.

What can we Learn from Patients' Ethical Thinking about the right 'not to know' in Genomics? Lessons from Cancer Genetic Testing for Genetic Counselling.

PubMed

Cowley, Lorraine

2016-10-01

This article is based on a qualitative empirical project about a distinct kinship group who were among the first identified internationally as having a genetic susceptibility to cancer (Lynch Syndrome). 50 were invited to participate (42 were tested; eight declined genetic testing). 15, who had all accepted testing, were interviewed. They form a unique case study. This study aimed to explore interviewees' experiences of genetic testing and how these influenced their family relationships. A key finding was that participants framed the decision to be tested as 'common sense'; the idea of choice around the decision was negated and replaced by a moral imperative to be tested. Those who did not follow 'common sense' were judged to be imprudent. Family members who declined testing were discussed negatively by participants. The article addresses what is ethically problematic about how test decliners were discussed and whether these ethical concerns extend to others who are offered genetic testing. Discussions showed that genetic testing was viewed as both an autonomous choice and a responsibility. Yet the apparent conflict between the right to autonomy and the moral imperative of responsibility allowed participants to defend test decliners' decisions by expressing a preference for or defending choice over responsibility. The 'right not to know' seemed an important moral construct to help ethically manage unpopular decisions made by close family who declined testing. In light of this research, the erosion of the 'right not to know' in the genomic age could have subtle yet profound consequences for family relationships. © 2016 The Authors. Bioethics Published by John Wiley & Sons Ltd.

What can we Learn from Patients’ Ethical Thinking about the right ‘not to know’ in Genomics? Lessons from Cancer Genetic Testing for Genetic Counselling

PubMed Central

2016-01-01

Abstract This article is based on a qualitative empirical project about a distinct kinship group who were among the first identified internationally as having a genetic susceptibility to cancer (Lynch Syndrome). 50 were invited to participate (42 were tested; eight declined genetic testing). 15, who had all accepted testing, were interviewed. They form a unique case study. This study aimed to explore interviewees’ experiences of genetic testing and how these influenced their family relationships. A key finding was that participants framed the decision to be tested as ‘common sense’; the idea of choice around the decision was negated and replaced by a moral imperative to be tested. Those who did not follow ‘common sense’ were judged to be imprudent. Family members who declined testing were discussed negatively by participants. The article addresses what is ethically problematic about how test decliners were discussed and whether these ethical concerns extend to others who are offered genetic testing. Discussions showed that genetic testing was viewed as both an autonomous choice and a responsibility. Yet the apparent conflict between the right to autonomy and the moral imperative of responsibility allowed participants to defend test decliners’ decisions by expressing a preference for or defending choice over responsibility. The ‘right not to know’ seemed an important moral construct to help ethically manage unpopular decisions made by close family who declined testing. In light of this research, the erosion of the ‘right not to know’ in the genomic age could have subtle yet profound consequences for family relationships. PMID:27523581

Motivation to Pursue Genetic Testing in Individuals with a Personal or Family History of Cardiac Events or Sudden Cardiac Death

PubMed Central

Erskine, Kathleen E.; Hidayatallah, Nadia Z.; Walsh, Christine A.; McDonald, Thomas V.; Cohen, Lilian; Marion, Robert W.; Dolan, Siobhan M.

2014-01-01

Genetic testing is becoming increasingly available for cardiac channelopathies, such as long QT syndrome and Brugada syndrome, which can lead to sudden cardiac death. Test results can be used to shape an individual’s medical management and to identify at-risk family members. In our qualitative study, all participants had a personal or family history of a diagnosed cardiac arrhythmia syndrome or sudden cardiac death. Open-ended interviews were conducted individually and in focus groups. Interviews were audio recorded, transcribed verbatim, and analyzed using a qualitative grounded-theory approach. Of 50 participants, 37 described their motivations for pursuing genetic testing for long QT syndrome or another cardiac channelopathy. Participants’ motivations included: to find an explanation for a family member’s sudden death, to relieve uncertainty regarding a diagnosis, to guide future medical management, to allay concern about children or other family members, and to comply with recommendations of physicians or family members. Perceived reasons not to pursue genetic testing included denial, fear, and lack of information. The genetic counseling and informed consent process can be enhanced by understanding and addressing an individual’s internal and external motivations either for or against pursuing genetic testing. PMID:24664857

A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic

PubMed Central

Madsen, Bo Eskerod; Browning, Sharon R.

2009-01-01

Resequencing is an emerging tool for identification of rare disease-associated mutations. Rare mutations are difficult to tag with SNP genotyping, as genotyping studies are designed to detect common variants. However, studies have shown that genetic heterogeneity is a probable scenario for common diseases, in which multiple rare mutations together explain a large proportion of the genetic basis for the disease. Thus, we propose a weighted-sum method to jointly analyse a group of mutations in order to test for groupwise association with disease status. For example, such a group of mutations may result from resequencing a gene. We compare the proposed weighted-sum method to alternative methods and show that it is powerful for identifying disease-associated genes, both on simulated and Encode data. Using the weighted-sum method, a resequencing study can identify a disease-associated gene with an overall population attributable risk (PAR) of 2%, even when each individual mutation has much lower PAR, using 1,000 to 7,000 affected and unaffected individuals, depending on the underlying genetic model. This study thus demonstrates that resequencing studies can identify important genetic associations, provided that specialised analysis methods, such as the weighted-sum method, are used. PMID:19214210

A Genome-Wide Association Analysis Reveals Epistatic Cancellation of Additive Genetic Variance for Root Length in Arabidopsis thaliana.

PubMed

Lachowiec, Jennifer; Shen, Xia; Queitsch, Christine; Carlborg, Örjan

2015-01-01

Efforts to identify loci underlying complex traits generally assume that most genetic variance is additive. Here, we examined the genetics of Arabidopsis thaliana root length and found that the genomic narrow-sense heritability for this trait in the examined population was statistically zero. The low amount of additive genetic variance that could be captured by the genome-wide genotypes likely explains why no associations to root length could be found using standard additive-model-based genome-wide association (GWA) approaches. However, as the broad-sense heritability for root length was significantly larger, and primarily due to epistasis, we also performed an epistatic GWA analysis to map loci contributing to the epistatic genetic variance. Four interacting pairs of loci were revealed, involving seven chromosomal loci that passed a standard multiple-testing corrected significance threshold. The genotype-phenotype maps for these pairs revealed epistasis that cancelled out the additive genetic variance, explaining why these loci were not detected in the additive GWA analysis. Small population sizes, such as in our experiment, increase the risk of identifying false epistatic interactions due to testing for associations with very large numbers of multi-marker genotypes in few phenotyped individuals. Therefore, we estimated the false-positive risk using a new statistical approach that suggested half of the associated pairs to be true positive associations. Our experimental evaluation of candidate genes within the seven associated loci suggests that this estimate is conservative; we identified functional candidate genes that affected root development in four loci that were part of three of the pairs. The statistical epistatic analyses were thus indispensable for confirming known, and identifying new, candidate genes for root length in this population of wild-collected A. thaliana accessions. We also illustrate how epistatic cancellation of the additive genetic variance explains the insignificant narrow-sense and significant broad-sense heritability by using a combination of careful statistical epistatic analyses and functional genetic experiments.

CLINICAL PROGRESS IN INHERITED RETINAL DEGENERATIONS: GENE THERAPY CLINICAL TRIALS AND ADVANCES IN GENETIC SEQUENCING.

PubMed

Hafler, Brian P

2017-03-01

Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies. This review serves to analyze clinical progress in genetic diagnostic testing and implications for retinal gene therapy. A literature search of PubMed and OMIM was conducted to relevant articles in inherited retinal dystrophies. Next-generation genetic sequencing allows the simultaneous analysis of all the approximately 250 genes that cause inherited retinal dystrophies. Reported diagnostic rates range are high and range from 51% to 57%. These new sequencing tools are highly accurate with sensitivities of 97.9% and specificities of 100%. Retinal gene therapy clinical trials are underway for multiple genes including RPE65, ABCA4, CHM, RS1, MYO7A, CNGA3, CNGB3, ND4, and MERTK for which a molecular diagnosis may be beneficial for patients. Comprehensive next-generation genetic sequencing of all retinal dystrophy genes is changing the paradigm for how retinal specialists perform genetic testing for inherited retinal degenerations. Not only are high diagnostic yields obtained, but mutations in genes with novel clinical phenotypes are also identified. In the era of retinal gene therapy clinical trials, identifying specific genetic defects will increasingly be of use to identify patients who may enroll in clinical studies and benefit from novel therapies.

Achieving behaviour change for detection of Lynch syndrome using the Theoretical Domains Framework Implementation (TDFI) approach: a study protocol.

PubMed

Taylor, Natalie; Long, Janet C; Debono, Deborah; Williams, Rachel; Salisbury, Elizabeth; O'Neill, Sharron; Eykman, Elizabeth; Braithwaite, Jeffrey; Chin, Melvin

2016-03-12

Lynch syndrome is an inherited disorder associated with a range of cancers, and found in 2-5 % of colorectal cancers. Lynch syndrome is diagnosed through a combination of significant family and clinical history and pathology. The definitive diagnostic germline test requires formal patient consent after genetic counselling. If diagnosed early, carriers of Lynch syndrome can undergo increased surveillance for cancers, which in turn can prevent late stage cancers, optimise treatment and decrease mortality for themselves and their relatives. However, over the past decade, international studies have reported that only a small proportion of individuals with suspected Lynch syndrome were referred for genetic consultation and possible genetic testing. The aim of this project is to use behaviour change theory and implementation science approaches to increase the number and speed of healthcare professional referrals of colorectal cancer patients with a high-likelihood risk of Lynch syndrome to appropriate genetic counselling services. The six-step Theoretical Domains Framework Implementation (TDFI) approach will be used at two large, metropolitan hospitals treating colorectal cancer patients. Steps are: 1) form local multidisciplinary teams to map current referral processes; 2) identify target behaviours that may lead to increased referrals using discussion supported by a retrospective audit; 3) identify barriers to those behaviours using the validated Influences on Patient Safety Behaviours Questionnaire and TDFI guided focus groups; 4) co-design interventions to address barriers using focus groups; 5) co-implement interventions; and 6) evaluate intervention impact. Chi square analysis will be used to test the difference in the proportion of high-likelihood risk Lynch syndrome patients being referred for genetic testing before and after intervention implementation. A paired t-test will be used to assess the mean time from the pathology test results to referral for high-likelihood Lynch syndrome patients pre-post intervention. Run charts will be used to continuously monitor change in referrals over time, based on scheduled monthly audits. This project is based on a tested and refined implementation strategy (TDFI approach). Enhancing the process of identifying and referring people at high-likelihood risk of Lynch syndrome for genetic counselling will improve outcomes for patients and their relatives, and potentially save public money.

Evaluation of the Affymetrix CytoScan® Dx Assay for Developmental Delay

PubMed Central

Webb, Bryn D.; Scharf, Rebecca J.; Spear, Emily A.; Edelmann, Lisa J.; Stroustrup, Annemarie

2015-01-01

The goal of molecular cytogenetic testing for children presenting with developmental delay is to identify or exclude genetic abnormalities that are associated with cognitive, behavioral, and/or motor symptoms. Until 2010, chromosome analysis was the standard first-line genetic screening test for evaluation of patients with developmental delay when a specific syndrome was not suspected. In 2010, The American College of Medical Genetics and several other groups recommended chromosomal microarray (CMA) as the first-line test in children with developmental delays, multiple congenital anomalies, and/or autism. This test is able to detect regions of genomic imbalances at a much finer resolution than G-banded karyotyping. Until recently, no CMA testing had been approved by the United States Food and Drug Administration (FDA). This review will focus on the use of the Affymetrix CytoScan® Dx Assay, the first CMA to receive FDA approval for the genetic evaluation of individuals with developmental delay. PMID:25350348

A Unified Framework for Association Analysis with Multiple Related Phenotypes

PubMed Central

Stephens, Matthew

2013-01-01

We consider the problem of assessing associations between multiple related outcome variables, and a single explanatory variable of interest. This problem arises in many settings, including genetic association studies, where the explanatory variable is genotype at a genetic variant. We outline a framework for conducting this type of analysis, based on Bayesian model comparison and model averaging for multivariate regressions. This framework unifies several common approaches to this problem, and includes both standard univariate and standard multivariate association tests as special cases. The framework also unifies the problems of testing for associations and explaining associations – that is, identifying which outcome variables are associated with genotype. This provides an alternative to the usual, but conceptually unsatisfying, approach of resorting to univariate tests when explaining and interpreting significant multivariate findings. The method is computationally tractable genome-wide for modest numbers of phenotypes (e.g. 5–10), and can be applied to summary data, without access to raw genotype and phenotype data. We illustrate the methods on both simulated examples, and to a genome-wide association study of blood lipid traits where we identify 18 potential novel genetic associations that were not identified by univariate analyses of the same data. PMID:23861737

Bayes factors based on robust TDT-type tests for family trio design.

PubMed

Yuan, Min; Pan, Xiaoqing; Yang, Yaning

2015-06-01

Adaptive transmission disequilibrium test (aTDT) and MAX3 test are two robust-efficient association tests for case-parent family trio data. Both tests incorporate information of common genetic models including recessive, additive and dominant models and are efficient in power and robust to genetic model specifications. The aTDT uses information of departure from Hardy-Weinberg disequilibrium to identify the potential genetic model underlying the data and then applies the corresponding TDT-type test, and the MAX3 test is defined as the maximum of the absolute value of three TDT-type tests under the three common genetic models. In this article, we propose three robust Bayes procedures, the aTDT based Bayes factor, MAX3 based Bayes factor and Bayes model averaging (BMA), for association analysis with case-parent trio design. The asymptotic distributions of aTDT under the null and alternative hypothesis are derived in order to calculate its Bayes factor. Extensive simulations show that the Bayes factors and the p-values of the corresponding tests are generally consistent and these Bayes factors are robust to genetic model specifications, especially so when the priors on the genetic models are equal. When equal priors are used for the underlying genetic models, the Bayes factor method based on aTDT is more powerful than those based on MAX3 and Bayes model averaging. When the prior placed a small (large) probability on the true model, the Bayes factor based on aTDT (BMA) is more powerful. Analysis of a simulation data about RA from GAW15 is presented to illustrate applications of the proposed methods.

Molecular characterization of high performance inbred lines of Brazilian common beans.

PubMed

Cardoso, P C B; Veiga, M M; de Menezes, I P P; Valdisser, P A M R; Borba, T C O; Melo, L C; Del Peloso, M J; Brondani, C; Vianello, R P

2013-02-06

The identification of germplasm genetic variability in breeding programs of the common bean (Phaseolus vulgaris) is essential for determining the potential of each combination of parent plants to obtain superior genotypes. The present study aimed to estimated the extent of genetic diversity in 172 lineages and cultivars of the common bean by integrating five tests of value for cultivation and use (VCU) that were conducted over the last eight years by the breeding program of Embrapa Arroz e Feijão in Brazil. Nine multilocus genotyping systems composed of 36 fluorescent microsatellite markers distributed across 11 different chromosomes of the common bean were used, of which 24 were polymorphic in all trials. One hundred and eighty-seven alleles were identified, with an average of 7.79 alleles per locus and an average gene diversity of 0.65. The combined probability of identity for all loci was 1.32 x 10(-16). Lineages that are more genetically divergent between the selection cycles were identified, allowing the breeding program to develop a crossbreed between elite genotypes with a low degree of genetic relatedness. HE values ranged from 0.31 to 0.63, with a large reduction in the genetic base over successive selection cycles. The test showed a significant degree of differentiation (FST = 0.159). Private alleles (26%) were identified and can be directly incorporated into the gene pool of cultivated germplasm, thereby contributing effectively to the expansion of genetic diversity in this bean-breeding program.

Genetic Testing for Autism Spectrum Disorders

ERIC Educational Resources Information Center

Bauer, Sarah C.; Msall, Michael E.

2011-01-01

Children with autism spectrum disorders (ASD) have unique developmental and behavioral phenotypes, and they have specific challenges with communication, social skills, and repetitive behaviors. At this time, no single etiology for ASD has been identified. However, evidence from family studies and linkage analyses suggests that genetic factors play…

Novel norovirus in dogs with diarrhea.

PubMed

Mesquita, João Rodrigo; Barclay, Leslie; Nascimento, Maria São José; Vinjé, Jan

2010-06-01

To identify the prevalence and genetic variability of noroviruses in dogs, we tested fecal samples by using reverse transcription-PCR. We found canine norovirus in 40% and 9% of dogs with and without diarrhea, respectively. The virus was genetically unrelated to other noroviruses and constitutes a tentative new genogroup.

Failure of replicating the association between hippocampal volume and 3 single-nucleotide polymorphisms identified from the European genome-wide association study in Asian populations.

PubMed

Li, Ming; Ohi, Kazutaka; Chen, Chunhui; He, Qinghua; Liu, Jie-Wei; Chen, Chuansheng; Luo, Xiong-Jian; Dong, Qi; Hashimoto, Ryota; Su, Bing

2014-12-01

Hippocampal volume is a key brain structure for learning ability and memory process, and hippocampal atrophy is a recognized biological marker of Alzheimer's disease. However, the genetic bases of hippocampal volume are still unclear although it is a heritable trait. Genome-wide association studies (GWASs) on hippocampal volume have implicated several significantly associated genetic variants in Europeans. Here, to test the contributions of these GWASs identified genetic variants to hippocampal volume in different ethnic populations, we screened the GWAS-identified candidate single-nucleotide polymorphisms in 3 independent healthy Asian brain imaging samples (a total of 990 subjects). The results showed that none of these single-nucleotide polymorphisms were associated with hippocampal volume in either individual or combined Asian samples. The replication results suggested a complexity of genetic architecture for hippocampal volume and potential genetic heterogeneity between different ethnic populations. Copyright © 2014 Elsevier Inc. All rights reserved.

Steroid-resistant nephrotic syndrome: impact of genetic testing.

PubMed

Kari, Jameela A; El-Desoky, Sherif M; Gari, Mamdooh; Malik, Khalid; Vega-Warner, Virginia; Lovric, Svjetlana; Bockenhauer, Detlef

2013-01-01

Mutations in several genes are known to cause steroid-resistant nephrotic syndome (SRNS), most commonly in NPHS1, NPHS2, and WT1. Our aims were to determine the frequency of mutations in these genes in children with SRNS, the response of patients with SRNS to various immunosuppressants, and the disease outcome, and to review the predictive value of genetic testing and renal biopsy result. A retrospective review was performed of the medical records for all children with SRNS who were treated and followed-up in the Pediatric Nephrology Unit of King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia from 2002-2012. We retrospectively reviewed the medical records of children above 1 year of age, who presented with SRNS to KAUH, Jeddah, Saudi Arabia, in the 10-year interval from 2002-2012 and for whom the results of genetic testing for NPHS1, NPHS2, and WT1 were available. We compared the clinical phenotype, including response to treatment and renal outcome to genotype data. We identified 44 children with a clinical diagnosis of SRNS in whom results of genetic testing were available. Presumably disease-causing mutations were detected in 5 children (11.4%) of which 3 (6.8%) had NPHS2 mutation and 2 (4.5%) had NPHS1 mutation. Renal biopsy revealed minimal change disease (MCD) or variants in 17 children, focal segmental glomerulosclerosis (FSGS) in 23 children, membranoproliferative changes (MPGN) in 2 children, and IgA nephropathy in another 2 children. Children with MCD on biopsy were more likely to respond to treatment than those with FSGS. None of those with an identified genetic cause showed any response to treatment. The frequency of identified disease-causing mutations in children older than 1 year with SRNS presented to KAUH was 11.4%, and these patients showed no response to treatment. Initial testing for gene mutation in children with SRNS may obviate the need for biopsy, and the use of immunosuppressive treatment in children with disease due to NPHS1 or NPHS2 mutations. Renal biopsy was useful in predicting response in those without genetic mutations.

Copy Number Variants and Exome Sequencing Analysis in Six Pairs of Chinese Monozygotic Twins Discordant for Congenital Heart Disease.

PubMed

Xu, Yuejuan; Li, Tingting; Pu, Tian; Cao, Ruixue; Long, Fei; Chen, Sun; Sun, Kun; Xu, Rang

2017-12-01

Congenital heart disease (CHD) is one of the most common birth defects. More than 200 susceptibility loci have been identified for CHDs, yet a large part of the genetic risk factors remain unexplained. Monozygotic (MZ) twins are thought to be completely genetically identical; however, discordant phenotypes have been found in MZ twins. Recent studies have demonstrated genetic differences between MZ twins. We aimed to test whether copy number variants (CNVs) and/or genetic mutation differences play a role in the etiology of CHDs by using single nucleotide polymorphism (SNP) genotyping arrays and whole exome sequencing of twin pairs discordant for CHDs. Our goal was to identify mutations present only in the affected twins, which could identify novel candidates for CHD susceptibility loci. We present a comprehensive analysis for the CNVs and genetic mutation results of the selected individuals but detected no consistent differences within the twin pairs. Our study confirms that chromosomal structure or genetic mutation differences do not seem to play a role in the MZ twins discordant for CHD.

Genes Contributing to Genetic Variation of Muscling in Sheep

PubMed Central

Tellam, Ross L.; Cockett, Noelle E.; Vuocolo, Tony; Bidwell, Christopher A.

2012-01-01

Selective breeding programs aiming to increase the productivity and profitability of the sheep meat industry use elite, progeny tested sires. The broad genetic traits of primary interest in the progeny of these sires include skeletal muscle yield, fat content, eating quality, and reproductive efficiency. Natural mutations in sheep that enhance muscling have been identified, while a number of genome scans have identified and confirmed quantitative trait loci (QTL) for skeletal muscle traits. The detailed phenotypic characteristics of sheep carrying these mutations or QTL affecting skeletal muscle show a number of common biological themes, particularly changes in developmental growth trajectories, alterations of whole animal morphology, and a shift toward fast twitch glycolytic fibers. The genetic, developmental, and biochemical mechanisms underpinning the actions of some of these genetic variants are described. This review critically assesses this research area, identifies gaps in knowledge, and highlights mechanistic linkages between genetic polymorphisms and skeletal muscle phenotypic changes. This knowledge may aid the discovery of new causal genetic variants and in some cases lead to the development of biochemical and immunological strategies aimed at enhancing skeletal muscle. PMID:22952470

Evolutionary Analysis of Heterochromatin Protein Compatibility by Interspecies Complementation in Saccharomyces

PubMed Central

Zill, Oliver A.; Scannell, Devin R.; Kuei, Jeffrey; Sadhu, Meru; Rine, Jasper

2012-01-01

The genetic bases for species-specific traits are widely sought, but reliable experimental methods with which to identify functionally divergent genes are lacking. In the Saccharomyces genus, interspecies complementation tests can be used to evaluate functional conservation and divergence of biological pathways or networks. Silent information regulator (SIR) proteins in S. bayanus provide an ideal test case for this approach because they show remarkable divergence in sequence and paralog number from those found in the closely related S. cerevisiae. We identified genes required for silencing in S. bayanus using a genetic screen for silencing-defective mutants. Complementation tests in interspecies hybrids identified an evolutionarily conserved Sir-protein-based silencing machinery, as defined by two interspecies complementation groups (SIR2 and SIR3). However, recessive mutations in S. bayanus SIR4 isolated from this screen could not be complemented by S. cerevisiae SIR4, revealing species-specific functional divergence in the Sir4 protein despite conservation of the overall function of the Sir2/3/4 complex. A cladistic complementation series localized the occurrence of functional changes in SIR4 to the S. cerevisiae and S. paradoxus branches of the Saccharomyces phylogeny. Most of this functional divergence mapped to sequence changes in the Sir4 PAD. Finally, a hemizygosity modifier screen in the interspecies hybrids identified additional genes involved in S. bayanus silencing. Thus, interspecies complementation tests can be used to identify (1) mutations in genetically underexplored organisms, (2) loci that have functionally diverged between species, and (3) evolutionary events of functional consequence within a genus. PMID:22923378

Neurocognitive endophenotypes for bipolar disorder identified in multiplex multigenerational families.

PubMed

Glahn, David C; Almasy, Laura; Barguil, Marcela; Hare, Elizabeth; Peralta, Juan Manuel; Kent, Jack W; Dassori, Albana; Contreras, Javier; Pacheco, Adriana; Lanzagorta, Nuria; Nicolini, Humberto; Raventós, Henriette; Escamilla, Michael A

2010-02-01

Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, a strategy for identifying risk genes is to identify and map quantitative intermediate phenotypes or endophenotypes. To adjudicate neurocognitive endophenotypes for bipolar disorder. All participants underwent diagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which test results are impaired in affected individuals, are sensitive to the genetic liability for the illness, and are genetically correlated with affection status. Central valley of Costa Rica; Mexico City, Mexico; and San Antonio, Texas. Seven hundred nine Latino individuals participated in the study. Of these, 660 were members of extended pedigrees with at least 2 siblings diagnosed as having bipolar disorder (n = 230). The remaining subjects were community control subjects drawn from each site who did not have a personal or family history of bipolar disorder or schizophrenia. Neurocognitive test performance. Two of the 22 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 cognitive measures compared with nonrelated healthy controls. Nonbipolar first-degree relatives were impaired on 5 of these, and the following 3 tests were genetically correlated with affection status: Digit Symbol Coding Task, Object Delayed Response Task, and immediate facial memory. This large-scale extended pedigree study of cognitive functioning in bipolar disorder identifies measures of processing speed, working memory, and declarative (facial) memory as candidate endophenotypes for bipolar disorder.

A systematic review of the factors associated with interest in predictive genetic testing for obesity, type II diabetes and heart disease.

PubMed

Collins, J; Ryan, L; Truby, H

2014-10-01

In the future, it may be possible for individuals to take a genetic test to determine their genetic predisposition towards developing lifestyle-related chronic diseases. A systematic review of the literature was undertaken to identify the factors associated with an interest in having predictive genetic testing for obesity, type II diabetes and heart disease amongst unaffected adults. Ovid Medline, PsycINFO and EMBASE online databases were searched using predefined search terms. Publications meeting the inclusion criteria (English language, free-living adult population not selected as a result of their disease diagnosis, reporting interest as an outcome, not related to a single gene inherited disease) were assessed for quality and content. Narrative synthesis of the results was undertaken. From the 2329 publications retrieved, eight studies met the inclusion criteria and were included in the review. Overall, the evidence base was small but of positive quality. Interest was associated with personal attitudes towards disease risk and the provision of information about genetic testing, shaped by perceived risk of disease and expected outcomes of testing. The role of demographic factors was investigated with largely inconclusive findings. Interest in predictive genetic testing for obesity, type II diabetes or heart disease was greatest amongst those who perceived the risk of disease to be high and/or the outcomes of testing to be beneficial. © 2013 The British Dietetic Association Ltd.

Applying Cystic Fibrosis Transmembrane Conductance Regulator Genetics and CFTR2 Data to Facilitate Diagnoses.

PubMed

Sosnay, Patrick R; Salinas, Danieli B; White, Terry B; Ren, Clement L; Farrell, Philip M; Raraigh, Karen S; Girodon, Emmanuelle; Castellani, Carlo

2017-02-01

As a Mendelian disease, genetics plays an integral role in the diagnosis of cystic fibrosis (CF). The identification of 2 disease-causing mutations in the CF transmembrane conductance regulator (CFTR) in an individual with a phenotype provides evidence that the disease is CF. However, not all variations in CFTR always result in CF. Therefore, for CFTR genotype to provide the same level of evidence of CFTR dysfunction as shown by direct tests such as sweat chloride or nasal potential difference, the mutations identified must be known to always result in CF. The use of CFTR genetics in CF diagnosis, therefore, relies heavily on mutation interpretation. Progress that has been made on mutation interpretation and annotation was reviewed at the recent CF Foundation Diagnosis Consensus Conference. A modified Delphi method was used to identify consensus statements on the use of genetic analysis in CF diagnosis. The largest recent advance in CF genetics has come through the Clinical and Functional Translation of CFTR (CFTR2) project. This undertaking seeks to characterize CFTR mutations from patients with CF around the world. The project also established guidelines for the clinical, functional, and population/penetrance criteria that can be used to interpret mutations not yet included in CFTR2's review. The use of CFTR genetics to aid in diagnosis of CF requires that the mutations identified have a known disease liability. The demonstration of 2 in trans mutations known to always result in CF is satisfactory evidence of CFTR dysfunction. However, if the identified mutations are known to be associated with variable outcomes, or have unknown consequence, that genotype may not result in a CF phenotype. In these cases, other tests of CFTR function may help. Copyright © 2016 Elsevier Inc. All rights reserved.

Detecting epistasis with the marginal epistasis test in genetic mapping studies of quantitative traits

PubMed Central

Zeng, Ping; Mukherjee, Sayan; Zhou, Xiang

2017-01-01

Epistasis, commonly defined as the interaction between multiple genes, is an important genetic component underlying phenotypic variation. Many statistical methods have been developed to model and identify epistatic interactions between genetic variants. However, because of the large combinatorial search space of interactions, most epistasis mapping methods face enormous computational challenges and often suffer from low statistical power due to multiple test correction. Here, we present a novel, alternative strategy for mapping epistasis: instead of directly identifying individual pairwise or higher-order interactions, we focus on mapping variants that have non-zero marginal epistatic effects—the combined pairwise interaction effects between a given variant and all other variants. By testing marginal epistatic effects, we can identify candidate variants that are involved in epistasis without the need to identify the exact partners with which the variants interact, thus potentially alleviating much of the statistical and computational burden associated with standard epistatic mapping procedures. Our method is based on a variance component model, and relies on a recently developed variance component estimation method for efficient parameter inference and p-value computation. We refer to our method as the “MArginal ePIstasis Test”, or MAPIT. With simulations, we show how MAPIT can be used to estimate and test marginal epistatic effects, produce calibrated test statistics under the null, and facilitate the detection of pairwise epistatic interactions. We further illustrate the benefits of MAPIT in a QTL mapping study by analyzing the gene expression data of over 400 individuals from the GEUVADIS consortium. PMID:28746338

Genetic testing for the risk of developing late effects among survivors of childhood cancer: Consumer understanding, acceptance, and willingness to pay.

PubMed

Georgiou, Gabrielle; Wakefield, Claire E; McGill, Brittany C; Fardell, Joanna E; Signorelli, Christina; Hanlon, Lucy; Tucker, Kathy; Patenaude, Andrea F; Cohn, Richard J

2016-09-15

Genetic testing to determine cancer survivors' risk of developing late effects from their cancer treatment will be increasingly used in survivorship care. This 2-stage study with 64 survivors of childhood cancer and their parents investigated the preferences and acceptability of testing among those who may be at risk of developing late effects. The first stage (Stage 1) identified the most commonly perceived benefits and concerns regarding genetic testing for the risk of late effects among 24 participants. In Stage 2, during interviews, 20 survivors (55% of whom were female; mean age, 26.0 years [range, 18-39 years]; standard deviation [SD], 0.80) and 20 parents (55% of whom were male; mean age of child survivor, 14.2 years [range, 10-19 years]; SD, 0.79) rated the 7 most common benefits and concerns from those identified in Stage 1. Interviews were transcribed verbatim and analyzed. Decisional balance ratios were calculated by dividing the participants' average concerns scores with the average benefits scores. Genetic testing for late effects was highly acceptable: 95% of participants leaned toward testing, and the majority (65.9%) would pay up to Australian $5000. The majority (97.2%) reported it was acceptable to wait for up to 6 months to receive results, and to be offered testing immediately after treatment or when the survivor reached adulthood (62.9%). Survivors and parents had a highly positive decisional balance (Mean (M), 0.5 [SD, 0.38] and M, 0.5 [SD, 0.39], respectively), indicating that perceived benefits outweighed concerns. Although to our knowledge clinical efficacy has yet to be clearly demonstrated, survivors and parents described positive interest in genetic testing for the risk of developing late effects. Perceived benefits outweighed harms, and the majority of participants would be willing to pay, and wait, for testing. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2876-2885. © 2016 American Cancer Society. © 2016 American Cancer Society.

Awareness, knowledge, perceptions, and attitudes towards genetic testing for cancer risk among ethnic minority groups: a systematic review.

PubMed

Hann, Katie E J; Freeman, Madeleine; Fraser, Lindsay; Waller, Jo; Sanderson, Saskia C; Rahman, Belinda; Side, Lucy; Gessler, Sue; Lanceley, Anne

2017-05-25

Genetic testing for risk of hereditary cancer can help patients to make important decisions about prevention or early detection. US and UK studies show that people from ethnic minority groups are less likely to receive genetic testing. It is important to understand various groups' awareness of genetic testing and its acceptability to avoid further disparities in health care. This review aims to identify and detail awareness, knowledge, perceptions, and attitudes towards genetic counselling/testing for cancer risk prediction in ethnic minority groups. A search was carried out in PsycInfo, CINAHL, Embase and MEDLINE. Search terms referred to ethnicity, genetic testing/counselling, cancer, awareness, knowledge, attitudes, and perceptions. Quantitative and qualitative studies, written in English, and published between 2000 and 2015, were included. Forty-one studies were selected for review: 39 from the US, and two from Australia. Results revealed low awareness and knowledge of genetic counselling/testing for cancer susceptibility amongst ethnic minority groups including African Americans, Asian Americans, and Hispanics. Attitudes towards genetic testing were generally positive; perceived benefits included positive implications for personal health and being able to inform family. However, negative attitudes were also evident, particularly the anticipated emotional impact of test results, and concerns about confidentiality, stigma, and discrimination. Chinese Australian groups were less studied, but of interest was a finding from qualitative research indicating that different views of who close family members are could impact on reported family history of cancer, which could in turn impact a risk assessment. Interventions are needed to increase awareness and knowledge of genetic testing for cancer risk and to reduce the perceived stigma and taboo surrounding the topic of cancer in ethnic minority groups. More detailed research is needed in countries other than the US and across a broader spectrum of ethnic minority groups to develop effective culturally sensitive approaches for cancer prevention.

Cost-Effectiveness Analysis of Different Genetic Testing Strategies for Lynch Syndrome in Taiwan.

PubMed

Chen, Ying-Erh; Kao, Sung-Shuo; Chung, Ren-Hua

2016-01-01

Patients with Lynch syndrome (LS) have a significantly increased risk of developing colorectal cancer (CRC) and other cancers. Genetic screening for LS among patients with newly diagnosed CRC aims to identify mutations in the disease-causing genes (i.e., the DNA mismatch repair genes) in the patients, to offer genetic testing for relatives of the patients with the mutations, and then to provide early prevention for the relatives with the mutations. Several genetic tests are available for LS, such as DNA sequencing for MMR genes and tumor testing using microsatellite instability and immunohistochemical analyses. Cost-effectiveness analyses of different genetic testing strategies for LS have been performed in several studies from different countries such as the US and Germany. However, a cost-effectiveness analysis for the testing has not yet been performed in Taiwan. In this study, we evaluated the cost-effectiveness of four genetic testing strategies for LS described in previous studies, while population-specific parameters, such as the mutation rates of the DNA mismatch repair genes and treatment costs for CRC in Taiwan, were used. The incremental cost-effectiveness ratios based on discounted life years gained due to genetic screening were calculated for the strategies relative to no screening and to the previous strategy. Using the World Health Organization standard, which was defined based on Taiwan's Gross Domestic Product per capita, the strategy based on immunohistochemistry as a genetic test followed by BRAF mutation testing was considered to be highly cost-effective relative to no screening. Our probabilistic sensitivity analysis results also suggest that the strategy has a probability of 0.939 of being cost-effective relative to no screening based on the commonly used threshold of $50,000 to determine cost-effectiveness. To the best of our knowledge, this is the first cost-effectiveness analysis for evaluating different genetic testing strategies for LS in Taiwan. The results will be informative for the government when considering offering screening for LS in patients newly diagnosed with CRC.

The genetics of anophthalmia and microphthalmia.

PubMed

Bardakjian, Tanya M; Schneider, Adele

2011-09-01

To summarize recent breakthroughs regarding the genes known to play a role in normal ocular development in humans and to elucidate the role mutations in these genes play in anophthalmia and microphthalmia. The main themes discussed within this article are the various documented genetic advances in identifying the various causes of anophthalmia and microphthalmia. In addition, the complex interplay of these genes during critical embryonic development will be addressed. The recent identification of many eye development genes has changed the ability to identify a cause of anophthalmia and microphthalmia in many individuals. Syndrome identification and the availability of genetic testing underscores the desirability of evaluation by a geneticist for all individuals with anophthalmia and microphthalmia in order to provide appropriate management, long-term guidance, and genetic counseling.

Ecological correlates of population genetic structure: a comparative approach using a vertebrate metacommunity.

PubMed

Manier, Mollie K; Arnold, Stevan J

2006-12-07

Identifying ecological factors associated with population genetic differentiation is important for understanding microevolutionary processes and guiding the management of threatened populations. We identified ecological correlates of several population genetic parameters for three interacting species (two garter snakes and an anuran) that occupy a common landscape. Using multiple regression analysis, we found that species interactions were more important in explaining variation in population genetic parameters than habitat and nearest-neighbour characteristics. Effective population size was best explained by census size, while migration was associated with differences in species abundance. In contrast, genetic distance was poorly explained by the ecological correlates that we tested, but geographical distance was prominent in models for all species. We found substantially different population dynamics for the prey species relative to the two predators, characterized by larger effective sizes, lower gene flow and a state of migration-drift equilibrium. We also identified an escarpment formed by a series of block faults that serves as a barrier to dispersal for the predators. Our results suggest that successful landscape-level management should incorporate genetic and ecological data for all relevant species, because even closely associated species can exhibit very different population genetic dynamics on the same landscape.

Isolation by environment in White-breasted Nuthatches (Sitta carolinensis) of the Madrean Archipelago sky islands: a landscape genomics approach.

PubMed

Manthey, Joseph D; Moyle, Robert G

2015-07-01

Understanding landscape processes driving patterns of population genetic differentiation and diversity has been a long-standing focus of ecology and evolutionary biology. Gene flow may be reduced by historical, ecological or geographic factors, resulting in patterns of isolation by distance (IBD) or isolation by environment (IBE). Although IBE has been found in many natural systems, most studies investigating patterns of IBD and IBE in nature have used anonymous neutral genetic markers, precluding inference of selection mechanisms or identification of genes potentially under selection. Using landscape genomics, the simultaneous study of genomic and ecological landscapes, we investigated the processes driving population genetic patterns of White-breasted Nuthatches (Sitta carolinensis) in sky islands (montane forest habitat islands) of the Madrean Archipelago. Using more than 4000 single nucleotide polymorphisms and multiple tests to investigate the relationship between genetic differentiation and geographic or ecological distance, we identified IBE, and a lack of IBD, among sky island populations of S. carolinensis. Using three tests to identify selection, we found 79 loci putatively under selection; of these, seven matched CDS regions in the Zebra Finch. The loci under selection were highly associated with climate extremes (maximum temperature of warmest month and minimum precipitation of driest month). These results provide evidence for IBE - disentangled from IBD - in sky island vertebrates and identify potential adaptive genetic variation. © 2015 John Wiley & Sons Ltd.

BRCAsearch: written pre-test information and BRCA1/2 germline mutation testing in unselected patients with newly diagnosed breast cancer.

PubMed

Nilsson, Martin P; Törngren, Therese; Henriksson, Karin; Kristoffersson, Ulf; Kvist, Anders; Silfverberg, Barbro; Borg, Åke; Loman, Niklas

2018-02-01

To evaluate a simplified method of pre-test information and germline BRCA1/2 mutation testing. In a prospective, single-arm study, comprehensive BRCA1/2 testing was offered to unselected patients with newly diagnosed breast cancer at three hospitals in south Sweden (BRCAsearch, ClinicalTrials.gov Identifier: NCT02557776). Pre-test information was provided by a standardized invitation letter, but the patients could contact a genetic counselor for telephone genetic counseling if they felt a need for that. Noncarriers were informed about the test result through a letter. Mutation carriers were contacted and offered an appointment for in-person post-test genetic counseling. During the period Feb 2, 2015-Aug 26, 2016, eight hundred and eighteen patients were invited to participate in the study. Through Jan 31, 2017, five hundred and forty-two (66.2%) of them consented to analysis of BRCA1 and BRCA2. Eleven pathogenic mutations were found (BRCA1, n = 2; BRCA2, n = 9), corresponding to a mutation prevalence of 2.0%. Six out of 11 fulfilled the Swedish BRCA testing criteria, and 9 out of 11 fulfilled the NCCN testing criteria. None of the BRCA-associated tumors were of the luminal A-like subtype. Very few patients contacted us for telephone genetic counseling or practical questions, suggesting that a majority felt that the written pre-test information was sufficient for them to make a decision on testing. Streamlining the process of pre-test information, genetic testing, and delivery of test results was feasible and was associated with an uptake of genetic testing in 2/3 of the breast cancer patients.

Nosology and Diagnosis of Rett Syndrome

ERIC Educational Resources Information Center

Matson, Johnny L.; Fodstad, Jill C.; Boisjoli, Jessica A.

2008-01-01

Rett Syndrome is one of the least commonly occurring autism spectrum disorders (ASD), but certainly one of the most devastating. A genetic profile has been identified, but checklists still have an important role for prescreening, especially before expensive genetic testing, and to provide precise strengths and weaknesses with respect to the core…

Clinical utility of genetic testing in pediatric drug-resistant epilepsy: a pilot study.

PubMed

Ream, Margie A; Mikati, Mohamad A

2014-08-01

The utility of genetic testing in pediatric drug-resistant epilepsy (PDRE), its yield in "real life" clinical practice, and the practical implications of such testing are yet to be determined. To start to address the above gaps in our knowledge as they apply to a patient population seen in a tertiary care center. We retrospectively reviewed our experience with the use of clinically available genetic tests in the diagnosis and management of PDRE in one clinic over one year. Genetic testing included, depending on clinical judgment, one or more of the following: karyotype, chromosomal microarray, single gene sequencing, gene sequencing panels, and/or whole exome sequencing (WES). We were more likely to perform genetic testing in patients with developmental delay, epileptic encephalopathy, and generalized epilepsy. In our unique population, the yield of specific genetic diagnosis was relatively high: karyotype 14.3%, microarray 16.7%, targeted single gene sequencing 15.4%, gene panels 46.2%, and WES 16.7%. Overall yield of diagnosis from at least one of the above tests was 34.5%. Disease-causing mutations that were not clinically suspected based on the patients' phenotypes and representing novel phenotypes were found in 6.9% (2/29), with an additional 17.2% (5/29) demonstrating pharmacologic variants. Three patients were incidentally found to be carriers of recessive neurologic diseases (10.3%). Variants of unknown significance (VUSs) were identified in 34.5% (10/29). We conclude that genetic testing had at least some utility in our patient population of PDRE, that future similar larger studies in various populations are warranted, and that clinics offering such tests must be prepared to address the complicated questions raised by the results of such testing. Copyright © 2014. Published by Elsevier Inc.

Genetic testing for Lynch syndrome: family communication and motivation.

PubMed

Leenen, Celine H M; Heijer, Mariska den; van der Meer, Conny; Kuipers, Ernst J; van Leerdam, Monique E; Wagner, Anja

2016-01-01

Current genetic counselling practice for Lynch syndrome (LS) relies on diagnosed index patients to inform their biological family about LS, referred to as the family-mediated approach. The objective of this study was to evaluate this approach and to identify factors influencing the uptake of genetic testing for LS. In 59 mutation carriers, 70 non carriers and 16 non-tested relatives socio-demographic characteristics, family communication regarding LS, experiences and attitudes towards the family-mediated approach and motivations for genetic testing, were assessed. The majority of all respondents (73 %) were satisfied with the family-mediated approach. Nevertheless, 59 % of the respondents experienced informing a family member and 57 % being informed by a family member as burdensome. Non-tested differed from tested respondents, in that they were younger, less closely related to the index patient and a lower proportion had children. The most important reasons for declining genetic testing were (1) anticipating problems with life insurance and mortgage, (2) being content with life as it is, and (3) not experiencing any physical complaints. In conclusion, the majority of respondents consider the current family-mediated information procedure acceptable, although the provision of information on LS by relatives may be burdensome. Special attention should be paid to communication of LS to more distant relatives.

Genetic advances in sarcomeric cardiomyopathies: state of the art

PubMed Central

Ho, Carolyn Y.; Charron, Philippe; Richard, Pascale; Girolami, Francesca; Van Spaendonck-Zwarts, Karin Y.; Pinto, Yigal

2015-01-01

Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomere mutations cause both hypertrophic and dilated cardiomyopathies. Sarcomere mutations also likely play a role in more complex phenotypes and overlap cardiomyopathies with features of hypertrophy, dilation, diastolic abnormalities, and non-compaction. Identification of the genetic cause of these important conditions provides unique opportunities to interrogate and characterize disease pathogenesis and pathophysiology, starting from the molecular level and expanding from there. With such insights, there is potential for clinical translation that may transform management of patients and families with inherited cardiomyopathies. If key pathways for disease development can be identified, they could potentially serve as targets for novel disease-modifying or disease-preventing therapies. By utilizing gene-based diagnostic testing, we can identify at-risk individuals prior to the onset of clinical disease, allowing for disease-modifying therapy to be initiated early in life, at a time that such treatment may be most successful. In this section, we review the current application of genetics in clinical management, focusing on hypertrophic cardiomyopathy as a paradigm; discuss state-of-the-art genetic testing technology; review emerging knowledge of gene expression in sarcomeric cardiomyopathies; and discuss both the prospects, as well as the challenges, of bringing genetics to medicine. PMID:25634555

Inherited medullary thyroid cancer and the duty to warn: revisiting Pate v. Threlkel in light of HIPAA.

PubMed

Rosenthal, M Sara; Pierce, Heather Hanson

2005-02-01

Familial medullary thyroid cancer (FMTC) is one of the few autosomal dominant cancers for which genetic testing provides a clear medical indication for prophylactic and/or curative therapy, and for which prophylactic thyroidectomy, followed by thyroid hormone replacement, presents a relatively low morbidity risk. Medullary thyroid cancer (MTC) is a particularly aggressive type of thyroid cancer, and screening by traditional biochemical markers yields a high proportion of advanced stage diagnoses in individuals from FMTC families. This is particularly hazardous since there are no curative systemic treatments for MTC. Genetic testing for germline mutations of the RET proto-oncogene provides a reliable method of identifying at-risk family members in those FMTC families in which a mutation has been identified in the proband. Prophylactic thyroidectomy in such at-risk family members has significantly reduced the proportion of advanced stage MTC diagnoses in MTC families. Since a clear medical benefit exists for genetic testing in family members, and a clear danger to family members exists in the absence of genetic counseling, establishing genetic diagnosis as standard of care has critical legal and ethical implications for medical providers caring for probands and family members. The "duty to warn," reinforced by the courts in the legal case of Pate v. Threlkel, may override recent confidentiality legislation, known as the HIPAA Privacy Rules, which came into effect April 12, 2003.

Who Will Benefit from Cancer Immunotherapy?

Cancer.gov

Researchers have identified a “genetic signature” in the tumors of patients with advanced melanoma who responded to a form of immunotherapy called checkpoint blockade. The results could be the basis for a test that identifies likely responders.

Ethics and Neuropsychiatric Genetics: A Review of Major Issues

PubMed Central

Hoge, Steven K.; Appelbaum, Paul S.

2012-01-01

Advances in neuropsychiatric genetics hold great hopes for improved prevention, diagnosis, and treatment. However, the power of genetic testing to identify individuals at increased risk for disorders and to convey information about relatives creates a set of complex ethical issues. Public attitudes are inevitably affected by the shadow of eugenics, with its history of distorting scientific findings to serve socio-political ends. Nonetheless, the growing availability of genetic tests means that more patients will seek genetic information, and physicians must manage the process of informed consent to allow meaningful decisions. Patients should be helped to understand the often-limited predictive power of current knowledge, potential psychological impact, risks of stigma and discrimination, and possible implications for family members. Decisions for predictive testing of children raise additional concerns, including distortions of family dynamics and negative effects on children’s self-image; testing is best deferred until adulthood unless preventive interventions exist. Pharmacogenomic testing, part of personalized medicine, may bring collateral susceptibility information for which patients should be prepared. The implications of genetic findings for families raise the question of whether physicians have duties to inform family members of implications for their health. Finally, participation in research in neuropsychiatric genetics evokes a broad range of ethical concerns, including the contentious issue of the extent to which results should be returned to individual subjects. As genetic science becomes more widely applied, the public will become more sophisticated and will be likely to demand a greater role in determining social policy on these issues. PMID:22272758

Outlier Loci and Selection Signatures of Simple Sequence Repeats (SSRs) in Flax (Linum usitatissimum L.).

PubMed

Soto-Cerda, Braulio J; Cloutier, Sylvie

2013-01-01

Genomic microsatellites (gSSRs) and expressed sequence tag-derived SSRs (EST-SSRs) have gained wide application for elucidating genetic diversity and population structure in plants. Both marker systems are assumed to be selectively neutral when making demographic inferences, but this assumption is rarely tested. In this study, three neutrality tests were assessed for identifying outlier loci among 150 SSRs (85 gSSRs and 65 EST-SSRs) that likely influence estimates of population structure in three differentiated flax sub-populations ( F ST  = 0.19). Moreover, the utility of gSSRs, EST-SSRs, and the combined sets of SSRs was also evaluated in assessing genetic diversity and population structure in flax. Six outlier loci were identified by at least two neutrality tests showing footprints of balancing selection. After removing the outlier loci, the STRUCTURE analysis and the dendrogram topology of EST-SSRs improved. Conversely, gSSRs and combined SSRs results did not change significantly, possibly as a consequence of the higher number of neutral loci assessed. Taken together, the genetic structure analyses established the superiority of gSSRs to determine the genetic relationships among flax accessions, although the combined SSRs produced the best results. Genetic diversity parameters did not differ statistically ( P  > 0.05) between gSSRs and EST-SSRs, an observation partially explained by the similar number of repeat motifs. Our study provides new insights into the ability of gSSRs and EST-SSRs to measure genetic diversity and structure in flax and confirms the importance of testing for the occurrence of outlier loci to properly assess natural and breeding populations, particularly in studies considering only few loci.

Do parental perceptions and motivations towards genetic testing and prenatal diagnosis for deafness vary in different cultures?

PubMed

Nahar, Risha; Puri, Ratna D; Saxena, Renu; Verma, Ishwar C

2013-01-01

Surveys of attitudes of individuals with deafness and their families towards genetic testing or prenatal diagnosis have mostly been carried out in the West. It is expected that the perceptions and attitudes would vary amongst persons of different cultures and economic background. There is little information on the prevailing attitudes for genetic testing and prenatal diagnosis for deafness in developing countries. Therefore, this study evaluates the motivations of Indian people with inherited hearing loss towards such testing. Twenty-eight families with history of congenital hearing loss (23 hearing parents with child/family member with deafness, 4 couples with both partners having deafness and 1 parent and child with deafness) participated in a semi-structured survey investigating their interest, attitudes, and intentions for using genetic and prenatal testing for deafness. Participants opinioned that proper management and care of individuals with deafness were handicapped by limited rehabilitation facilities with significant financial and social burden. Nineteen (68%) opted for genetic testing. Twenty-six (93%) expressed high interest in prenatal diagnosis, while 19 (73%) would consider termination of an affected fetus. Three hearing couples, in whom the causative mutations were identified, opted for prenatal diagnosis. On testing, all the three fetuses were affected and the hearing parents elected to terminate the pregnancies. This study provides an insight into the contrasting perceptions towards hearing disability in India and its influence on the desirability of genetic testing and prenatal diagnosis. Copyright © 2012 Wiley Periodicals, Inc.

Genetic screening and diagnosis in epilepsy?

PubMed

Sisodiya, Sanjay M

2015-04-01

Genetic discovery has been extremely rapid over the last year, with many new discoveries illuminating novel mechanisms and pathways. In particular, the application of whole exome and whole genome sequencing has identified many new genetic causes of the epilepsies. As such methods become increasingly available, it will be critical for practicing neurologists to be acquainted with them. This review surveys some important developments over the last year. The range of tests available to the clinician is wide, and likely soon to be dominated by whole exome and whole genome sequencing. Both whole exome and whole genome sequencing have usually proven to be more powerful than most existing tests. Many new genes have been implicated in the epilepsies, with emerging evidence of the involvement of particular multigene pathways. For the practicing clinician, it will be important to appreciate progress in the field, and to prepare for the application of novel genetic testing in clinical practice, as genetic data are likely to contribute importantly for many people with epilepsy.

A decade of molecular genetic testing for MODY: a retrospective study of utilization in The Netherlands.

PubMed

Weinreich, Stephanie S; Bosma, Astrid; Henneman, Lidewij; Rigter, Tessel; Spruijt, Carla M J; Grimbergen, Anneliese J E M A; Breuning, Martijn H; de Koning, Eelco J P; Losekoot, Monique; Cornel, Martina C

2015-01-01

Genetic testing for maturity-onset diabetes of the young (MODY) may be relevant for treatment and prognosis in patients with usually early-onset, non-ketotic, insulin-sensitive diabetes and for monitoring strategies in non-diabetic mutation carriers. This study describes the first 10 years of genetic testing for MODY in The Netherlands in terms of volume and test positive rate, medical setting, purpose of the test and age of patients tested. Some analyses focus on the most prevalent subtype, HNF1A MODY. Data were retrospectively extracted from a laboratory database. In total, 502 individuals were identified with a pathogenic mutation in HNF4A, GCK or HNF1A between 2001 and 2010. Although mutation scanning for MODY was used at an increasing rate, cascade testing was only used for one relative, on average, per positive index patient. Testing for HNF1A MODY was mostly requested by internists and paediatricians, often from regional hospitals. Primary care physicians and clinical geneticists rarely requested genetic testing for HNF1A MODY. Clinical geneticists requested cascade testing relatively more often than other health professionals. A substantial proportion (currently 29%) of HNF1A MODY probands was at least 40 years old at the time of testing. In conclusion, the number of individuals genetically tested for MODY so far in The Netherlands is low compared with previously predicted numbers of patients. Doctors' valuation of the test and patients' and family members' response to (an offer of) genetic testing on the other hand need to be investigated. Efforts may be needed to develop and implement translational guidelines.

CAP/ACMG proficiency testing for biochemical genetics laboratories: a summary of performance.

PubMed

Oglesbee, Devin; Cowan, Tina M; Pasquali, Marzia; Wood, Timothy C; Weck, Karen E; Long, Thomas; Palomaki, Glenn E

2018-01-01

PurposeTesting for inborn errors of metabolism is performed by clinical laboratories worldwide, each utilizing laboratory-developed procedures. We sought to summarize performance in the College of American Pathologists' (CAP) proficiency testing (PT) program and identify opportunities for improving laboratory quality. When evaluating PT data, we focused on a subset of laboratories that have participated in at least one survey since 2010.MethodsAn analysis of laboratory performance (2004 to 2014) on the Biochemical Genetics PT Surveys, a program administered by CAP and the American College of Medical Genetics and Genomics. Analytical and interpretive performance was evaluated for four tests: amino acids, organic acids, acylcarnitines, and mucopolysaccharides.ResultsSince 2010, 150 laboratories have participated in at least one of four PT surveys. Analytic sensitivities ranged from 88.2 to 93.4%, while clinical sensitivities ranged from 82.4 to 91.0%. Performance was higher for US participants and for more recent challenges. Performance was lower for challenges with subtle findings or complex analytical patterns.ConclusionUS clinical biochemical genetics laboratory proficiency is satisfactory, with a minority of laboratories accounting for the majority of errors. Our findings underscore the complex nature of clinical biochemical genetics testing and highlight the necessity of continuous quality management.

Molecular and immunogenetic analysis of major histocompatibility haplotypes in Northern Bobwhite enable direct identification of corresponding haplotypes in an endangered subspecies, the Masked Bobwhite

USGS Publications Warehouse

Drake, B.M.; Goto, R.M.; Miller, M.M.; Gee, G.F.; Briles, W.E.

1999-01-01

The major histocompatibility complex (MHC) is a group of genetic loci coding for haplotypes that have been associated with fitness traits in mammals and birds. Such associations suggest that MHC diversity may be an indicator of overall genetic fitness of endangered or threatened species. The MHC haplotypes of a captive population of 12 families of northern bobwhites (Colinus virginianus) were identified using a combination of immunogenetic and molecular techniques. Alloantisera were produced within families of northern bobwhites and were then tested for differential agglutination of erythrocytes of all members of each family. The pattern of reactions determined from testing these alloantisera identified a single genetic system of alloantigens in the northern bobwhites, resulting in the assignment of a tentative genotype to each individual within the quail families. Restriction fragment patterns of the DNA of each bird were determined using the chicken MHC B-G cDNA probe bg11. The concordance between the restriction fragment patterns and the alloantisera reactions showed that the alloantisera had identified the MHC of the northern bobwhite and supported the tentative genotype assignments, identifying at least 12 northern bobwhite MHC haplotypes.

Letting the family know: balancing ethics and effectiveness when notifying relatives about genetic testing for a familial disorder.

PubMed

Suthers, G K; Armstrong, J; McCormack, J; Trott, D

2006-08-01

To increase the awareness among at risk relatives of the availability of genetic testing for a familial disorder while respecting their autonomy and privacy. This was a comparison of preintervention and postintervention cohorts of families carried out in a state wide clinical service providing genetic counselling and testing for people at risk of familial adult onset cancer. Unaffected relatives who were not clients of the service in 74 kindreds with familial mutations causing familial breast and ovarian cancer, hereditary non-polyposis colorectal cancer, or Cowden syndrome were included in the study. In the baseline cohort (41 kindreds), family members who were clients of the clinical service and had been shown to be carriers of mutations were asked to advise relatives that genetic testing was available. In the intervention cohort (33 kindreds), the clinical service obtained consent to advise at risk relatives by letter that genetic testing was available. The main outcome measures were: (a) proportion of unaffected first and second degree relatives of the proband in each family whose genetic status was clarified within 2 years of the mutation being identified in the family, and (b) concerns regarding privacy and autonomy voiced by relatives receiving these letters. In the baseline cohort, the average proportion of relatives in each family whose genetic status was clarified was 23%. In the intervention cohort, the average proportion of relatives in each family whose genetic status was clarified was 40% (p = 0.001). None of the relatives in the intervention cohort complained of a breach of privacy or autonomy. Clinical services can take an effective and proactive approach to notifying relatives who are not their clients of the availability of genetic testing without compromising principles of privacy and autonomy.

Direct-to-patient BRCA1 testing: the Twoj Styl experience.

PubMed

Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Debniak, Tadeusz; Metcalfe, Kelly; Narod, Steven A; Lubiński, Jan

2006-12-01

Ideally, a genetic screening program for cancer should offer testing to all women who qualify, and who wish to participate, and who might benefit from the test. As the number of preventive options for women at high risk for hereditary breast cancer expands, the demand for testing increases. However, many women do not have ready access to testing because of cost, and many others have not been recognized by their physicians to be candidates for testing. It is possible to increase women's awareness about hereditary cancer through the popular press. Genetic testing was offered to 5000 Polish women through an announcement placed in a popular women's magazine (Twoj Styl) in October 2001. A total of 5024 women who qualified received a free genetic test for three mutations in BRCA1 which are common in Poland. Out of these, 198 women (3.9%) were found to carry a BRCA1 mutation. The overall cost per mutation detected was 630 US dollars--approximately 50-100 times less than the equivalent cost in North America. Genetic counseling was offered to women with a positive test or with a significant family history of breast or ovarian cancer. The great majority of women who took part in the program expressed a high degree of satisfaction and after one year approximately two-thirds of identified mutation carriers had complied with our recommendations for breast cancer screening. We found this model of genetic testing and delivery of genetic information to be very efficient in a population in which founder mutations predominate. There is a need for similar studies in other populations.

40 CFR 172.45 - Requirement for a notification.

Code of Federal Regulations, 2012 CFR

2012-07-01

... EXPERIMENTAL USE PERMITS Notification for Certain Genetically Modified Microbial Pesticides § 172.45... plans to conduct small-scale testing of a type of microbial pesticide identified in paragraph (c) of... tests: (1) Small-scale tests that involve an intentional environmental introduction of that microbial...

40 CFR 172.45 - Requirement for a notification.

Code of Federal Regulations, 2014 CFR

2014-07-01

... EXPERIMENTAL USE PERMITS Notification for Certain Genetically Modified Microbial Pesticides § 172.45... plans to conduct small-scale testing of a type of microbial pesticide identified in paragraph (c) of... tests: (1) Small-scale tests that involve an intentional environmental introduction of that microbial...

40 CFR 172.45 - Requirement for a notification.

Code of Federal Regulations, 2011 CFR

2011-07-01

... EXPERIMENTAL USE PERMITS Notification for Certain Genetically Modified Microbial Pesticides § 172.45... plans to conduct small-scale testing of a type of microbial pesticide identified in paragraph (c) of... tests: (1) Small-scale tests that involve an intentional environmental introduction of that microbial...

40 CFR 172.45 - Requirement for a notification.

Code of Federal Regulations, 2013 CFR

2013-07-01

... EXPERIMENTAL USE PERMITS Notification for Certain Genetically Modified Microbial Pesticides § 172.45... plans to conduct small-scale testing of a type of microbial pesticide identified in paragraph (c) of... tests: (1) Small-scale tests that involve an intentional environmental introduction of that microbial...

Systematic review of the empirical investigation of resources to support decision-making regarding BRCA1 and BRCA2 genetic testing in women with breast cancer.

PubMed

Grimmett, Chloe; Pickett, Karen; Shepherd, Jonathan; Welch, Karen; Recio-Saucedo, Alejandra; Streit, Elke; Seers, Helen; Armstrong, Anne; Cutress, Ramsey I; Evans, D Gareth; Copson, Ellen; Meiser, Bettina; Eccles, Diana; Foster, Claire

2018-05-01

Identify existing resources developed and/or evaluated empirically in the published literature designed to support women with breast cancer making decisions regarding genetic testing for BRCA1/2 mutations. Systematic review of seven electronic databases. Studies were included if they described or evaluated resources that were designed to support women with breast cancer in making a decision to have genetic counselling or testing for familial breast cancer. Outcome and process evaluations, using any type of study design, as well as articles reporting the development of decision aids, were eligible for inclusion. Total of 9 publications, describing 6 resources were identified. Resources were effective at increasing knowledge or understanding of hereditary breast cancer. Satisfaction with resources was high. There was no evidence that any resource increased distress, worry or decisional conflict. Few resources included active functionalities for example, values-based exercises, to support decision-making. Tailored resources supporting decision-making may be helpful and valued by patients and increase knowledge of hereditary breast cancer, without causing additional distress. Clinicians should provide supportive written information to patients where it is available. However, there is a need for robustly developed decision tools to support decision-making around genetic testing in women with breast cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

CLINICAL PROGRESS IN INHERITED RETINAL DEGENERATIONS: GENE THERAPY CLINICAL TRIALS AND ADVANCES IN GENETIC SEQUENCING

PubMed Central

HAFLER, BRIAN P.

2017-01-01

Purpose Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies. This review serves to analyze clinical progress in genetic diagnostic testing and implications for retinal gene therapy. Methods A literature search of PubMed and OMIM was conducted to relevant articles in inherited retinal dystrophies. Results Next-generation genetic sequencing allows the simultaneous analysis of all the approximately 250 genes that cause inherited retinal dystrophies. Reported diagnostic rates range are high and range from 51% to 57%. These new sequencing tools are highly accurate with sensitivities of 97.9% and specificities of 100%. Retinal gene therapy clinical trials are underway for multiple genes including RPE65, ABCA4, CHM, RS1, MYO7A, CNGA3, CNGB3, ND4, and MERTK for which a molecular diagnosis may be beneficial for patients. Conclusion Comprehensive next-generation genetic sequencing of all retinal dystrophy genes is changing the paradigm for how retinal specialists perform genetic testing for inherited retinal degenerations. Not only are high diagnostic yields obtained, but mutations in genes with novel clinical phenotypes are also identified. In the era of retinal gene therapy clinical trials, identifying specific genetic defects will increasingly be of use to identify patients who may enroll in clinical studies and benefit from novel therapies. PMID:27753762

POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance

PubMed Central

Bellido, Fernando; Pineda, Marta; Aiza, Gemma; Valdés-Mas, Rafael; Navarro, Matilde; Puente, Diana A.; Pons, Tirso; González, Sara; Iglesias, Silvia; Darder, Esther; Piñol, Virginia; Soto, José Luís; Valencia, Alfonso; Blanco, Ignacio; Urioste, Miguel; Brunet, Joan; Lázaro, Conxi; Capellá, Gabriel; Puente, Xose S.; Valle, Laura

2016-01-01

Purpose: Germ-line mutations in the exonuclease domains of POLE and POLD1 have been recently associated with polyposis and colorectal cancer (CRC) predisposition. Here, we aimed to gain a better understanding of the phenotypic characteristics of this syndrome to establish specific criteria for POLE and POLD1 mutation screening and to help define the clinical management of mutation carriers. Genet Med 18 4, 325–332. Methods: The exonuclease domains of POLE and POLD1 were studied in 529 kindred, 441 with familial nonpolyposis CRC and 88 with polyposis, by using pooled DNA amplification and massively parallel sequencing. Genet Med 18 4, 325–332. Results: Seven novel or rare genetic variants were identified. In addition to the POLE p.L424V recurrent mutation in a patient with polyposis, CRC and oligodendroglioma, six novel or rare POLD1 variants (four of them, p.D316H, p.D316G, p.R409W, and p.L474P, with strong evidence for pathogenicity) were identified in nonpolyposis CRC families. Phenotypic data from these and previously reported POLE/POLD1 carriers point to an associated phenotype characterized by attenuated or oligo-adenomatous colorectal polyposis, CRC, and probably brain tumors. In addition, POLD1 mutations predispose to endometrial and breast tumors. Genet Med 18 4, 325–332. Conclusion: Our results widen the phenotypic spectrum of the POLE/POLD1-associated syndrome and identify novel pathogenic variants. We propose guidelines for genetic testing and surveillance recommendations. Genet Med 18 4, 325–332. PMID:26133394

“Soldier's Heart”: A Genetic Basis for Elevated Cardiovascular Disease Risk Associated with Post-traumatic Stress Disorder

PubMed Central

Pollard, Harvey B.; Shivakumar, Chittari; Starr, Joshua; Eidelman, Ofer; Jacobowitz, David M.; Dalgard, Clifton L.; Srivastava, Meera; Wilkerson, Matthew D.; Stein, Murray B.; Ursano, Robert J.

2016-01-01

“Soldier's Heart,” is an American Civil War term linking post-traumatic stress disorder (PTSD) with increased propensity for cardiovascular disease (CVD). We have hypothesized that there might be a quantifiable genetic basis for this linkage. To test this hypothesis we identified a comprehensive set of candidate risk genes for PTSD, and tested whether any were also independent risk genes for CVD. A functional analysis algorithm was used to identify associated signaling networks. We identified 106 PTSD studies that report one or more polymorphic variants in 87 candidate genes in 83,463 subjects and controls. The top upstream drivers for these PTSD risk genes are predicted to be the glucocorticoid receptor (NR3C1) and Tumor Necrosis Factor alpha (TNFA). We find that 37 of the PTSD candidate risk genes are also candidate independent risk genes for CVD. The association between PTSD and CVD is significant by Fisher's Exact Test (P = 3 × 10−54). We also find 15 PTSD risk genes that are independently associated with Type 2 Diabetes Mellitus (T2DM; also significant by Fisher's Exact Test (P = 1.8 × 10−16). Our findings offer quantitative evidence for a genetic link between post-traumatic stress and cardiovascular disease, Computationally, the common mechanism for this linkage between PTSD and CVD is innate immunity and NFκB-mediated inflammation. PMID:27721742

"Soldier's Heart": A Genetic Basis for Elevated Cardiovascular Disease Risk Associated with Post-traumatic Stress Disorder.

PubMed

Pollard, Harvey B; Shivakumar, Chittari; Starr, Joshua; Eidelman, Ofer; Jacobowitz, David M; Dalgard, Clifton L; Srivastava, Meera; Wilkerson, Matthew D; Stein, Murray B; Ursano, Robert J

2016-01-01

"Soldier's Heart," is an American Civil War term linking post-traumatic stress disorder (PTSD) with increased propensity for cardiovascular disease (CVD). We have hypothesized that there might be a quantifiable genetic basis for this linkage. To test this hypothesis we identified a comprehensive set of candidate risk genes for PTSD, and tested whether any were also independent risk genes for CVD. A functional analysis algorithm was used to identify associated signaling networks. We identified 106 PTSD studies that report one or more polymorphic variants in 87 candidate genes in 83,463 subjects and controls. The top upstream drivers for these PTSD risk genes are predicted to be the glucocorticoid receptor (NR3C1) and Tumor Necrosis Factor alpha (TNFA). We find that 37 of the PTSD candidate risk genes are also candidate independent risk genes for CVD. The association between PTSD and CVD is significant by Fisher's Exact Test ( P = 3 × 10 -54 ). We also find 15 PTSD risk genes that are independently associated with Type 2 Diabetes Mellitus (T2DM; also significant by Fisher's Exact Test ( P = 1.8 × 10 -16 ). Our findings offer quantitative evidence for a genetic link between post-traumatic stress and cardiovascular disease, Computationally, the common mechanism for this linkage between PTSD and CVD is innate immunity and NFκB-mediated inflammation.

Prioritizing individual genetic variants after kernel machine testing using variable selection.

PubMed

He, Qianchuan; Cai, Tianxi; Liu, Yang; Zhao, Ni; Harmon, Quaker E; Almli, Lynn M; Binder, Elisabeth B; Engel, Stephanie M; Ressler, Kerry J; Conneely, Karen N; Lin, Xihong; Wu, Michael C

2016-12-01

Kernel machine learning methods, such as the SNP-set kernel association test (SKAT), have been widely used to test associations between traits and genetic polymorphisms. In contrast to traditional single-SNP analysis methods, these methods are designed to examine the joint effect of a set of related SNPs (such as a group of SNPs within a gene or a pathway) and are able to identify sets of SNPs that are associated with the trait of interest. However, as with many multi-SNP testing approaches, kernel machine testing can draw conclusion only at the SNP-set level, and does not directly inform on which one(s) of the identified SNP set is actually driving the associations. A recently proposed procedure, KerNel Iterative Feature Extraction (KNIFE), provides a general framework for incorporating variable selection into kernel machine methods. In this article, we focus on quantitative traits and relatively common SNPs, and adapt the KNIFE procedure to genetic association studies and propose an approach to identify driver SNPs after the application of SKAT to gene set analysis. Our approach accommodates several kernels that are widely used in SNP analysis, such as the linear kernel and the Identity by State (IBS) kernel. The proposed approach provides practically useful utilities to prioritize SNPs, and fills the gap between SNP set analysis and biological functional studies. Both simulation studies and real data application are used to demonstrate the proposed approach. © 2016 WILEY PERIODICALS, INC.

Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia

PubMed Central

Wen, Wei Xiong; Allen, Jamie; Lai, Kah Nyin; Mariapun, Shivaani; Hasan, Siti Norhidayu; Ng, Pei Sze; Lee, Daphne Shin-Chi; Lee, Sheau Yee; Yoon, Sook-Yee; Lim, Joanna; Lau, Shao Yan; Decker, Brennan; Pooley, Karen; Dorling, Leila; Luccarini, Craig; Baynes, Caroline; Conroy, Don M; Harrington, Patricia; Simard, Jacques; Yip, Cheng Har; Mohd Taib, Nur Aishah; Ho, Weang Kee; Antoniou, Antonis C; Dunning, Alison M; Easton, Douglas F

2018-01-01

Background Genetic testing for BRCA1 and BRCA2 is offered typically to selected women based on age of onset and family history of cancer. However, current internationally accepted genetic testing referral guidelines are built mostly on data from cancer genetics clinics in women of European descent. To evaluate the appropriateness of such guidelines in Asians, we have determined the prevalence of germ line variants in an unselected cohort of Asian patients with breast cancer and healthy controls. Methods Germ line DNA from a hospital-based study of 2575 unselected patients with breast cancer and 2809 healthy controls were subjected to amplicon-based targeted sequencing of exonic and proximal splice site junction regions of BRCA1 and BRCA2 using the Fluidigm Access Array system, with sequencing conducted on a Illumina HiSeq2500 platform. Variant calling was performed with GATK UnifiedGenotyper and were validated by Sanger sequencing. Results Fifty-five (2.1%) BRCA1 and 66 (2.6%) BRCA2 deleterious mutations were identified among patients with breast cancer and five (0.18%) BRCA1 and six (0.21%) BRCA2 mutations among controls. One thousand one hundred and eighty-six (46%) patients and 97 (80%) carriers fulfilled the National Comprehensive Cancer Network guidelines for genetic testing. Conclusion Five per cent of unselected Asian patients with breast cancer carry deleterious variants in BRCA1 or BRCA2. While current referral guidelines identified the majority of carriers, one in two patients would be referred for genetic services. Given that such services are largely unavailable in majority of low-resource settings in Asia, our study highlights the need for more efficient guidelines to identify at-risk individuals in Asia. PMID:28993434

Cancer genetic risk assessment and referral patterns in primary care.

PubMed

Vig, Hetal S; Armstrong, Joanne; Egleston, Brian L; Mazar, Carla; Toscano, Michele; Bradbury, Angela R; Daly, Mary B; Meropol, Neal J

2009-12-01

This study was undertaken to describe cancer risk assessment practices among primary care providers (PCPs). An electronic survey was sent to PCPs affiliated with a single insurance carrier. Demographic and practice characteristics associated with cancer genetic risk assessment and testing activities were described. Latent class analysis supported by likelihood ratio tests was used to define PCP profiles with respect to the level of engagement in genetic risk assessment and referral activity based on demographic and practice characteristics. 860 physicians responded to the survey (39% family practice, 29% internal medicine, 22% obstetrics/gynecology (OB/GYN), 10% other). Most respondents (83%) reported that they routinely assess hereditary cancer risk; however, only 33% reported that they take a full, three-generation pedigree for risk assessment. OB/GYN specialty, female gender, and physician access to a genetic counselor were independent predictors of referral to cancer genetics specialists. Three profiles of PCPs, based upon referral practice and extent of involvement in genetics evaluation, were defined. Profiles of physician characteristics associated with varying levels of engagement with cancer genetic risk assessment and testing can be identified. These profiles may ultimately be useful in targeting decision support tools and services.

Health care professionals' attitudes towards population-based genetic testing and risk-stratification for ovarian cancer: a cross-sectional survey.

PubMed

Hann, Katie E J; Fraser, Lindsay; Side, Lucy; Gessler, Sue; Waller, Jo; Sanderson, Saskia C; Freeman, Madeleine; Jacobs, Ian; Lanceley, Anne

2017-12-16

Ovarian cancer is usually diagnosed at a late stage when outcomes are poor. Personalised ovarian cancer risk prediction, based on genetic and epidemiological information and risk stratified management in adult women could improve outcomes. Examining health care professionals' (HCP) attitudes to ovarian cancer risk stratified management, willingness to support women, self-efficacy (belief in one's own ability to successfully complete a task), and knowledge about ovarian cancer will help identify training needs in anticipation of personalised ovarian cancer risk prediction being introduced. An anonymous survey was distributed online to HCPs via relevant professional organisations in the UK. Kruskal-Wallis tests and pairwise comparisons were used to compare knowledge and self-efficacy scores between different types of HCPs, and attitudes toward population-based genetic testing and risk stratified management were described. Content analysis was undertaken of free text responses concerning HCPs willingness to discuss risk management options with women. One hundred forty-six eligible HCPs completed the survey: oncologists (31%); genetics clinicians (30%); general practitioners (22%); gynaecologists (10%); nurses (4%); and 'others'. Scores for knowledge of ovarian cancer and genetics, and self-efficacy in conducting a cancer risk consultation were generally high but significantly lower for general practitioners compared to genetics clinicians, oncologists, and gynaecologists. Support for population-based genetic testing was not high (<50%). Attitudes towards ovarian cancer risk stratification were mixed, although the majority of participants indicated a willingness to discuss management options with patients. Larger samples are required to investigate attitudes to population-based genetic testing for ovarian cancer risk and to establish why some HCPs are hesitant to offer testing to all adult female patients. If ovarian cancer risk assessment using genetic testing and non-genetic information including epidemiological information is rolled out on a population basis, training will be needed for HCPs in primary care to enable them to provide appropriate support to women at each stage of the process.

Predicting Landscape-Genetic Consequences of Habitat Loss, Fragmentation and Mobility for Multiple Species of Woodland Birds

PubMed Central

Amos, J. Nevil; Bennett, Andrew F.; Mac Nally, Ralph; Newell, Graeme; Pavlova, Alexandra; Radford, James Q.; Thomson, James R.; White, Matt; Sunnucks, Paul

2012-01-01

Inference concerning the impact of habitat fragmentation on dispersal and gene flow is a key theme in landscape genetics. Recently, the ability of established approaches to identify reliably the differential effects of landscape structure (e.g. land-cover composition, remnant vegetation configuration and extent) on the mobility of organisms has been questioned. More explicit methods of predicting and testing for such effects must move beyond post hoc explanations for single landscapes and species. Here, we document a process for making a priori predictions, using existing spatial and ecological data and expert opinion, of the effects of landscape structure on genetic structure of multiple species across replicated landscape blocks. We compare the results of two common methods for estimating the influence of landscape structure on effective distance: least-cost path analysis and isolation-by-resistance. We present a series of alternative models of genetic connectivity in the study area, represented by different landscape resistance surfaces for calculating effective distance, and identify appropriate null models. The process is applied to ten species of sympatric woodland-dependant birds. For each species, we rank a priori the expectation of fit of genetic response to the models according to the expected response of birds to loss of structural connectivity and landscape-scale tree-cover. These rankings (our hypotheses) are presented for testing with empirical genetic data in a subsequent contribution. We propose that this replicated landscape, multi-species approach offers a robust method for identifying the likely effects of landscape fragmentation on dispersal. PMID:22363508

Seeking the Cause of Correlations among Mental Abilities: Large Twin Analysis in a National Testing Program.

ERIC Educational Resources Information Center

Page, Ellis B.; Jarjoura, David

1979-01-01

A computer scan of ACT Assessment records identified 3,427 sets of twins. The Hardy-Weinberg rule was used to estimate the proportion of monozygotic twins in the sample. Matrices of genetic and environmental influences were produced. The heaviest loadings were clearly in the genetic matrix. (SJL)

Development of a Genomic DNA Reference Material Panel for Myotonic Dystrophy Type 1 (DM1) Genetic Testing

PubMed Central

Kalman, Lisa; Tarleton, Jack; Hitch, Monica; Hegde, Madhuri; Hjelm, Nick; Berry-Kravis, Elizabeth; Zhou, Lili; Hilbert, James E.; Luebbe, Elizabeth A.; Moxley, Richard T.; Toji, Lorraine

2014-01-01

Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG triplet repeat in the 3′ untranslated region of the DMPK gene that encodes a serine-threonine kinase. Patients with larger repeats tend to have a more severe phenotype. Clinical laboratories require reference and quality control materials for DM1 diagnostic and carrier genetic testing. Well-characterized reference materials are not available. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing community, the National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members, and the Coriell Cell Repositories, has established and characterized cell lines from patients with DM1 to create a reference material panel. The CTG repeats in genomic DNA samples from 10 DM1 cell lines were characterized in three clinical genetic testing laboratories using PCR and Southern blot analysis. DMPK alleles in the samples cover four of five DM1 clinical categories: normal (5 to 34 repeats), mild (50 to 100 repeats), classical (101 to 1000 repeats), and congenital (>1000 repeats). We did not identify or establish Coriell cell lines in the premutation range (35 to 49 repeats). These samples are publicly available for quality control, proficiency testing, test development, and research and should help improve the accuracy of DM1 testing. PMID:23680132

Integrating evolutionary and functional approaches to infer adaptation at specific loci.

PubMed

Storz, Jay F; Wheat, Christopher W

2010-09-01

Inferences about adaptation at specific loci are often exclusively based on the static analysis of DNA sequence variation. Ideally,population-genetic evidence for positive selection serves as a stepping-off point for experimental studies to elucidate the functional significance of the putatively adaptive variation. We argue that inferences about adaptation at specific loci are best achieved by integrating the indirect, retrospective insights provided by population-genetic analyses with the more direct, mechanistic insights provided by functional experiments. Integrative studies of adaptive genetic variation may sometimes be motivated by experimental insights into molecular function, which then provide the impetus to perform population genetic tests to evaluate whether the functional variation is of adaptive significance. In other cases, studies may be initiated by genome scans of DNA variation to identify candidate loci for recent adaptation. Results of such analyses can then motivate experimental efforts to test whether the identified candidate loci do in fact contribute to functional variation in some fitness-related phenotype. Functional studies can provide corroborative evidence for positive selection at particular loci, and can potentially reveal specific molecular mechanisms of adaptation.

Classifying Married Adults Diagnosed with Alpha-1 Antitrypsin Deficiency Based on Spousal Communication Patterns Using Latent Class Analysis: Insights for Intervention

PubMed Central

Smith, Rachel A.; Wienke, Sara E.; Baker, Michelle K.

2013-01-01

Married adults are increasingly exposed to test results that indicate an increased genetic risk for adult-onset conditions. For example, a SERPINA1 mutation, associated with alpha-1 antitrypsin deficiency (AATD), predisposes affected individuals to diseases such as chronic obstructive pulmonary disease (COPD) and cancer, which are often detected in adulthood. Married adults are likely to discuss genetic test results with their spouses, and interpersonal research suggests that spouses’ communication patterns differ. Latent class analysis was used to identify subgroups of spousal communication patterns about AATD results from a sample of married adults in the Alpha-1 Research Registry (N = 130). A five-class model was identified, and the subgroups were consistent with existing spousal-communication typologies. This study also showed that genetic beliefs (e.g., genetic stigma), emotions, and experiences (e.g., insurance difficulties) covaried with membership in particular subgroups. Understanding these differences can serve as the foundation for the creation of effective, targeted communications interventions to address the specific needs and conversational patterns of different kinds of couples. PMID:24177906

Comprehensive genetic testing for primary immunodeficiency disorders in a tertiary hospital: 10-year experience in Auckland, New Zealand.

PubMed

Woon, See-Tarn; Ameratunga, Rohan

2016-01-01

New Zealand is a developed geographically isolated country in the South Pacific with a population of 4.4 million. Genetic diagnosis is the standard of care for most patients with primary immunodeficiency disorders (PIDs). Since 2005, we have offered a comprehensive genetic testing service for PIDs and other immune-related disorders with a published sequence. Here we present results for this program, over the first decade, between 2005 and 2014. We undertook testing in 228 index cases and 32 carriers during this time. The three most common test requests were for X-linked lymphoproliferative (XLP), tumour necrosis factor receptor associated periodic syndrome (TRAPS) and haemophagocytic lymphohistiocytosis (HLH). Of the 32 suspected XLP cases, positive diagnoses were established in only 2 patients. In contrast, genetic defects in 8 of 11 patients with suspected X-linked agammaglobulinemia (XLA) were confirmed. Most XLA patients were initially identified from absence of B cells. Overall, positive diagnoses were made in about 23% of all tests requested. The diagnostic rate was lowest for several conditions with locus heterogeneity. Thorough clinical characterisation of patients can assist in prioritising which genes should be tested. The clinician-driven customised comprehensive genetic service has worked effectively for New Zealand. Next generation sequencing will play an increasing role in disorders with locus heterogeneity.

Parent-child genetic testing for familial hypercholesterolaemia in an Australian context.

PubMed

Pang, Jing; Martin, Andrew C; Bates, Timothy R; Hooper, Amanda J; Bell, Damon A; Burnett, John R; Norman, Richard; Watts, Gerald F

2018-04-06

The aim of this study was to evaluate the clinical outcome of parent-child testing for familial hypercholesterolaemia (FH) employing genetic testing and the likely additional cost of treating each child. Parent-child testing for gene variants causative of FH was carried out according to Australian guidelines. The number of new cases detected, the low-density lipoprotein (LDL)-cholesterol that best predicted a mutation and the proportional reduction in LDL-cholesterol following statin treatment was evaluated. Treatment costs were calculated as the cost per mmol/L reduction in LDL-cholesterol. A total of 126 adult patients, known to have a pathogenic mutation causative of FH, and their children were studied. From 244 children identified, 148 (60.7%) were genetically screened; 84 children were identified as mutative positive (M+) and 64 as mutative negative. Six of the M+ children were already on statin treatment; 40 were subsequently treated with low-dose statins, with LDL-cholesterol falling significantly by 38% (P < 0.001). The estimated cost per mmol/L reduction of LDL-cholesterol of a child receiving statins from ages 10 to 18 years is AU$1361, which can potentially be cost-effective. An LDL-cholesterol threshold of 3.5 mmol/L had a sensitivity of 92.8% and specificity of 96.6% for the detection of a mutation. Genetic testing of children of affected parents with FH is an effective means of detecting new cases of FH. Cascade testing can enable early statin therapy with significant reductions in LDL-cholesterol concentration. © 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

Psychological Distress, Anxiety, and Depression of Cancer-Affected BRCA1/2 Mutation Carriers: a Systematic Review.

PubMed

Ringwald, Johanna; Wochnowski, Christina; Bosse, Kristin; Giel, Katrin Elisabeth; Schäffeler, Norbert; Zipfel, Stephan; Teufel, Martin

2016-10-01

Understanding the intermediate- and long-term psychological consequences of genetic testing for cancer patients has led to encouraging research, but a clear consensus of the psychosocial impact and clinical routine for cancer-affected BRCA1 and BRCA2 mutation carriers is still missing. We performed a systematic review of intermediate- and long-term studies investigating the psychological impact like psychological distress, anxiety, and depression in cancer-affected BRCA mutation carriers compared to unaffected mutation carriers. This review included the screening of 1243 studies. Eight intermediate- and long-term studies focusing on distress, anxiety, and depression symptoms among cancer-affected mutation carriers at least six months after the disclosure of genetic testing results were included. Studies reported a great variety of designs, methods, and patient outcomes. We found evidence indicating that cancer-affected mutation carriers experienced a negative effect in relation to psychological well-being in terms of an increase in symptoms of distress, anxiety, and depression in the first months after test disclosure. In the intermediate- and long-term, no significant clinical relevant symptoms occurred. However, none of the included studies used specific measurements, which can clearly identify psychological burdens of cancer-affected mutation carriers. We concluded that current well-implemented distress screening instruments are not sufficient for precisely identifying the psychological burden of genetic testing. Therefore, future studies should implement coping strategies, specific personality structures, the impact of genetic testing, supportive care needs and disease management behaviour to clearly screen for the possible intermediate- and long-term psychological impact of a positive test disclosure.

Understanding of BRCA1/2 genetic tests results: the importance of objective and subjective numeracy.

PubMed

Hanoch, Yaniv; Miron-Shatz, Talya; Rolison, Jonathan J; Ozanne, Elissa

2014-10-01

The majority of women (71%) who undergo BRCA1/2 testing-designed to identify genetic mutations associated with increased risk of cancer-receive results that are termed 'ambiguous' or 'uninformative negative'. How women interpret these results and the association with numerical ability was examined. In this study, 477 women at increased risk for breast and ovarian cancer were recruited via the Cancer Genetics Network. They were presented with information about the four different possible BRCA1/2 test results-positive, true negative, ambiguous and uninformative negative-and asked to indicate which of six options represents the best response. Participants were then asked which treatment options they thought a woman receiving the results should discuss with her doctor. Finally, participants completed measures of objective and subjective numeracy. Almost all of the participants correctly interpreted the positive and negative BRCA1/2 genetic test results. However, they encountered difficulties interpreting the uninformative and ambiguous BRCA1/2 genetic test results. Participants were almost equally likely to think either that the woman had learned nothing from the test result or that she was as likely to develop cancer as the average woman. Highly numerate participants were more likely to correctly interpret inconclusive test results (ambiguous, OR = 1.62; 95% CI [1.28, 2.07]; p < 0.001; uninformative, OR = 1.40; 95% CI [1.10, 1.80]). Given the medical and psychological ramifications of genetic testing, healthcare professionals should consider devoting extra effort to ensuring proper comprehension of ambiguous and uninformative negative test results by women. Copyright © 2014 John Wiley & Sons, Ltd.

How are genetic test results being used by Australian life insurers?

PubMed

Barlow-Stewart, K; Liepins, M; Doble, A; Otlowski, M

2018-06-11

In Australia, the USA and many Asian countries the life insurance industry is self-regulated. Individuals must disclose genetic test results known to them in applications for new or updated policies including cover for critical care, income protection and death. There is limited information regarding how underwriting decisions are made for policies with such disclosures. The Australian Financial Services Council (FSC) provided de-identified data collected on applications with genetic test result disclosure from its life insurance member companies 2010-2013 to enable repetition of an independent examination undertaken of applications 1999-2003: age; gender; genetic condition; testing result; decision-maker; and insurance cover. Data was classified as to test result alone or additional other factors relevant to risk and decision. Where necessary, the FSC facilitated clarification by insurers. 345/548 applications related to adult-onset conditions. The genetic test result solely influenced the decision in 165/345 applications: positive (n = 23), negative (n = 139) and pending (n = 3). Detailed analyses of the decisions in each of these result categories are presented with specific details of 11 test cases. Policies with standard decisions were provided for all negative test results with evidence of reassessment of previous non-standard decisions and 20/23 positive results with recognition of risk reduction strategies. Disclosure of positive results for breast/ovarian cancer, Lynch syndrome and hereditary spastic paraplegia, and three pending results, generated non-standard decisions. The examination demonstrates some progress in addressing concerns in regard to utilisation of genetic test information but the self-regulatory system in Australia only goes some way in meeting internationally recommended best practice.

Estimating genetic effects and quantifying missing heritability explained by identified rare-variant associations.

PubMed

Liu, Dajiang J; Leal, Suzanne M

2012-10-05

Next-generation sequencing has led to many complex-trait rare-variant (RV) association studies. Although single-variant association analysis can be performed, it is grossly underpowered. Therefore, researchers have developed many RV association tests that aggregate multiple variant sites across a genetic region (e.g., gene), and test for the association between the trait and the aggregated genotype. After these aggregate tests detect an association, it is only possible to estimate the average genetic effect for a group of RVs. As a result of the "winner's curse," such an estimate can be biased. Although for common variants one can obtain unbiased estimates of genetic parameters by analyzing a replication sample, for RVs it is desirable to obtain unbiased genetic estimates for the study where the association is identified. This is because there can be substantial heterogeneity of RV sites and frequencies even among closely related populations. In order to obtain an unbiased estimate for aggregated RV analysis, we developed bootstrap-sample-split algorithms to reduce the bias of the winner's curse. The unbiased estimates are greatly important for understanding the population-specific contribution of RVs to the heritability of complex traits. We also demonstrate both theoretically and via simulations that for aggregate RV analysis the genetic variance for a gene or region will always be underestimated, sometimes substantially, because of the presence of noncausal variants or because of the presence of causal variants with effects of different magnitudes or directions. Therefore, even if RVs play a major role in the complex-trait etiologies, a portion of the heritability will remain missing, and the contribution of RVs to the complex-trait etiologies will be underestimated. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Mapping eQTLs in the Norfolk Island Genetic Isolate Identifies Candidate Genes for CVD Risk Traits

PubMed Central

Benton, Miles C.; Lea, Rod A.; Macartney-Coxson, Donia; Carless, Melanie A.; Göring, Harald H.; Bellis, Claire; Hanna, Michelle; Eccles, David; Chambers, Geoffrey K.; Curran, Joanne E.; Harper, Jacquie L.; Blangero, John; Griffiths, Lyn R.

2013-01-01

Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10−7) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations. PMID:24314549

Effects of canine parvovirus strain variations on diagnostic test results and clinical management of enteritis in dogs.

PubMed

Markovich, Jessica E; Stucker, Karla M; Carr, Alaina H; Harbison, Carole E; Scarlett, Janet M; Parrish, Colin R

2012-07-01

To estimate the prevalence of canine parvovirus (CPV) strains among dogs with enteritis admitted to a referral hospital in the southwestern United States during an 11-month period and to compare diagnostic test results, disease severity, and patient outcome among CPV strains. Prospective observational study. 72 dogs with histories and clinical signs of parvoviral enteritis. For each dog, a fecal sample or rectal swab specimen was evaluated for CPV antigen via an ELISA. Subsequently, fecal samples (n = 42 dogs) and pharyngeal swab specimens (16) were obtained and tested for CPV antigen via an ELISA and CPV DNA via a PCR assay. For specimens with CPV-positive results via PCR assay, genetic sequencing was performed to identify the CPV strain. 56 dogs tested positive for CPV via ELISA or PCR assay. For 42 fecal samples tested via both ELISA and PCR assay, 27 had positive results via both assays, whereas 6 had positive PCR assay results only. Ten pharyngeal swab specimens yielded positive PCR assay results. Genetic sequencing was performed on 34 fecal or pharyngeal swab specimens that had CPV-positive PCR assay results; 25 (73.5%) were identified as containing CPV type-2c, and 9 (26.5%) were identified as containing CPV type-2b. No association was found between CPV strain and disease severity or clinical outcome. CPV type-2b and CPV type-2c posed similar health risks for dogs; therefore, genetic sequencing of CPV does not appear necessary for clinical management of infected patients. The diagnostic tests used could detect CPV type-2c.

Predictive genetic testing in minors for late-onset conditions: a chronological and analytical review of the ethical arguments.

PubMed

Mand, Cara; Gillam, Lynn; Delatycki, Martin B; Duncan, Rony E

2012-09-01

Predictive genetic testing is now routinely offered to asymptomatic adults at risk for genetic disease. However, testing of minors at risk for adult-onset conditions, where no treatment or preventive intervention exists, has evoked greater controversy and inspired a debate spanning two decades. This review aims to provide a detailed longitudinal analysis and concludes by examining the debate's current status and prospects for the future. Fifty-three relevant theoretical papers published between 1990 and December 2010 were identified, and interpretative content analysis was employed to catalogue discrete arguments within these papers. Novel conclusions were drawn from this review. While the debate's first voices were raised in opposition of testing and their arguments have retained currency over many years, arguments in favour of testing, which appeared sporadically at first, have gained momentum more recently. Most arguments on both sides are testable empirical claims, so far untested, rather than abstract ethical or philosophical positions. The dispute, therein, lies not so much in whether minors should be permitted to access predictive genetic testing but whether these empirical claims on the relative benefits or harms of testing should be assessed.

Understanding of multigene test results among males undergoing germline testing for inherited prostate cancer: Implications for genetic counseling.

PubMed

Giri, Veda N; Obeid, Elias; Hegarty, Sarah E; Gross, Laura; Bealin, Lisa; Hyatt, Colette; Fang, Carolyn Y; Leader, Amy

2018-04-14

Genetic testing (GT) for prostate cancer (PCA) is rising, with limited insights regarding genetic counseling (GC) needs of males. Genetic Evaluation of Men (GEM) is a prospective multigene testing study for inherited PCA. Men undergoing GC were surveyed on knowledge of cancer risk and genetics (CRG) and understanding of personal GT results to identify GC needs. GEM participants with or high-risk for PCA were recruited. Pre-test GC was in-person, with video and handout, or via telehealth. Post-test disclosure was in-person, by phone, or via telehealth. Clinical and family history data were obtained from participant surveys and medical records. Participants completed measures of knowledge of CRG, literacy, and numeracy pre-test and post-test. Understanding of personal genetic results was assessed post-test. Factors associated with knowledge of CRG and understanding of personal genetic results were examined using multivariable linear regression or McNemar's test. Among 109 men who completed pre- and post-GT surveys, multivariable analysis revealed family history meeting hereditary cancer syndrome (HCS) criteria was significantly predictive of higher baseline knowledge (P = 0.040). Of 101 men who responded definitively regarding understanding of results, 13 incorrectly reported their result (McNemar's P < 0.001). Factors significantly associated with discordance between reported and actual results included having a variant of uncertain significance (VUS) (P < 0.001) and undergoing GC via pre-test video and post-test phone disclosure (P = 0.015). While meeting criteria for HCS was associated with higher knowledge of CRG, understanding of personal GT results was lacking among a subset of males with VUS. A more exploratory finding was lack of understanding of results among men who underwent GC utilizing video and phone. Studies optimizing GC strategies for males undergoing multigene testing for inherited PCA are warranted. © 2018 Wiley Periodicals, Inc.

Ethnic, racial and cultural identity and perceived benefits and barriers related to genetic testing for breast cancer among at-risk women of African descent in New York City.

PubMed

Sussner, K M; Edwards, T A; Thompson, H S; Jandorf, L; Kwate, N O; Forman, A; Brown, K; Kapil-Pair, N; Bovbjerg, D H; Schwartz, M D; Valdimarsdottir, H B

2011-01-01

Due to disparities in the use of genetic services, there has been growing interest in examining beliefs and attitudes related to genetic testing for breast and/or ovarian cancer risk among women of African descent. However, to date, few studies have addressed critical cultural variations among this minority group and their influence on such beliefs and attitudes. We assessed ethnic, racial and cultural identity and examined their relationships with perceived benefits and barriers related to genetic testing for cancer risk in a sample of 160 women of African descent (49% self-identified African American, 39% Black-West Indian/Caribbean, 12% Black-Other) who met genetic risk criteria and were participating in a larger longitudinal study including the opportunity for free genetic counseling and testing in New York City. All participants completed the following previously validated measures: (a) the multi-group ethnic identity measure (including ethnic search and affirmation subscales) and other-group orientation for ethnic identity, (b) centrality to assess racial identity, and (c) Africentrism to measure cultural identity. Perceived benefits and barriers related to genetic testing included: (1) pros/advantages (including family-related pros), (2) cons/disadvantages (including family-related cons, stigma and confidentiality concerns), and (3) concerns about abuses of genetic testing. In multivariate analyses, several ethnic identity elements showed significant, largely positive relationships to perceived benefits about genetic testing for breast and/or ovarian cancer risk, the exception being ethnic search, which was positively associated with cons/disadvantages, in general, and family-related cons/disadvantages. Racial identity (centrality) showed a significant association with confidentiality concerns. Cultural identity (Africentrism) was not related to perceived benefits and/or barriers. Ethnic and racial identity may influence perceived benefits and barriers related to genetic testing for breast and/or ovarian cancer risk among at-risk women of African descent. Genetic counseling services may want to take into account these factors in the creation of culturally-appropriate services which best meet the needs of this heterogenous population. Copyright © 2011 S. Karger AG, Basel.

Can the ability to adapt to exercise be considered a talent-and if so, can we test for it?

PubMed

Pickering, Craig; Kiely, John

2017-11-29

Talent identification (TI) is a popular and hugely important topic within sports performance, with an ever-increasing amount of resources dedicated to unveiling the next sporting star. However, at present, most TI processes appear to select high-performing individuals at the present point in time, as opposed to identifying those individuals with the greatest capacity to improve. This represents a potential inefficiency within the TI process, reducing its effectiveness. In this article, we discuss whether the ability to adapt favorably, and with a large magnitude, to physical training can be considered a talent, testing it against proposed criteria. We also discuss whether, if such an ability can be considered a talent, being able to test for it as part of the TI process would be advantageous. Given that such a capacity is partially heritable, driven by genetic variation between individuals that mediate the adaptive response, we also explore whether the information gained from genetic profiling can be used to identify those with the greatest capacity to improve. Although there are some ethical hurdles which must be considered, the use of genetic information to identify those individuals with the greatest capacity appears to hold promise and may improve both the efficiency and effectiveness of contemporary TI programmes.

Genetic Analysis of Reduced γ-Tocopherol Content in Ethiopian Mustard Seeds.

PubMed

García-Navarro, Elena; Fernández-Martínez, José M; Pérez-Vich, Begoña; Velasco, Leonardo

2016-01-01

Ethiopian mustard (Brassica carinata A. Braun) line BCT-6, with reduced γ-tocopherol content in the seeds, has been previously developed. The objective of this research was to conduct a genetic analysis of seed tocopherols in this line. BCT-6 was crossed with the conventional line C-101 and the F1, F2, and BC plant generations were analyzed. Generation mean analysis using individual scaling tests indicated that reduced γ-tocopherol content fitted an additive-dominant genetic model with predominance of additive effects and absence of epistatic interactions. This was confirmed through a joint scaling test and additional testing of the goodness of fit of the model. Conversely, epistatic interactions were identified for total tocopherol content. Estimation of the minimum number of genes suggested that both γ- and total tocopherol content may be controlled by two genes. A positive correlation between total tocopherol content and the proportion of γ-tocopherol was identified in the F2 generation. Additional research on the feasibility of developing germplasm with high tocopherol content and reduced concentration of γ-tocopherol is required.

The genetic basis of female reproductive disorders: Etiology and clinical testing ☆

PubMed Central

Layman, Lawrence C.

2013-01-01

With the advent of improved molecular biology techniques, the genetic basis of an increasing number of reproductive disorders has been elucidated. Mutations in at least 20 genes cause hypogonadotropic hypogonadism including Kallmann syndrome in about 35–40% of patients. The two most commonly involved genes are FGFR1 and CHD7. When combined pituitary hormone deficiency includes hypogonadotropic hypogonadism as a feature, PROP1 mutations are the most common of the six genes involved. For hypergonadotropic hypogonadism, mutations in 14 genes cause gonadal failure in 15% of affected females, most commonly in FMR1. In eugonadal disorders, activating FSHR mutations have been identified for spontaneous ovarian hyperstimulation syndrome; and WNT4 mutations have been described in mullerian aplasia. For other eugonadal disorders, such as endometriosis, polycystic ovary syndrome, and leiomyomata, specific germline gene mutations have not been identified, but some chromosomal regions are associated with the corresponding phenotype. Practical genetic testing is possible to perform in both hypogonadotropic and hypergonadotropic hypogonadism and spontaneous ovarian hyperstimulation syndrome. However, clinical testing for endometriosis, polycystic ovary syndrome, and leiomyomata is not currently practical for the clinician. PMID:23499866

Identifying future models for delivering genetic services: a nominal group study in primary care

PubMed Central

Elwyn, Glyn; Edwards, Adrian; Iredale, Rachel; Davies, Peter; Gray, Jonathon

2005-01-01

Background To enable primary care medical practitioners to generate a range of possible service delivery models for genetic counselling services and critically assess their suitability. Methods Modified nominal group technique using in primary care professional development workshops. Results 37 general practitioners in Wales, United Kingdom too part in the nominal group process. The practitioners who attended did not believe current systems were sufficient to meet anticipated demand for genetic services. A wide range of different service models was proposed, although no single option emerged as a clear preference. No argument was put forward for genetic assessment and counselling being central to family practice, neither was there a voice for the view that the family doctor should become skilled at advising patients about predictive genetic testing and be able to counsel patients about the wider implications of genetic testing for patients and their family members, even for areas such as common cancers. Nevertheless, all the preferred models put a high priority on providing the service in the community, and often co-located in primary care, by clinicians who had developed expertise. Conclusion There is a need for a wider debate about how healthcare systems address individual concerns about genetic concerns and risk, especially given the increasing commercial marketing of genetic tests. PMID:15831099

A Simple Test Identifies Selection on Complex Traits.

PubMed

Beissinger, Tim; Kruppa, Jochen; Cavero, David; Ha, Ngoc-Thuy; Erbe, Malena; Simianer, Henner

2018-05-01

Important traits in agricultural, natural, and human populations are increasingly being shown to be under the control of many genes that individually contribute only a small proportion of genetic variation. However, the majority of modern tools in quantitative and population genetics, including genome-wide association studies and selection-mapping protocols, are designed to identify individual genes with large effects. We have developed an approach to identify traits that have been under selection and are controlled by large numbers of loci. In contrast to existing methods, our technique uses additive-effects estimates from all available markers, and relates these estimates to allele-frequency change over time. Using this information, we generate a composite statistic, denoted [Formula: see text] which can be used to test for significant evidence of selection on a trait. Our test requires pre- and postselection genotypic data but only a single time point with phenotypic information. Simulations demonstrate that [Formula: see text] is powerful for identifying selection, particularly in situations where the trait being tested is controlled by many genes, which is precisely the scenario where classical approaches for selection mapping are least powerful. We apply this test to breeding populations of maize and chickens, where we demonstrate the successful identification of selection on traits that are documented to have been under selection. Copyright © 2018 Beissinger et al.

Nemesis Autonomous Test System

NASA Technical Reports Server (NTRS)

Barltrop, Kevin J.; Lee, Cin-Young; Horvath, Gregory A,; Clement, Bradley J.

2012-01-01

A generalized framework has been developed for systems validation that can be applied to both traditional and autonomous systems. The framework consists of an automated test case generation and execution system called Nemesis that rapidly and thoroughly identifies flaws or vulnerabilities within a system. By applying genetic optimization and goal-seeking algorithms on the test equipment side, a "war game" is conducted between a system and its complementary nemesis. The end result of the war games is a collection of scenarios that reveals any undesirable behaviors of the system under test. The software provides a reusable framework to evolve test scenarios using genetic algorithms using an operation model of the system under test. It can automatically generate and execute test cases that reveal flaws in behaviorally complex systems. Genetic algorithms focus the exploration of tests on the set of test cases that most effectively reveals the flaws and vulnerabilities of the system under test. It leverages advances in state- and model-based engineering, which are essential in defining the behavior of autonomous systems. It also uses goal networks to describe test scenarios.

Genetics and the investigation of developmental delay/intellectual disability.

PubMed

Srour, Myriam; Shevell, Michael

2014-04-01

Global developmental delay and intellectual disabilities are common reasons for diagnostic assessment by paediatricians. There are a multiplicity of possible causes many of which have genetic, management and treatment implications for the child and family. Genetic causes are estimated to be responsible for approximately a quarter to one-half of identified cases. The multiplicity of individually rare genetic causes challenges the practitioner with respect to the selection of diagnostic tests and accurate diagnosis. To assist the practitioner practice guidelines have been formulated and these are reviewed and summarised in this particular article.

The behavioral genetics of nonhuman primates: Status and prospects.

PubMed

Rogers, Jeffrey

2018-01-01

The complexity and diversity of primate behavior have long attracted the attention of ethologists, psychologists, behavioral ecologists, and neuroscientists. Recent studies have advanced our understanding of the nature of genetic influences on differences in behavior among individuals within species. A number of analyses have focused on the genetic analysis of behavioral reactions to specific experimental tests, providing estimates of the degree of genetic control over reactivity, and beginning to identify the genes involved. Substantial progress is also being made in identifying genetic factors that influence the structure and function of the primate brain. Most of the published studies on these topics have examined either cercopithecines or chimpanzees, though a few studies have addressed these questions in other primate species. One potentially important line of research is beginning to identify the epigenetic processes that influence primate behavior, thus revealing specific cellular and molecular mechanisms by which environmental experiences can influence gene expression or gene function relevant to behavior. This review summarizes many of these studies of non-human primate behavioral genetics. The primary focus is on analyses that address the nature of the genes and genetic processes that affect differences in behavior among individuals within non-human primate species. Analyses of between species differences and potential avenues for future research are also discussed. © 2018 American Association of Physical Anthropologists.

Genetic Structure of Bluefin Tuna in the Mediterranean Sea Correlates with Environmental Variables

PubMed Central

Riccioni, Giulia; Stagioni, Marco; Landi, Monica; Ferrara, Giorgia; Barbujani, Guido; Tinti, Fausto

2013-01-01

Background Atlantic Bluefin Tuna (ABFT) shows complex demography and ecological variation in the Mediterranean Sea. Genetic surveys have detected significant, although weak, signals of population structuring; catch series analyses and tagging programs identified complex ABFT spatial dynamics and migration patterns. Here, we tested the hypothesis that the genetic structure of the ABFT in the Mediterranean is correlated with mean surface temperature and salinity. Methodology We used six samples collected from Western and Central Mediterranean integrated with a new sample collected from the recently identified easternmost reproductive area of Levantine Sea. To assess population structure in the Mediterranean we used a multidisciplinary framework combining classical population genetics, spatial and Bayesian clustering methods and a multivariate approach based on factor analysis. Conclusions FST analysis and Bayesian clustering methods detected several subpopulations in the Mediterranean, a result also supported by multivariate analyses. In addition, we identified significant correlations of genetic diversity with mean salinity and surface temperature values revealing that ABFT is genetically structured along two environmental gradients. These results suggest that a preference for some spawning habitat conditions could contribute to shape ABFT genetic structuring in the Mediterranean. However, further studies should be performed to assess to what extent ABFT spawning behaviour in the Mediterranean Sea can be affected by environmental variation. PMID:24260341

Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy.

PubMed

Dudley, Beth; Karloski, Eve; Monzon, Federico A; Singhi, Aatur D; Lincoln, Stephen E; Bahary, Nathan; Brand, Randall E

2018-04-15

Approximately 10% of pancreatic adenocarcinoma (PC) cases are attributed to hereditary causes. Individuals with PC and a personal history of another cancer associated with hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS) may be more likely to carry germline mutations. Participants with PC and a history of cancer were selected from a pancreatic disease registry. Of 1296 individuals with PC, 149 had a relevant history of cancer. If banked DNA was available, a multigene panel was performed for individuals who had not 1) previously had a mutation identified through clinical testing or 2) undergone clinical multigene panel testing with no mutations detected. Twenty-two of 124 individuals with PC and another HBOC- or LS-related cancer who underwent genetic testing had a mutation identified in a PC susceptibility gene (18%). If prostate cancer is excluded, the mutation prevalence increased to 23% (21/93). Mutation carriers were more likely to have more than 1 previous cancer diagnosis (P = .001), to have had clinical genetic testing (P = .001), and to meet National Comprehensive Cancer Network (NCCN) genetic testing criteria (P < .001). Approximately 23% of mutation carriers did not meet NCCN HBOC or LS testing guidelines based on their personal cancer history and reported cancer history in first-degree relatives. At least 18% of individuals with PC and a personal history of other HBOC- or LS-related cancers carry mutations in a PC susceptibility gene based on our data, suggesting that criteria for genetic testing in individuals with PC should include consideration of previous cancer history. Cancer 2018;124:1691-700. © 2018 American Cancer Society. © 2018 American Cancer Society.

The clinical introduction of genetic testing for Alzheimer disease. An ethical perspective.

PubMed

Post, S G; Whitehouse, P J; Binstock, R H; Bird, T D; Eckert, S K; Farrer, L A; Fleck, L M; Gaines, A D; Juengst, E T; Karlinsky, H; Miles, S; Murray, T H; Quaid, K A; Relkin, N R; Roses, A D; St George-Hyslop, P H; Sachs, G A; Steinbock, B; Truschke, E F; Zinn, A B

1997-03-12

Primary caregivers should be aware of recent progress in the genetics of Alzheimer disease (AD) and of the clinical and ethical considerations raised regarding the introduction of genetic testing for purposes of disease prediction and susceptibility (risk) analysis in asymptomatic individuals and diagnosis in patients who present clinically with dementia. This statement addresses arguments for and against clinical genetic testing. The 20 participants were selected by the investigators (S.G.P., T.H.M., A.B.Z., and P.J.W.) to achieve balance in the areas of genetics, counseling, ethics, and public policy, and to include leadership from related consensus projects. The consensus group met twice in closed meetings and carried on extensive correspondence over 2 years (1995-1997). The project was supported by the National Human Genome Research Institute of the National Institutes of Health. All 4 involved chromosomes were discussed in group meetings against a background of information from several focus group sessions with AD-affected families. The focus groups comprised volunteers identified by the Cleveland Area Chapter of the Alzheimer's Disease and Related Disorders Association and represented a variety of ethnic populations. The first draft was written in April 1996 by the principal investigator (S.G.P.) after the consensus group had met twice. The draft was mailed to all consensus group members 3 times over 6 months for extensive response and redrafting by the principal investigator until all members were satisfied. Except for autosomal dominant early-onset families, genetic testing in asymptomatic individuals is unwarranted. Use of APOE genetic testing as a diagnostic adjunct in patients already presenting with dementia may prove useful but it remains under investigation. The premature introduction of genetic testing and possible adverse consequences are to be avoided.

Testing Models for the Contributions of Genes and Environment to Developmental Change in Adolescent Depression

PubMed Central

Eaves, Lindon J.; Maes, Hermine; Silberg, Judy L.

2015-01-01

We tested two models to identify the genetic and environmental processes underlying longitudinal changes in depression among adolescents. The first assumes that observed changes in covariance structure result from the unfolding of inherent, random individual differences in the overall levels and rates of change in depression over time (random growth curves). The second assumes that observed changes are due to time-specific random effects (innovations) accumulating over time (autoregressive effects). We found little evidence of age-specific genetic effects or persistent genetic innovations. Instead, genetic effects are consistent with a gradual unfolding in the liability to depression and rates of change with increasing age. Likewise, the environment also creates significant individual differences in overall levels of depression and rates of change. However, there are also time-specific environmental experiences that persist with fidelity. The implications of these differing genetic and environmental mechanisms in the etiology of depression are considered. PMID:25894924

Testing Models for the Contributions of Genes and Environment to Developmental Change in Adolescent Depression.

PubMed

Gillespie, Nathan A; Eaves, Lindon J; Maes, Hermine; Silberg, Judy L

2015-07-01

We tested two models to identify the genetic and environmental processes underlying longitudinal changes in depression among adolescents. The first assumes that observed changes in covariance structure result from the unfolding of inherent, random individual differences in the overall levels and rates of change in depression over time (random growth curves). The second assumes that observed changes are due to time-specific random effects (innovations) accumulating over time (autoregressive effects). We found little evidence of age-specific genetic effects or persistent genetic innovations. Instead, genetic effects are consistent with a gradual unfolding in the liability to depression and rates of change with increasing age. Likewise, the environment also creates significant individual differences in overall levels of depression and rates of change. However, there are also time-specific environmental experiences that persist with fidelity. The implications of these differing genetic and environmental mechanisms in the etiology of depression are considered.

New and emerging technologies for genetic toxicity testing.

PubMed

Lynch, Anthony M; Sasaki, Jennifer C; Elespuru, Rosalie; Jacobson-Kram, David; Thybaud, Véronique; De Boeck, Marlies; Aardema, Marilyn J; Aubrecht, Jiri; Benz, R Daniel; Dertinger, Stephen D; Douglas, George R; White, Paul A; Escobar, Patricia A; Fornace, Albert; Honma, Masamitsu; Naven, Russell T; Rusling, James F; Schiestl, Robert H; Walmsley, Richard M; Yamamura, Eiji; van Benthem, Jan; Kim, James H

2011-04-01

The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Project Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity (IVGT) Testing established an Emerging Technologies and New Strategies Workgroup to review the current State of the Art in genetic toxicology testing. The aim of the workgroup was to identify promising technologies that will improve genotoxicity testing and assessment of in vivo hazard and risk, and that have the potential to help meet the objectives of the IVGT. As part of this initiative, HESI convened a workshop in Washington, DC in May 2008 to discuss mature, maturing, and emerging technologies in genetic toxicology. This article collates the abstracts of the New and Emerging Technologies Workshop together with some additional technologies subsequently considered by the workgroup. Each abstract (available in the online version of the article) includes a section addressed specifically to the strengths, weaknesses, opportunities, and threats associated with the respective technology. Importantly, an overview of the technologies and an indication of how their use might be aligned with the objectives of IVGT are presented. In particular, consideration was given with regard to follow-up testing of positive results in the standard IVGT tests (i.e., Salmonella Ames test, chromosome aberration assay, and mouse lymphoma assay) to add weight of evidence and/or provide mechanism of action for improved genetic toxicity risk assessments in humans. Copyright © 2010 Wiley-Liss, Inc.

Gene-Based Association Analysis for Censored Traits Via Fixed Effect Functional Regressions.

PubMed

Fan, Ruzong; Wang, Yifan; Yan, Qi; Ding, Ying; Weeks, Daniel E; Lu, Zhaohui; Ren, Haobo; Cook, Richard J; Xiong, Momiao; Swaroop, Anand; Chew, Emily Y; Chen, Wei

2016-02-01

Genetic studies of survival outcomes have been proposed and conducted recently, but statistical methods for identifying genetic variants that affect disease progression are rarely developed. Motivated by our ongoing real studies, here we develop Cox proportional hazard models using functional regression (FR) to perform gene-based association analysis of survival traits while adjusting for covariates. The proposed Cox models are fixed effect models where the genetic effects of multiple genetic variants are assumed to be fixed. We introduce likelihood ratio test (LRT) statistics to test for associations between the survival traits and multiple genetic variants in a genetic region. Extensive simulation studies demonstrate that the proposed Cox RF LRT statistics have well-controlled type I error rates. To evaluate power, we compare the Cox FR LRT with the previously developed burden test (BT) in a Cox model and sequence kernel association test (SKAT), which is based on mixed effect Cox models. The Cox FR LRT statistics have higher power than or similar power as Cox SKAT LRT except when 50%/50% causal variants had negative/positive effects and all causal variants are rare. In addition, the Cox FR LRT statistics have higher power than Cox BT LRT. The models and related test statistics can be useful in the whole genome and whole exome association studies. An age-related macular degeneration dataset was analyzed as an example. © 2016 WILEY PERIODICALS, INC.

Gene-based Association Analysis for Censored Traits Via Fixed Effect Functional Regressions

PubMed Central

Fan, Ruzong; Wang, Yifan; Yan, Qi; Ding, Ying; Weeks, Daniel E.; Lu, Zhaohui; Ren, Haobo; Cook, Richard J; Xiong, Momiao; Swaroop, Anand; Chew, Emily Y.; Chen, Wei

2015-01-01

Summary Genetic studies of survival outcomes have been proposed and conducted recently, but statistical methods for identifying genetic variants that affect disease progression are rarely developed. Motivated by our ongoing real studies, we develop here Cox proportional hazard models using functional regression (FR) to perform gene-based association analysis of survival traits while adjusting for covariates. The proposed Cox models are fixed effect models where the genetic effects of multiple genetic variants are assumed to be fixed. We introduce likelihood ratio test (LRT) statistics to test for associations between the survival traits and multiple genetic variants in a genetic region. Extensive simulation studies demonstrate that the proposed Cox RF LRT statistics have well-controlled type I error rates. To evaluate power, we compare the Cox FR LRT with the previously developed burden test (BT) in a Cox model and sequence kernel association test (SKAT) which is based on mixed effect Cox models. The Cox FR LRT statistics have higher power than or similar power as Cox SKAT LRT except when 50%/50% causal variants had negative/positive effects and all causal variants are rare. In addition, the Cox FR LRT statistics have higher power than Cox BT LRT. The models and related test statistics can be useful in the whole genome and whole exome association studies. An age-related macular degeneration dataset was analyzed as an example. PMID:26782979

Differentiation of mixed biological traces in sexual assaults using DNA fragment analysis

PubMed Central

Apostolov, Аleksandar

2014-01-01

During the investigation of sexual abuse, it is not rare that mixed genetic material from two or more persons is detected. In such cases, successful profiling can be achieved using DNA fragment analysis, resulting in individual genetic profiles of offenders and their victims. This has led to an increase in the percentage of identified perpetrators of sexual offenses. The classic and modified genetic models used, allowed us to refine and implement appropriate extraction, polymerase chain reaction and electrophoretic procedures with individual assessment and approach to conducting research. Testing mixed biological traces using DNA fragment analysis appears to be the only opportunity for identifying perpetrators in gang rapes. PMID:26019514

Genetic testing of the FBN1 gene in Chinese patients with Marfan/Marfan-like syndrome.

PubMed

Yang, Hang; Luo, Mingyao; Chen, Qianlong; Fu, Yuanyuan; Zhang, Jing; Qian, Xiangyang; Sun, Xiaogang; Fan, Yuxin; Zhou, Zhou; Chang, Qian

2016-08-01

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder typically involving the ocular, skeletal and cardiovascular systems, and aortic aneurysms/dissection mainly contributes to its mortality. Here, we performed genetic testing of the FBN1 gene in 39 Chinese probands with Marfan/Marfan-like syndrome and their related family members by Sanger sequencing. In total, 29 pathogenic/likely pathogenic FBN1 mutations, including 17 novel ones, were identified. In addition, most MFS patients with aortic disease (62%) had a truncating or splicing mutation. These results expand the FBN1 mutation spectrum and enrich our knowledge of genotype-phenotype correlations. Genetic testing for MFS and its related aortic diseases is increasingly important for early intervention and treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Caught you: threats to confidentiality due to the public release of large-scale genetic data sets

PubMed Central

2010-01-01

Background Large-scale genetic data sets are frequently shared with other research groups and even released on the Internet to allow for secondary analysis. Study participants are usually not informed about such data sharing because data sets are assumed to be anonymous after stripping off personal identifiers. Discussion The assumption of anonymity of genetic data sets, however, is tenuous because genetic data are intrinsically self-identifying. Two types of re-identification are possible: the "Netflix" type and the "profiling" type. The "Netflix" type needs another small genetic data set, usually with less than 100 SNPs but including a personal identifier. This second data set might originate from another clinical examination, a study of leftover samples or forensic testing. When merged to the primary, unidentified set it will re-identify all samples of that individual. Even with no second data set at hand, a "profiling" strategy can be developed to extract as much information as possible from a sample collection. Starting with the identification of ethnic subgroups along with predictions of body characteristics and diseases, the asthma kids case as a real-life example is used to illustrate that approach. Summary Depending on the degree of supplemental information, there is a good chance that at least a few individuals can be identified from an anonymized data set. Any re-identification, however, may potentially harm study participants because it will release individual genetic disease risks to the public. PMID:21190545

Caught you: threats to confidentiality due to the public release of large-scale genetic data sets.

PubMed

Wjst, Matthias

2010-12-29

Large-scale genetic data sets are frequently shared with other research groups and even released on the Internet to allow for secondary analysis. Study participants are usually not informed about such data sharing because data sets are assumed to be anonymous after stripping off personal identifiers. The assumption of anonymity of genetic data sets, however, is tenuous because genetic data are intrinsically self-identifying. Two types of re-identification are possible: the "Netflix" type and the "profiling" type. The "Netflix" type needs another small genetic data set, usually with less than 100 SNPs but including a personal identifier. This second data set might originate from another clinical examination, a study of leftover samples or forensic testing. When merged to the primary, unidentified set it will re-identify all samples of that individual. Even with no second data set at hand, a "profiling" strategy can be developed to extract as much information as possible from a sample collection. Starting with the identification of ethnic subgroups along with predictions of body characteristics and diseases, the asthma kids case as a real-life example is used to illustrate that approach. Depending on the degree of supplemental information, there is a good chance that at least a few individuals can be identified from an anonymized data set. Any re-identification, however, may potentially harm study participants because it will release individual genetic disease risks to the public.

Genetic advances in sarcomeric cardiomyopathies: state of the art.

PubMed

Ho, Carolyn Y; Charron, Philippe; Richard, Pascale; Girolami, Francesca; Van Spaendonck-Zwarts, Karin Y; Pinto, Yigal

2015-04-01

Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomere mutations cause both hypertrophic and dilated cardiomyopathies. Sarcomere mutations also likely play a role in more complex phenotypes and overlap cardiomyopathies with features of hypertrophy, dilation, diastolic abnormalities, and non-compaction. Identification of the genetic cause of these important conditions provides unique opportunities to interrogate and characterize disease pathogenesis and pathophysiology, starting from the molecular level and expanding from there. With such insights, there is potential for clinical translation that may transform management of patients and families with inherited cardiomyopathies. If key pathways for disease development can be identified, they could potentially serve as targets for novel disease-modifying or disease-preventing therapies. By utilizing gene-based diagnostic testing, we can identify at-risk individuals prior to the onset of clinical disease, allowing for disease-modifying therapy to be initiated early in life, at a time that such treatment may be most successful. In this section, we review the current application of genetics in clinical management, focusing on hypertrophic cardiomyopathy as a paradigm; discuss state-of-the-art genetic testing technology; review emerging knowledge of gene expression in sarcomeric cardiomyopathies; and discuss both the prospects, as well as the challenges, of bringing genetics to medicine. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Solar Radiation-Associated Adaptive SNP Genetic Differentiation in Wild Emmer Wheat, Triticum dicoccoides.

PubMed

Ren, Jing; Chen, Liang; Jin, Xiaoli; Zhang, Miaomiao; You, Frank M; Wang, Jirui; Frenkel, Vladimir; Yin, Xuegui; Nevo, Eviatar; Sun, Dongfa; Luo, Ming-Cheng; Peng, Junhua

2017-01-01

Whole-genome scans with large number of genetic markers provide the opportunity to investigate local adaptation in natural populations and identify candidate genes under positive selection. In the present study, adaptation genetic differentiation associated with solar radiation was investigated using 695 polymorphic SNP markers in wild emmer wheat originated in a micro-site at Yehudiyya, Israel. The test involved two solar radiation niches: (1) sun, in-between trees; and (2) shade, under tree canopy, separated apart by a distance of 2-4 m. Analysis of molecular variance showed a small (0.53%) but significant portion of overall variation between the sun and shade micro-niches, indicating a non-ignorable genetic differentiation between sun and shade habitats. Fifty SNP markers showed a medium (0.05 ≤ F ST ≤ 0.15) or high genetic differentiation ( F ST > 0.15). A total of 21 outlier loci under positive selection were identified by using four different F ST -outlier testing algorithms. The markers and genome locations under positive selection are consistent with the known patterns of selection. These results suggested that genetic differentiation between sun and shade habitats is substantial, radiation-associated, and therefore ecologically determined. Hence, the results of this study reflected effects of natural selection through solar radiation on EST-related SNP genetic diversity, resulting presumably in different adaptive complexes at a micro-scale divergence. The present work highlights the evolutionary theory and application significance of solar radiation-driven natural selection in wheat improvement.

Clinical exome sequencing reports: current informatics practice and future opportunities.

PubMed

Swaminathan, Rajeswari; Huang, Yungui; Astbury, Caroline; Fitzgerald-Butt, Sara; Miller, Katherine; Cole, Justin; Bartlett, Christopher; Lin, Simon

2017-11-01

The increased adoption of clinical whole exome sequencing (WES) has improved the diagnostic yield for patients with complex genetic conditions. However, the informatics practice for handling information contained in whole exome reports is still in its infancy, as evidenced by the lack of a common vocabulary within clinical sequencing reports generated across genetic laboratories. Genetic testing results are mostly transmitted using portable document format, which can make secondary analysis and data extraction challenging. This paper reviews a sample of clinical exome reports generated by Clinical Laboratory Improvement Amendments-certified genetic testing laboratories at tertiary-care facilities to assess and identify common data elements. Like structured radiology reports, which enable faster information retrieval and reuse, structuring genetic information within clinical WES reports would help facilitate integration of genetic information into electronic health records and enable retrospective research on the clinical utility of WES. We identify elements listed as mandatory according to practice guidelines but are currently missing from some of the clinical reports, which might help to organize the data when stored within structured databases. We also highlight elements, such as patient consent, that, although they do not appear within any of the current reports, may help in interpreting some of the information within the reports. Integrating genetic and clinical information would assist the adoption of personalized medicine for improved patient care and outcomes. © The Author 2017. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Should I Perform Genetic Testing? A Qualitative Look into the Decision Making Considerations of Religious Israeli Undergraduate Students.

PubMed

Siani, Merav; Assaraf, Orit Ben-Zvi

2016-10-01

The aim of this study is to draw a picture of the concerns that guide the decision making of Israeli religious undergraduate students and the complex considerations they take into account while facing the need to have genetic testing or to attend a genetic counseling session. We examined how the religious affiliation of the students influences their perceptions toward genetics and how these are expressed. Qualitative data were collected from 51 semi-structured interviews with students, in which recurring themes were identified using 'thematic analysis.' The codes from the thematic analysis were obtained according to 'grounded theory'. Our results show that religious undergraduate students' decision making in these issues is influenced by factors that fall under three main categories: knowledge and perceptions, values, and norms. In order to include all the components of influence, we created the Triple C model: "Culture influences Choices towards genetic Counseling" which aims to generalize the complex decision making considerations that we detected. Our model places religion, as part of culture, as its central point of influence that impacts all three of the main categories we detected. It also traces the bidirectional influences that each of these main categories have on one another. Using this model may help identify the sociocultural differences between different types of patients, helping genetic counselors to better assist them in addressing their genetic status by tailoring the counseling more specifically to the patient's cultural uniqueness.

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

PubMed

Preston, Rebecca; Stuart, Helen M; Lennon, Rachel

2017-11-27

Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in childhood and has a significant risk of rapid progression to end-stage renal disease. The identification of over 50 monogenic causes of SRNS has revealed dysfunction in podocyte-associated proteins in the pathogenesis of proteinuria, highlighting their essential role in glomerular function. Recent technological advances in high-throughput sequencing have enabled indication-driven genetic panel testing for patients with SRNS. The availability of genetic testing, combined with the significant phenotypic variability of monogenic SRNS, poses unique challenges for clinicians when directing genetic testing. This highlights the need for clear clinical guidelines that provide a systematic approach for mutational screening in SRNS. The likelihood of identifying a causative mutation is inversely related to age at disease onset and is increased with a positive family history or the presence of extra-renal manifestations. An unequivocal molecular diagnosis could allow for a personalised treatment approach with weaning of immunosuppressive therapy, avoidance of renal biopsy and provision of accurate, well-informed genetic counselling. Identification of novel causative mutations will continue to unravel the pathogenic mechanisms of glomerular disease and provide new insights into podocyte biology and glomerular function.

Personal genome testing: Test characteristics to clarify the discourse on ethical, legal and societal issues

PubMed Central

2011-01-01

Background As genetics technology proceeds, practices of genetic testing have become more heterogeneous: many different types of tests are finding their way to the public in different settings and for a variety of purposes. This diversification is relevant to the discourse on ethical, legal and societal issues (ELSI) surrounding genetic testing, which must evolve to encompass these differences. One important development is the rise of personal genome testing on the basis of genetic profiling: the testing of multiple genetic variants simultaneously for the prediction of common multifactorial diseases. Currently, an increasing number of companies are offering personal genome tests directly to consumers and are spurring ELSI-discussions, which stand in need of clarification. This paper presents a systematic approach to the ELSI-evaluation of personal genome testing for multifactorial diseases along the lines of its test characteristics. Discussion This paper addresses four test characteristics of personal genome testing: its being a non-targeted type of testing, its high analytical validity, low clinical validity and problematic clinical utility. These characteristics raise their own specific ELSI, for example: non-targeted genetic profiling poses serious problems for information provision and informed consent. Questions about the quantity and quality of the necessary information, as well as about moral responsibilities with regard to the provision of information are therefore becoming central themes within ELSI-discussions of personal genome testing. Further, the current low level of clinical validity of genetic profiles raises questions concerning societal risks and regulatory requirements, whereas simultaneously it causes traditional ELSI-issues of clinical genetics, such as psychological and health risks, discrimination, and stigmatization, to lose part of their relevance. Also, classic notions of clinical utility are challenged by the newer notion of 'personal utility.' Summary Consideration of test characteristics is essential to any valuable discourse on the ELSI of personal genome testing for multifactorial diseases. Four key characteristics of the test - targeted/non-targeted testing, analytical validity, clinical validity and clinical utility - together determine the applicability and the relevance of ELSI to specific tests. The paper identifies and discusses four areas of interest for the ELSI-debate on personal genome testing: informational problems, risks, regulatory issues, and the notion of personal utility. PMID:21672210

The IQ Quantitative Trait Loci Project: A Critique.

ERIC Educational Resources Information Center

King, David

1998-01-01

Describes the IQ Quantitative Trait Loci (QTL) project, an attempt to identify genes underlying IQ score variations using maps from the Human Genome Project. The essay argues against funding the IQ QTL project because it will end the debates about the genetic basis of intelligence and may lead directly to eugenic programs of genetic testing. (SLD)

Life trajectories, genetic testing, and risk reduction decisions in 18–39 year old women at risk for hereditary breast and ovarian cancer

PubMed Central

Williams, Janet K.; Bowers, Barbara J.; Calzone, Kathleen

2009-01-01

This qualitative study identified four life trajectories that influenced the decision in young women to have genetic testing for mutations in BRCA1/2 and subsequent risk reduction decisions after receiving a positive mutation result. Fifty nine women between the ages of 18–39 years were interviewed in this grounded theory study, 44 of those tested were found to have a mutation in either BRCA1 or BRCA2. Of those with a mutation, 23 had no history of cancer and 21 had a breast cancer diagnosis. Analysis of the 44 participants tested found that risk reducing decisions were related to the life trajectories that preceded genetic testing. These life trajectories included: 1) Long-standing awareness of breast cancer in the family, 2) Loss of one’s mother to breast cancer at a young age, 3) Expression of concern by a health care provider, and 4) Personal diagnosis of breast cancer. Understanding possible influences behind decision making for genetic testing and risk reduction in young women may assist health care providers in offering age appropriate guidance and support. PMID:18979190

Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.

PubMed

Kerns, Sarah L; Dorling, Leila; Fachal, Laura; Bentzen, Søren; Pharoah, Paul D P; Barnes, Daniel R; Gómez-Caamaño, Antonio; Carballo, Ana M; Dearnaley, David P; Peleteiro, Paula; Gulliford, Sarah L; Hall, Emma; Michailidou, Kyriaki; Carracedo, Ángel; Sia, Michael; Stock, Richard; Stone, Nelson N; Sydes, Matthew R; Tyrer, Jonathan P; Ahmed, Shahana; Parliament, Matthew; Ostrer, Harry; Rosenstein, Barry S; Vega, Ana; Burnet, Neil G; Dunning, Alison M; Barnett, Gillian C; West, Catharine M L

2016-08-01

Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08-4.69, p-value 4.16×10(-8)) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90-3.86, p-value=3.21×10(-8)). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling. Copyright © 2016 The Ohio State University Wexner Medical Center. Published by Elsevier B.V. All rights reserved.

Barriers to carrier testing for adult cystic fibrosis sibs: the importance of not knowing.

PubMed

Fanos, J H; Johnson, J P

1995-10-23

Early experience in centers offering population screening for cystic fibrosis (CF) has shown that few of the public are taking advantage of the offer [Miller, 1993: New Scientist 139:6]. There is similar low utilization among adult CF sibs [Fanos and Johnson, 1993: Am J Hum Genet 53:A51]. The purpose of this study was to identify factors motivating or interfering with the pursuit of carrier testing in adult CF sibs. Eighty-four adult CF sibs and their spouses, drawn from Children's Hospital, Oakland, CA, and Children's Hospital, Boston, MA, were interviewed for about an hour, and qualitative material was coded on various themes. Structural and psychological barriers to the transmission of genetic information were identified: 1) sibs encountered difficulty in obtaining information concerning availability of testing; 2) parental guilt and blame prevents parents from discussing genetic issues with the sib; 3) sibs rarely discuss testing with each other; 4) the CF patient or parent often has difficulty with the implications of the sib seeking carrier testing; 5) family and individual myths about carrier status influence the sib's decision to seek testing; 6) statistical odds have lost meaning in families where the rare has already occurred; 7) the sib fears loss of interpersonal desirability; and 8) carrier status can serve an important function in binding guilt. Remaining unaware of their carrier status may serve significant psychological functions for individuals at risk.

A genetic diagnosis of maturity-onset diabetes of the young (MODY): experiences of patients and family members.

PubMed

Bosma, A R; Rigter, T; Weinreich, S S; Cornel, M C; Henneman, L

2015-10-01

Genetic testing for maturity-onset diabetes of the young (MODY) facilitates a correct diagnosis, enabling treatment optimization and allowing monitoring of asymptomatic family members. To date, the majority of people with MODY remain undiagnosed. To identify patients' needs and areas for improving care, this study explores the experiences of patients and family members who have been genetically tested for MODY. Fourteen semi-structured interviews with patients and the parents of patients, and symptomatic and asymptomatic family members were conducted. Atlas.ti was used for thematic analysis. Most people with MODY were initially misdiagnosed with Type 1 or Type 2 diabetes; they had been seeking for the correct diagnosis for a long time. Reasons for having a genetic test included reassurance, removing the uncertainty of developing diabetes (in asymptomatic family members) and informing relatives. Reasons against testing were the fear of genetic discrimination and not having symptoms. Often a positive genetic test result did not come as a surprise. Both patients and family members were satisfied with the decision to get tested because it enabled them to adjust their lifestyle and treatment accordingly. All participants experienced a lack of knowledge of MODY among healthcare professionals, in their social environment and in patient organizations. Additionally, problems with the reimbursement of medical expenses were reported. Patients and family members are generally positive about genetic testing for MODY. More education of healthcare professionals and attention on the part of diabetes organizations is needed to increase awareness and optimize care and support for people with MODY. © 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.

When the face says it all: dysmorphology in identifying syndromic causes of epilepsy.

PubMed

Dixit, Abhijit; Suri, Mohnish

2016-04-01

Identifying the underlying cause of epilepsy often helps in choosing the appropriate management, suggests the long-term prognosis and clarifies the risk of the same condition in relatives. Epilepsy has many causes and a small but significant proportion of affected people have an identifiable genetic cause. Here, we discuss the role of genetic testing in adults with epilepsy, focusing on dysmorphic features noticeable on physical examination that might provide a strong clue to a specific genetic syndrome. We give illustrative examples of recognisable facial 'gestalt'. An astute clinician can recognise such clues and significantly shorten the process of making the underlying diagnosis in their patient. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.

PubMed

Vissers, Lisenka E L M; van Nimwegen, Kirsten J M; Schieving, Jolanda H; Kamsteeg, Erik-Jan; Kleefstra, Tjitske; Yntema, Helger G; Pfundt, Rolph; van der Wilt, Gert Jan; Krabbenborg, Lotte; Brunner, Han G; van der Burg, Simone; Grutters, Janneke; Veltman, Joris A; Willemsen, Michèl A A P

2017-09-01

Implementation of novel genetic diagnostic tests is generally driven by technological advances because they promise shorter turnaround times and/or higher diagnostic yields. Other aspects, including impact on clinical management or cost-effectiveness, are often not assessed in detail prior to implementation. We studied the clinical utility of whole-exome sequencing (WES) in complex pediatric neurology in terms of diagnostic yield and costs. We analyzed 150 patients (and their parents) presenting with complex neurological disorders of suspected genetic origin. In a parallel study, all patients received both the standard diagnostic workup (e.g., cerebral imaging, muscle biopsies or lumbar punctures, and sequential gene-by-gene-based testing) and WES simultaneously. Our unique study design allowed direct comparison of diagnostic yield of both trajectories and provided insight into the economic implications of implementing WES in this diagnostic trajectory. We showed that WES identified significantly more conclusive diagnoses (29.3%) than the standard care pathway (7.3%) without incurring higher costs. Exploratory analysis of WES as a first-tier diagnostic test indicates that WES may even be cost-saving, depending on the extent of other tests being omitted. Our data support such a use of WES in pediatric neurology for disorders of presumed genetic origin.Genet Med advance online publication 23 March 2017.

A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology

PubMed Central

Vissers, Lisenka E.L.M.; van Nimwegen, Kirsten J.M.; Schieving, Jolanda H.; Kamsteeg, Erik-Jan; Kleefstra, Tjitske; Yntema, Helger G.; Pfundt, Rolph; van der Wilt, Gert Jan; Krabbenborg, Lotte; Brunner, Han G.; van der Burg, Simone; Grutters, Janneke; Veltman, Joris A.; Willemsen, Michèl A.A.P.

2017-01-01

Purpose: Implementation of novel genetic diagnostic tests is generally driven by technological advances because they promise shorter turnaround times and/or higher diagnostic yields. Other aspects, including impact on clinical management or cost-effectiveness, are often not assessed in detail prior to implementation. Methods: We studied the clinical utility of whole-exome sequencing (WES) in complex pediatric neurology in terms of diagnostic yield and costs. We analyzed 150 patients (and their parents) presenting with complex neurological disorders of suspected genetic origin. In a parallel study, all patients received both the standard diagnostic workup (e.g., cerebral imaging, muscle biopsies or lumbar punctures, and sequential gene-by-gene–based testing) and WES simultaneously. Results: Our unique study design allowed direct comparison of diagnostic yield of both trajectories and provided insight into the economic implications of implementing WES in this diagnostic trajectory. We showed that WES identified significantly more conclusive diagnoses (29.3%) than the standard care pathway (7.3%) without incurring higher costs. Exploratory analysis of WES as a first-tier diagnostic test indicates that WES may even be cost-saving, depending on the extent of other tests being omitted. Conclusion: Our data support such a use of WES in pediatric neurology for disorders of presumed genetic origin. Genet Med advance online publication 23 March 2017 PMID:28333917

Genetic testing in women with breast cancer: implications for treatment.

PubMed

Paterson, Robin; Phillips, Kelly-Anne

2017-11-01

Mutations in either the BRCA1 or BRCA2 genes are responsible for approximately 42,000 cases of breast cancer annually. Identifying these germline mutations in a woman with breast cancer is important because it can influence her immediate and long-term management and has important implications for other family members. Areas covered: This review highlights how treatment-focussed genetic testing for BRCA1 and BRCA2 mutations can potentially influence cancer treatment and secondary prevention decisions in women with breast cancer. Expert commentary: Testing women with breast cancer for BRCA1 and BRCA2 germline mutations has the potential to decrease cancer burden and improve cancer outcomes. It can help optimise surgical and systemic therapy approaches. Clinicians should actively consider whether genetic testing is appropriate for each woman with breast cancer, and if so should instigate it early in the treatment trajectory when it can most influence cancer care.

Random regression models using Legendre orthogonal polynomials to evaluate the milk production of Alpine goats.

PubMed

Silva, F G; Torres, R A; Brito, L F; Euclydes, R F; Melo, A L P; Souza, N O; Ribeiro, J I; Rodrigues, M T

2013-12-11

The objective of this study was to identify the best random regression model using Legendre orthogonal polynomials to evaluate Alpine goats genetically and to estimate the parameters for test day milk yield. On the test day, we analyzed 20,710 records of milk yield of 667 goats from the Goat Sector of the Universidade Federal de Viçosa. The evaluated models had combinations of distinct fitting orders for polynomials (2-5), random genetic (1-7), and permanent environmental (1-7) fixed curves and a number of classes for residual variance (2, 4, 5, and 6). WOMBAT software was used for all genetic analyses. A random regression model using the best Legendre orthogonal polynomial for genetic evaluation of milk yield on the test day of Alpine goats considered a fixed curve of order 4, curve of genetic additive effects of order 2, curve of permanent environmental effects of order 7, and a minimum of 5 classes of residual variance because it was the most economical model among those that were equivalent to the complete model by the likelihood ratio test. Phenotypic variance and heritability were higher at the end of the lactation period, indicating that the length of lactation has more genetic components in relation to the production peak and persistence. It is very important that the evaluation utilizes the best combination of fixed, genetic additive and permanent environmental regressions, and number of classes of heterogeneous residual variance for genetic evaluation using random regression models, thereby enhancing the precision and accuracy of the estimates of parameters and prediction of genetic values.

Analyzing the most frequent disease loci in targeted patient categories optimizes disease gene identification and test accuracy worldwide.

PubMed

Lebo, Roger V; Tonk, Vijay S

2015-01-21

Our genomewide studies support targeted testing the most frequent genetic diseases by patient category: (1) pregnant patients, (2) at-risk conceptuses, (3) affected children, and (4) abnormal adults. This approach not only identifies most reported disease causing sequences accurately, but also minimizes incorrectly identified additional disease causing loci. Diseases were grouped in descending order of occurrence from four data sets: (1) GeneTests 534 listed population prevalences, (2) 4129 high risk prenatal karyotypes, (3) 1265 affected patient microarrays, and (4) reanalysis of 25,452 asymptomatic patient results screened prenatally for 108 genetic diseases. These most frequent diseases are categorized by transmission: (A) autosomal recessive, (B) X-linked, (C) autosomal dominant, (D) microscopic chromosome rearrangements, (E) submicroscopic copy number changes, and (F) frequent ethnic diseases. Among affected and carrier patients worldwide, most reported mutant genes would be identified correctly according to one of four patient categories from at-risk couples with <64 tested genes to affected adults with 314 tested loci. Three clinically reported patient series confirmed this approach. First, only 54 targeted chromosomal sites would have detected all 938 microscopically visible unbalanced karyotypes among 4129 karyotyped POC, CVS, and amniocentesis samples. Second, 37 of 48 reported aneuploid regions were found among our 1265 clinical microarrays confirming the locations of 8 schizophrenia loci and 20 aneuploidies altering intellectual ability, while also identifying 9 of the most frequent deletion syndromes. Third, testing 15 frequent genes would have identified 124 couples with a 1 in 4 risk of a fetus with a recessive disease compared to the 127 couples identified by testing all 108 genes, while testing all mutations in 15 genes could have identified more couples. Testing the most frequent disease causing abnormalities in 1 of 8 reported disease loci [~1 of 84 total genes] will identify ~ 7 of 8 reported abnormal Caucasian newborn genotypes. This would eliminate ~8 to 10 of ~10 Caucasian newborn gene sequences selected as abnormal that are actually normal variants identified when testing all ~2500 diseases looking for the remaining 1 of 8 disease causing genes. This approach enables more accurate testing within available laboratory and reimbursement resources.

A fast boosting-based screening method for large-scale association study in complex traits with genetic heterogeneity.

PubMed

Wang, Lu-Yong; Fasulo, D

2006-01-01

Genome-wide association study for complex diseases will generate massive amount of single nucleotide polymorphisms (SNPs) data. Univariate statistical test (i.e. Fisher exact test) was used to single out non-associated SNPs. However, the disease-susceptible SNPs may have little marginal effects in population and are unlikely to retain after the univariate tests. Also, model-based methods are impractical for large-scale dataset. Moreover, genetic heterogeneity makes the traditional methods harder to identify the genetic causes of diseases. A more recent random forest method provides a more robust method for screening the SNPs in thousands scale. However, for more large-scale data, i.e., Affymetrix Human Mapping 100K GeneChip data, a faster screening method is required to screening SNPs in whole-genome large scale association analysis with genetic heterogeneity. We propose a boosting-based method for rapid screening in large-scale analysis of complex traits in the presence of genetic heterogeneity. It provides a relatively fast and fairly good tool for screening and limiting the candidate SNPs for further more complex computational modeling task.

A roadmap for the genetic analysis of renal aging

PubMed Central

Noordmans, Gerda A; Hillebrands, Jan-Luuk; van Goor, Harry; Korstanje, Ron

2015-01-01

Several studies show evidence for the genetic basis of renal disease, which renders some individuals more prone than others to accelerated renal aging. Studying the genetics of renal aging can help us to identify genes involved in this process and to unravel the underlying pathways. First, this opinion article will give an overview of the phenotypes that can be observed in age-related kidney disease. Accurate phenotyping is essential in performing genetic analysis. For kidney aging, this could include both functional and structural changes. Subsequently, this article reviews the studies that report on candidate genes associated with renal aging in humans and mice. Several loci or candidate genes have been found associated with kidney disease, but identification of the specific genetic variants involved has proven to be difficult. CUBN, UMOD, and SHROOM3 were identified by human GWAS as being associated with albuminuria, kidney function, and chronic kidney disease (CKD). These are promising examples of genes that could be involved in renal aging, and were further mechanistically evaluated in animal models. Eventually, we will provide approaches for performing genetic analysis. We should leverage the power of mouse models, as testing in humans is limited. Mouse and other animal models can be used to explain the underlying biological mechanisms of genes and loci identified by human GWAS. Furthermore, mouse models can be used to identify genetic variants associated with age-associated histological changes, of which Far2, Wisp2, and Esrrg are examples. A new outbred mouse population with high genetic diversity will facilitate the identification of genes associated with renal aging by enabling high-resolution genetic mapping while also allowing the control of environmental factors, and by enabling access to renal tissues at specific time points for histology, proteomics, and gene expression. PMID:26219736

Genetic architecture for susceptibility to gout in the KARE cohort study.

PubMed

Shin, Jimin; Kim, Younyoung; Kong, Minyoung; Lee, Chaeyoung

2012-06-01

This study aimed to identify functional associations of cis-regulatory regions with gout susceptibility using data resulted from a genome-wide association study (GWAS), and to show a genetic architecture for gout with interaction effects among genes within each of the identified functions. The GWAS was conducted with 8314 control subjects and 520 patients with gout in the Korea Association REsource cohort. However, genetic associations with any individual nucleotide variants were not discovered by Bonferroni multiple testing in the GWAS (P>1.42 × 10(-7)). Genomic regions enrichment analysis was employed to identify functional associations of cis-regulatory regions. This analysis revealed several biological processes associated with gout susceptibility, and they were quite different from those with serum uric acid level. Epistasis for susceptibility to gout was estimated using entropy decomposition with selected genes within each biological process identified by the genomic regions enrichment analysis. Some epistases among nucleotide sequence variants for gout susceptibility were found to be larger than their individual effects. This study provided the first evidence that genetic factors for gout susceptibility greatly differed from those for serum uric acid level, which may suggest that research endeavors for identifying genetic factors for gout susceptibility should not be heavily dependent on pathogenesis of uric acid. Interaction effects between genes should be examined to explain a large portion of phenotypic variability for gout susceptibility.

A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes.

PubMed

Buys, Saundra S; Sandbach, John F; Gammon, Amanda; Patel, Gayle; Kidd, John; Brown, Krystal L; Sharma, Lavania; Saam, Jennifer; Lancaster, Johnathan; Daly, Mary B

2017-05-15

As panel testing becomes more common in clinical practice, it is important to understand the prevalence and trends associated with the pathogenic variants (PVs) identified. This is especially true for genetically heterogeneous cancers, such as breast cancer (BC), in which PVs in different genes may be associated with various risks and cancer subtypes. The authors evaluated the outcomes of genetic testing among women who had a personal history of BC. A total of 35,409 women with a single diagnosis of BC who underwent clinical genetic testing with a 25-gene panel were included in the current analysis. Women with multiple BCs and men with BC were excluded. The frequency and distribution of PVs were assessed for the overall cohort, among women with triple-negative BC (TNBC) (n = 4797), and by age at diagnosis. PVs were identified in 9.3% of women tested; 51.5% of PVs were identified in genes other than breast cancer 1 (BRCA1) and BRCA2, including checkpoint kinase 2 (CHEK2) (11.7%), ataxia telangiectasia mutated (ATM; ATM serine/threonine kinase) (9.7%), and partner and localizer of BRCA2 (PALB2) (9.3%). The prevalence of PVs in BRCA1, PALB2, BRCA1-associated RING domain 1 (BARD1), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and RAD51 paralog C (RAD51C) was statistically higher among women with TNBC. The PV rate was higher among women aged <40 years, lower among women aged >59 years, and relatively constant (8.5%-9.0%) among women who were diagnosed between ages 40 and 59 years. These results demonstrate that panel testing increased the number of women identified as carrying a PV in this cohort compared with BRCA testing alone. Furthermore, the proportion of women identified who carried a PV in this cohort did not decrease between ages 40 and 59 years. Cancer 2017;123:1721-1730. © 2017 American Cancer Society. © 2017 American Cancer Society.

Differential Antidepressant-Like Response to Lithium Treatment between Mouse Strains: Effects of Sex, Maternal Care, and Mixed Genetic Background

PubMed Central

Can, Adem; Piantadosi, Sean C.; Gould, Todd D.

2013-01-01

Background Lithium is a mood stabilizer with both antidepressant and antimanic properties, though its mechanism of action is unclear. Identifying the genetic factors that influence lithium's therapeutic actions will be an important step to assist in identifying such mechanisms. We previously reported that lithium treatment of male mice has antidepressant-like effects in the C57BL/6J strain but that such effects were absent in the BALB/cJ strain. Objectives To assess the roles of both genetic, and non-genetic factors such as sex and non-shared environmental factors that may mediate differential behavioral responses to lithium. Methods Mice were treated with lithium for ten days and then tested in the forced swim test followed by lithium discontinuation and retesting to assess effects of lithium withdrawal. We also assessed effects of sex and cross-fostering on lithium response between the C57BL/6J and BALB/cJ strains, and antidepressant-like effects of lithium in the hybrid CB6F1/J strain that is derived from C57BL/6J and BALB/cJ parental strains. Results Neither sex nor maternal care significantly influenced the differential antidepressant-like profile of lithium. Withdrawal from lithium treatment reversed antidepressant-like effects in the C57BL/6J strain, but had no effects in BALB/cJ mice. Lithium treatment did not result in antidepressant-like effects in the CB6F1/J strain. Conclusions Genetic factors are likely primarily responsible for differential antidepressant-like effects of lithium in the C57BL/6J and BALB/cJ strains. Future studies identifying such genetic factors may help to elucidate the neurobiological mechanisms of lithium's therapeutic actions. PMID:23503701

Social-group identity and population substructure in admixed populations in New Mexico and Latin America.

PubMed

Healy, Meghan E; Hill, Deirdre; Berwick, Marianne; Edgar, Heather; Gross, Jessica; Hunley, Keith

2017-01-01

We examined the relationship between continental-level genetic ancestry and racial and ethnic identity in an admixed population in New Mexico with the goal of increasing our understanding of how racial and ethnic identity influence genetic substructure in admixed populations. Our sample consists of 98 New Mexicans who self-identified as Hispanic or Latino (NM-HL) and who further categorized themselves by race and ethnic subgroup membership. The genetic data consist of 270 newly-published autosomal microsatellites from the NM-HL sample and previously published data from 57 globally distributed populations, including 13 admixed samples from Central and South America. For these data, we 1) summarized the major axes of genetic variation using principal component analyses, 2) performed tests of Hardy Weinberg equilibrium, 3) compared empirical genetic ancestry distributions to those predicted under a model of admixture that lacked substructure, 4) tested the hypotheses that individuals in each sample had 100%, 0%, and the sample-mean percentage of African, European, and Native American ancestry. We found that most NM-HL identify themselves and their parents as belonging to one of two groups, conforming to a region-specific narrative that distinguishes recent immigrants from Mexico from individuals whose families have resided in New Mexico for generations and who emphasize their Spanish heritage. The "Spanish" group had significantly lower Native American ancestry and higher European ancestry than the "Mexican" group. Positive FIS values, PCA plots, and heterogeneous ancestry distributions suggest that most Central and South America admixed samples also contain substructure, and that this substructure may be related to variation in social identity. Genetic substructure appears to be common in admixed populations in the Americas and may confound attempts to identify disease-causing genes and to understand the social causes of variation in health outcomes and social inequality.

A probabilistic method for testing and estimating selection differences between populations

PubMed Central

He, Yungang; Wang, Minxian; Huang, Xin; Li, Ran; Xu, Hongyang; Xu, Shuhua; Jin, Li

2015-01-01

Human populations around the world encounter various environmental challenges and, consequently, develop genetic adaptations to different selection forces. Identifying the differences in natural selection between populations is critical for understanding the roles of specific genetic variants in evolutionary adaptation. Although numerous methods have been developed to detect genetic loci under recent directional selection, a probabilistic solution for testing and quantifying selection differences between populations is lacking. Here we report the development of a probabilistic method for testing and estimating selection differences between populations. By use of a probabilistic model of genetic drift and selection, we showed that logarithm odds ratios of allele frequencies provide estimates of the differences in selection coefficients between populations. The estimates approximate a normal distribution, and variance can be estimated using genome-wide variants. This allows us to quantify differences in selection coefficients and to determine the confidence intervals of the estimate. Our work also revealed the link between genetic association testing and hypothesis testing of selection differences. It therefore supplies a solution for hypothesis testing of selection differences. This method was applied to a genome-wide data analysis of Han and Tibetan populations. The results confirmed that both the EPAS1 and EGLN1 genes are under statistically different selection in Han and Tibetan populations. We further estimated differences in the selection coefficients for genetic variants involved in melanin formation and determined their confidence intervals between continental population groups. Application of the method to empirical data demonstrated the outstanding capability of this novel approach for testing and quantifying differences in natural selection. PMID:26463656

The challenge of juvenile Huntington disease: to test or not to test.

PubMed

Koutsis, Georgios; Karadima, Georgia; Kladi, Athina; Panas, Marios

2013-03-12

In a cohort of patients with suspected juvenile-onset Huntington disease (HD), we compared HD expansion-positive and -negative cases in order to identify parameters that may allow differentiating between them and may act as a guide to clinicians contemplating genetic testing. We analyzed the clinical and genetic characteristics of 76 juvenile-onset patients referred consecutively for HD genetic testing over a 16-year period. In total, 24 patients were positive for the HD expansion (7.8% of our HD cohort). Mean age at onset of expanded cases was similar to unexpanded cases. All expanded cases had a family history of genetically confirmed HD compared to only 13.5% of unexpanded cases (p = 0.000). Clinical symptoms at onset or at presentation could not differentiate between expanded and unexpanded patients. Although criteria suggested by previous reports allowed statistical differentiation between the 2 groups, they were not sufficiently sensitive and specific to be used in clinical context and performed less satisfactorily than presence of a family history of HD alone. A diagnosis of juvenile HD should be primarily contemplated in symptomatic children with a family history of HD, although a proportion of these will test negative. With no family history of HD, juvenile HD is very unlikely and genetic testing should never delay searching for other causes. The specific nature of symptoms at onset or at presentation is of limited value in guiding the decision to test or not to test.

Development of a genomic DNA reference material panel for myotonic dystrophy type 1 (DM1) genetic testing.

PubMed

Kalman, Lisa; Tarleton, Jack; Hitch, Monica; Hegde, Madhuri; Hjelm, Nick; Berry-Kravis, Elizabeth; Zhou, Lili; Hilbert, James E; Luebbe, Elizabeth A; Moxley, Richard T; Toji, Lorraine

2013-07-01

Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG triplet repeat in the 3' untranslated region of the DMPK gene that encodes a serine-threonine kinase. Patients with larger repeats tend to have a more severe phenotype. Clinical laboratories require reference and quality control materials for DM1 diagnostic and carrier genetic testing. Well-characterized reference materials are not available. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing community, the National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members, and the Coriell Cell Repositories, has established and characterized cell lines from patients with DM1 to create a reference material panel. The CTG repeats in genomic DNA samples from 10 DM1 cell lines were characterized in three clinical genetic testing laboratories using PCR and Southern blot analysis. DMPK alleles in the samples cover four of five DM1 clinical categories: normal (5 to 34 repeats), mild (50 to 100 repeats), classical (101 to 1000 repeats), and congenital (>1000 repeats). We did not identify or establish Coriell cell lines in the premutation range (35 to 49 repeats). These samples are publicly available for quality control, proficiency testing, test development, and research and should help improve the accuracy of DM1 testing. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Scale-dependent genetic structure of the Idaho giant salamander (Dicamptodon aterrimus) in stream networks.

PubMed

Mullen, Lindy B; Arthur Woods, H; Schwartz, Michael K; Sepulveda, Adam J; Lowe, Winsor H

2010-03-01

The network architecture of streams and rivers constrains evolutionary, demographic and ecological processes of freshwater organisms. This consistent architecture also makes stream networks useful for testing general models of population genetic structure and the scaling of gene flow. We examined genetic structure and gene flow in the facultatively paedomorphic Idaho giant salamander, Dicamptodon aterrimus, in stream networks of Idaho and Montana, USA. We used microsatellite data to test population structure models by (i) examining hierarchical partitioning of genetic variation in stream networks; and (ii) testing for genetic isolation by distance along stream corridors vs. overland pathways. Replicated sampling of streams within catchments within three river basins revealed that hierarchical scale had strong effects on genetic structure and gene flow. amova identified significant structure at all hierarchical scales (among streams, among catchments, among basins), but divergence among catchments had the greatest structural influence. Isolation by distance was detected within catchments, and in-stream distance was a strong predictor of genetic divergence. Patterns of genetic divergence suggest that differentiation among streams within catchments was driven by limited migration, consistent with a stream hierarchy model of population structure. However, there was no evidence of migration among catchments within basins, or among basins, indicating that gene flow only counters the effects of genetic drift at smaller scales (within rather than among catchments). These results show the strong influence of stream networks on population structure and genetic divergence of a salamander, with contrasting effects at different hierarchical scales.

Genetic diversity and structure of managed and semi-natural populations of cocoa (Theobroma cacao) in the Huallaga and Ucayali Valleys of Peru.

PubMed

Zhang, Dapeng; Arevalo-Gardini, Enrique; Mischke, Sue; Zúñiga-Cernades, Luis; Barreto-Chavez, Alejandro; Del Aguila, Jorge Adriazola

2006-09-01

Cocoa (Theobroma cacao) is indigenous to the Amazon region of South America, and it is well known that the Peruvian Amazon harbours a large number of diverse cocoa populations. A small fraction of the diversity has been collected and maintained as an ex-situ germplasm repository in Peru. However, incorrect labelling of accessions and lack of information on genetic diversity have hindered efficient conservation and use of this germplasm. This study targeted assessment of genetic diversity and population structure in a managed and a semi-natural population. Using a capillary electrophoresis genotyping system, 105 cocoa accessions collected from the Huallaga and Ucayali valleys of Peru were fingerprinted. Based on 15 loci SSR profiles, genetic identity was examined for each accession and duplicates identified, population structure assessed and genetic diversity analysed in these two populations. Ten synonymous mislabelled groups were identified among the 105 accessions. The germplasm group in the Huallaga valley was clearly separated from the group in Ucayali valley by the Bayesian assignment test. The Huallaga group has lower genetic diversity, both in terms of allelic richness and of gene diversity, than the Ucayali group. Analysis of molecular variance suggested genetic substructure in the Ucayali group. Significant spatial correlation between genetic distance and geographical distances was detected in the Ucayali group by Mantel tests. These results substantiate the hypothesis that the Peruvian Amazon hosts a high level of cocoa genetic diversity, and the diversity has a spatial structure. The introduction of exotic seed populations into the Peruvian Amazon is changing the cocoa germplasm spectrum in this region. The spatial structure of cocoa diversity recorded here highlights the need for additional collecting and conservation measures for natural and semi-natural cocoa populations.

Breast Cancer in a 19-Year-Old Female Adolescent Identified with Li-Fraumeni Syndrome.

PubMed

Jay, Allison M; Hamame, Anthony S; Dul, Carrie; Wesen, Cheryl

2017-02-01

Breast cancer is rare in adolescents. In one study, breast carcinoma accounted for 0.02% of breast masses surgically removed in young women. We report a case of breast cancer in a 19-year-old woman who was found to have Li-Fraumeni Syndrome. The patient presented with a new, hard, nonmobile lump in the right breast which prompted her to seek medical attention. A biopsy identified invasive ductal carcinoma. Genetic testing showed a p53 mutation associated with Li-Fraumeni syndrome. Although breast masses in young women are mostly benign, one must entertain the possibility of more serious conditions when a breast mass is identified with concerning medical or physical findings. Genetic testing might be informative for such patients. Copyright © 2016 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

Clues to unraveling the coral species problem: distinguishing species from geographic variation in Porites across the Pacific with molecular markers and microskeletal traits

PubMed Central

Wellington, Gerrard M.; Fox, George E.; Toonen, Robert J.

2015-01-01

Morphological variation in the geographically widespread coral Porites lobata can make it difficult to distinguish from other massive congeneric species. This morphological variation could be attributed to geographic variability, phenotypic plasticity, or a combination of such factors. We examined genetic and microscopic morphological variability in P. lobata samples from the Galápagos, Easter Island, Tahiti, Fiji, Rarotonga, and Australia. Panamanian P. evermanni specimens were used as a previously established distinct outgroup against which to test genetic and morphological methods of discrimination. We employed a molecular analysis of variance (AMOVA) based on ribosomal internal transcribed spacer region (ITS) sequence, principal component analysis (PCA) of skeletal landmarks, and Mantel tests to compare genetic and morphological variation. Both genetic and morphometric methods clearly distinguished P. lobata and P. evermanni, while significant genetic and morphological variance was attributed to differences among geographic regions for P. lobata. Mantel tests indicate a correlation between genetic and morphological variation for P. lobata across the Pacific. Here we highlight landmark morphometric measures that correlate well with genetic differences, showing promise for resolving species of Porites, one of the most ubiquitous yet challenging to identify architects of coral reefs. PMID:25674364

The significant effects of puberty on the genetic diathesis of binge eating in girls.

PubMed

Klump, Kelly L; Culbert, Kristen M; O'Connor, Shannon; Fowler, Natasha; Burt, S Alexandra

2017-08-01

Recent data show significant phenotypic and genetic associations between ovarian hormones and binge eating in adulthood. Theories of hormonal risk focus on puberty and the possibility that hormone activation induces changes in genetic effects that then lead to differential risk for binge eating in postpuberty and adulthood. Although this theory is difficult to test in humans, an indirect test is to examine whether genetic influences on binge eating increase during the pubertal period in girls. Prior work has shown pubertal increases in genetic influences on overall disordered eating symptoms, but no study to date has examined binge eating. The present study was the first to examine these increases for binge eating. Participants included 1,568 female twins (aged 8-25 years) from the Michigan State University Twin Registry. Binge eating and pubertal development were assessed with self-report questionnaires. Twin moderation models showed significant linear increases in genetic effects from prepuberty (5%) to postpuberty (42%), even after controlling for the effects of age and body mass index. Results provide critical support for increased genetic influences on binge eating during puberty. Additional studies are needed to identify hormonal mechanisms and fully test contemporary models of ovarian hormone risk. © 2017 Wiley Periodicals, Inc.

Joint Identification of Genetic Variants for Physical Activity in Korean Population

PubMed Central

Kim, Jayoun; Kim, Jaehee; Min, Haesook; Oh, Sohee; Kim, Yeonjung; Lee, Andy H.; Park, Taesung

2014-01-01

There has been limited research on genome-wide association with physical activity (PA). This study ascertained genetic associations between PA and 344,893 single nucleotide polymorphism (SNP) markers in 8842 Korean samples. PA data were obtained from a validated questionnaire that included information on PA intensity and duration. Metabolic equivalent of tasks were calculated to estimate the total daily PA level for each individual. In addition to single- and multiple-SNP association tests, a pathway enrichment analysis was performed to identify the biological significance of SNP markers. Although no significant SNP was found at genome-wide significance level via single-SNP association tests, 59 genetic variants mapped to 76 genes were identified via a multiple SNP approach using a bootstrap selection stability measure. Pathway analysis for these 59 variants showed that maturity onset diabetes of the young (MODY) was enriched. Joint identification of SNPs could enable the identification of multiple SNPs with good predictive power for PA and a pathway enriched for PA. PMID:25026172

Positive perception of pharmacogenetic testing for psychotropic medications

PubMed Central

Lanktree, Matthew B; Zai, Gwyneth; VanderBeek, Laura E; Giuffra, Daniel E; Smithson, David S; Kipp, Lucas B; Dalseg, Timothy R; Speechley, Mark; Kennedy, James L

2014-01-01

Introduction Pharmacogenetics attempts to identify inter-individual genetic differences that are predictive of variable drug response and propensity to side effects, with the prospect of assisting physicians to select the most appropriate drug and dosage for treatment. However, many concerns regarding genetic tests exist. We sought to test the opinions of undergraduate science and medical students in southern Ontario universities toward pharmacogenetic testing. Methods and Results Questionnaires were completed by 910 undergraduate medicine and science students from 2005 to 2007. Despite students' concerns that the results of genetic tests may be used for other purposes without consent (71%) or lead to discrimination (78%), an overwhelming number of students were in favor of pharmacogenetic testing (90%). Discussion To our knowledge, this study is the first to survey a large sample for their attitude toward pharmacogenetic testing for psychotropic medications. Our results indicate that, although concerns remain and scientific advancements are required, respondents were in support of pharmacogenetic testing for medications used to treat schizophrenia. © 2014 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd. PMID:24604560

Germline Variation in HSD3B1 as a Novel Biomarker in Prostate Cancer

DTIC Science & Technology

2017-10-01

metastasis. Taken together, these results indicate that HSD3B1 genotype is a powerful genetic biomarker of resistance to ADT, and can be used to...salvage ADT. We analyzed differences in these endpoints according to genotype using an additive genetic model with the log-rank trend test...indicate that HSD3B1 genotype is a powerful genetic biomarker of resistance to ADT, and can be used to identify men who might benefit from escalated

A unified genetic association test robust to latent population structure for a count phenotype.

PubMed

Song, Minsun

2018-06-04

Confounding caused by latent population structure in genome-wide association studies has been a big concern despite the success of genome-wide association studies at identifying genetic variants associated with complex diseases. In particular, because of the growing interest in association mapping using count phenotype data, it would be interesting to develop a testing framework for genetic associations that is immune to population structure when phenotype data consist of count measurements. Here, I propose a solution for testing associations between single nucleotide polymorphisms and a count phenotype in the presence of an arbitrary population structure. I consider a classical range of models for count phenotype data. Under these models, a unified test for genetic associations that protects against confounding was derived. An algorithm was developed to efficiently estimate the parameters that are required to fit the proposed model. I illustrate the proposed approach using simulation studies and an empirical study. Both simulated and real-data examples suggest that the proposed method successfully corrects population structure. Copyright © 2018 John Wiley & Sons, Ltd.

Testing Genetic Pleiotropy with GWAS Summary Statistics for Marginal and Conditional Analyses.

PubMed

Deng, Yangqing; Pan, Wei

2017-12-01

There is growing interest in testing genetic pleiotropy, which is when a single genetic variant influences multiple traits. Several methods have been proposed; however, these methods have some limitations. First, all the proposed methods are based on the use of individual-level genotype and phenotype data; in contrast, for logistical, and other, reasons, summary statistics of univariate SNP-trait associations are typically only available based on meta- or mega-analyzed large genome-wide association study (GWAS) data. Second, existing tests are based on marginal pleiotropy, which cannot distinguish between direct and indirect associations of a single genetic variant with multiple traits due to correlations among the traits. Hence, it is useful to consider conditional analysis, in which a subset of traits is adjusted for another subset of traits. For example, in spite of substantial lowering of low-density lipoprotein cholesterol (LDL) with statin therapy, some patients still maintain high residual cardiovascular risk, and, for these patients, it might be helpful to reduce their triglyceride (TG) level. For this purpose, in order to identify new therapeutic targets, it would be useful to identify genetic variants with pleiotropic effects on LDL and TG after adjusting the latter for LDL; otherwise, a pleiotropic effect of a genetic variant detected by a marginal model could simply be due to its association with LDL only, given the well-known correlation between the two types of lipids. Here, we develop a new pleiotropy testing procedure based only on GWAS summary statistics that can be applied for both marginal analysis and conditional analysis. Although the main technical development is based on published union-intersection testing methods, care is needed in specifying conditional models to avoid invalid statistical estimation and inference. In addition to the previously used likelihood ratio test, we also propose using generalized estimating equations under the working independence model for robust inference. We provide numerical examples based on both simulated and real data, including two large lipid GWAS summary association datasets based on ∼100,000 and ∼189,000 samples, respectively, to demonstrate the difference between marginal and conditional analyses, as well as the effectiveness of our new approach. Copyright © 2017 by the Genetics Society of America.

Ehlers-Danlos syndrome

MedlinePlus

... down to children. This can be determined through testing and evaluations suggested by your provider or genetic counselor. Identifying any significant health risks may help prevent severe complications by vigilant screening ...

Genetic Testing in Pancreatic Ductal Adenocarcinoma: Implications for Prevention and Treatment.

PubMed

Peters, Mary Linton B; Tseng, Jennifer F; Miksad, Rebecca A

2016-07-01

This article reviews the progress to date and future directions for investigation of germline and somatic genetic testing to inform pancreatic adenocarcinoma (PDAC) treatment, screening, and prevention strategies. We searched PubMed to identify recent articles regarding genetic testing in pancreatic cancer, including both germline and somatic testing, and recent genome-wide association studies. References were specifically hand searched as relevant. Guidelines for testing and screening high-risk individuals were included. We searched clinicaltrials.gov to review the current landscape of active clinical trials. Approximately 10% of PDACs are associated with an identified germline mutation. Although germline mutations may inform treatment options and identify high-risk individuals for screening in other cancers, the data on PDAC are only now emerging. For example, poly adenosine diphosphate ribose polymerase (PARP) inhibitors are under investigation for BRCA-associated PDAC. Somatic mutations have also been identified in PDAC. However, current data are limited regarding treatment for potential PDAC somatic driver mutations. Although erlotinib is used in PDAC, its use is not targeted based on a tumor marker. Many tyrosine kinase inhibitors targeted toward potential driver mutations and critical pathways are in development, including BRAF/MEK, ALK, and CDK4/6. A consensus on screening strategies for individuals at high risk for PDAC is still evolving because of the relatively low prevalence of the disease, the relative invasiveness of endoscopic procedures often used as part of screening, and the lack of a clear survival benefit. Pancreatic cancer has been slower to move toward genomic testing, partially because of a lower prevalence of mutations and partially because of a limited effect of results on treatment choices outside a clinical trial. This is an area of active investigation, and we anticipate that there will be both preventive and therapeutic implications of driver mutations in the coming decade. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Genome-wide association study for rotator cuff tears identifies two significant single-nucleotide polymorphisms.

PubMed

Tashjian, Robert Z; Granger, Erin K; Farnham, James M; Cannon-Albright, Lisa A; Teerlink, Craig C

2016-02-01

The precise etiology of rotator cuff disease is unknown, but prior evidence suggests a role for genetic factors. Limited data exist identifying specific genes associated with rotator cuff tearing. The purpose of this study was to identify specific genes or genetic variants associated with rotator cuff tearing by a genome-wide association study with an independent set of rotator cuff tear cases. A set of 311 full-thickness rotator cuff tear cases genotyped on the Illumina 5M single-nucleotide polymorphism (SNP) platform were used in a genome-wide association study with 2641 genetically matched white population controls available from the Illumina iControls database. Tests of association were performed with GEMMA software at 257,558 SNPs that compose the intersection of Illumina SNP platforms and that passed general quality control metrics. SNPs were considered significant if P < 1.94 × 10(-7) (Bonferroni correction: 0.05/257,558). Tests of association revealed 2 significantly associated SNPs, one occurring in SAP30BP (rs820218; P = 3.8E-9) on chromosome 17q25 and another occurring in SASH1 (rs12527089; P = 1.9E-7) on chromosome 6q24. This study represents the first attempt to identify genetic factors influencing rotator cuff tearing by a genome-wide association study using a dense/complete set of SNPs. Two SNPs were significantly associated with rotator cuff tearing, residing in SAP30BP on chromosome 17 and SASH1 on chromosome 6. Both genes are associated with the cellular process of apoptosis. Identification of potential genes or genetic variants associated with rotator cuff tearing may help in identifying individuals at risk for the development of rotator cuff tearing. Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Genetic parameters for body weight from birth to calving and associations between weights with test-day, health, and female fertility traits.

PubMed

Yin, Tong; König, Sven

2018-03-01

A data set including 57,868 records for calf birth weight (CABW) and 9,462 records for weight at first insemination (IBW) were used for the estimation of direct and maternal genetic effects in Holstein Friesian dairy cattle. Furthermore, CABW and IBW were correlated with test-day production records and health traits in first-lactation cows, and with nonreturn rates in heifers. Health traits considered overall disease categories from the International Committee for Animal Recording diagnosis key, including the general disease status, diarrhea, respiratory diseases, mastitis, claw disorders, female fertility disorders, and metabolic disorders. For single-trait measurements of CABW and IBW, animal models with maternal genetic effects were applied. The direct heritability was 0.47 for CABW and 0.20 for IBW, and the direct genetic correlation between CABW and IBW was 0.31. A moderate maternal heritability (0.19) was identified for CABW, but the maternal genetic effect was close to zero for IBW. The correlation between direct and maternal genetic effects was antagonistic for CABW (-0.39) and for IBW (-0.24). In bivariate animal models, only weak genetic and phenotypic correlations were identified between CABW and IBW with either test-day production or health traits in early lactation. Apart from metabolic disorders, there was a general tendency for increasing disease susceptibilities with increasing CABW. The genetic correlation between IBW and nonreturn rates in heifers after 56 d and after 90 d was slightly positive (0.18), but close to zero when correlating nonreturn rates with CABW. For the longitudinal BW structure from birth to the age of 24 mo, random regression models with the time-dependent covariate "age in months" were applied. Evaluation criteria (Bayesian information criterion and residual variances) suggested Legendre polynomials of order 3 to modeling the longitudinal body weight (BW) structure. Direct heritabilities around birth and insemination dates were slightly larger than estimates for CABW and IBW from the single-trait models, but maternal heritabilities were exactly the same from both models. Genetic correlations between BW were close to 1 for neighboring age classes, but decreased with increasing time spans. The genetic correlation between BW at d 0 (birth date) and at 24 mo was even negative (-0.20). Random regression model estimates confirmed the antagonistic relationship between direct and maternal genetic effects, especially during calfhood. This study based on a large data set in dairy cattle confirmed genetic parameters and (co)variance components for BW as identified in beef cattle populations. However, BW records from an early stage of life were inappropriate early predictors for dairy cow health and productivity. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

[Willingness of Students of Economics to Pay for Predictive Oncological Genetic Testing - An Empirical Analysis].

PubMed

Siol, V; Lange, A; Prenzler, A; Neubauer, S; Frank, M

2017-05-01

Objectives: The present study aims to investigate the interest of young adults in predictive oncological genetic testing and their willingness to pay for such a test. Furthermore, major determinants of the 2 variables of interest were identified. Methods: 348 students of economics from the Leibniz University of Hanover were queried in July 2013 using an extensive questionnaire. Among other things, the participants were asked if they are interested in information about the probability to develop cancer in the future and their willingness to pay for such information. Data were analysed using descriptive statistics and ordinal probit regressions. Additionally marginal effects were calculated. Results: About 50% of the students were interested in predictive oncological genetic testing and were willing to pay for the test. Moreover, the participants who were willing to pay for the test partly attach high monetary values to the information that could so be obtained. The study shows that the interest of the students and their willingness to pay were primarily influenced by individual attitudes and perceptions. Conclusions: The study proves that young adults were interested in predictive genetic testing and appreciate information about their probability of develop cancer someday. © Georg Thieme Verlag KG Stuttgart · New York.

Quantitative genetic analysis of the bTB diagnostic single intradermal comparative cervical test (SICCT).

PubMed

Tsairidou, Smaragda; Brotherstone, Susan; Coffey, Mike; Bishop, Stephen C; Woolliams, John A

2016-11-24

Bovine tuberculosis (bTB) is a disease of significant economic importance and is a persistent animal health problem with implications for public health worldwide. Control of bTB in the UK has relied on diagnosis through the single intradermal comparative cervical test (SICCT). However, limitations in the sensitivity of this test hinder successful eradication and the control of bTB remains a major challenge. Genetic selection for cattle that are more resistant to bTB infection can assist in bTB control. The aim of this study was to conduct a quantitative genetic analysis of SICCT measurements collected during bTB herd testing. Genetic selection for bTB resistance will be partially informed by SICCT-based diagnosis; therefore it is important to know whether, in addition to increasing bTB resistance, this might also alter genetically the epidemiological characteristics of SICCT. Our main findings are that: (1) the SICCT test is robust at the genetic level, since its hierarchy and comparative nature provide substantial protection against random genetic changes that arise from genetic drift and from correlated responses among its components due to either natural or artificial selection; (2) the comparative nature of SICCT provides effective control for initial skin thickness and age-dependent differences; and (3) continuous variation in SICCT is only lowly heritable and has a weak correlation with SICCT positivity among healthy animals which was not significantly different from zero (P > 0.05). These emerging results demonstrate that genetic selection for bTB resistance is unlikely to change the probability of correctly identifying non-infected animals, i.e. the test's specificity, while reducing the overall number of cases. This study cannot exclude all theoretical risks from selection on resistance to bTB infection but the role of SICCT in disease control is unlikely to be rapidly undermined, with any adverse correlated responses expected to be weak and slow, which allow them to be monitored and managed.

A Simple Test of Class-Level Genetic Association Can Reveal Novel Cardiometabolic Trait Loci.

PubMed

Qian, Jing; Nunez, Sara; Reed, Eric; Reilly, Muredach P; Foulkes, Andrea S

2016-01-01

Characterizing the genetic determinants of complex diseases can be further augmented by incorporating knowledge of underlying structure or classifications of the genome, such as newly developed mappings of protein-coding genes, epigenetic marks, enhancer elements and non-coding RNAs. We apply a simple class-level testing framework, termed Genetic Class Association Testing (GenCAT), to identify protein-coding gene association with 14 cardiometabolic (CMD) related traits across 6 publicly available genome wide association (GWA) meta-analysis data resources. GenCAT uses SNP-level meta-analysis test statistics across all SNPs within a class of elements, as well as the size of the class and its unique correlation structure, to determine if the class is statistically meaningful. The novelty of findings is evaluated through investigation of regional signals. A subset of findings are validated using recently updated, larger meta-analysis resources. A simulation study is presented to characterize overall performance with respect to power, control of family-wise error and computational efficiency. All analysis is performed using the GenCAT package, R version 3.2.1. We demonstrate that class-level testing complements the common first stage minP approach that involves individual SNP-level testing followed by post-hoc ascribing of statistically significant SNPs to genes and loci. GenCAT suggests 54 protein-coding genes at 41 distinct loci for the 13 CMD traits investigated in the discovery analysis, that are beyond the discoveries of minP alone. An additional application to biological pathways demonstrates flexibility in defining genetic classes. We conclude that it would be prudent to include class-level testing as standard practice in GWA analysis. GenCAT, for example, can be used as a simple, complementary and efficient strategy for class-level testing that leverages existing data resources, requires only summary level data in the form of test statistics, and adds significant value with respect to its potential for identifying multiple novel and clinically relevant trait associations.

A Genetic Test Predicts Providence Brace Success for Adolescent Idiopathic Scoliosis When Failure Is Defined as Progression to >45 Degrees.

PubMed

Bohl, Daniel D; Telles, Connor J; Ruiz, Ferrin K; Badrinath, Raghav; DeLuca, Peter A; Grauer, Jonathan N

2016-04-01

Retrospective cohort. To determine whether a genetic test is associated with successful Providence bracing for adolescent idiopathic scoliosis (AIS). Genetic factors have been defined that predict the risk of progression of AIS in a polygenic fashion. From these data, a commercially available genetic test, ScoliScore, was developed. It is now used in clinical practice for counseling and to guide clinical management. Bracing is a mainstay of treatment for AIS. Large efforts have been made recently to reduce potential confounding across studies of different braces; however, none of these have considered genetics as a potential confounder. In particular, ScoliScore has not been evaluated in a population undergoing bracing. We conducted a retrospective cohort study in which we identified a population of AIS patients who were initiated with Providence bracing and followed over time. Although these patients did not necessarily fit the commercial indications for ScoliScore, we contacted the patients and obtained a saliva sample from each for genetic analysis. We then tested whether ScoliScore correlated with the outcome of their bracing therapy. We were able to contact and invite 25 eligible subjects, of whom 16 (64.0%) returned samples for laboratory analysis. Patients were followed for an average of 2.3 years (range, 1.1-4 y) after initiation of the Providence brace. Eight patients (50.0%) progressed to >45 degrees, whereas the other 8 patients (50.0%) did not. The mean ScoliScore among those who progressed to >45 degrees was higher than that among those who did not (176 vs. 112, P=0.030). We demonstrate that a genetic test correlates with bracing outcome. It may be appropriate for future bracing studies to include analysis of genetic predisposition to limit potential confounding.

Exome Sequencing Identifies Potential Risk Variants for Mendelian Disorders at High Prevalence in Qatar

PubMed Central

Rodriguez-Flores, Juan L.; Fakhro, Khalid; Hackett, Neil R.; Salit, Jacqueline; Fuller, Jennifer; Agosto-Perez, Francisco; Gharbiah, Maey; Malek, Joel A.; Zirie, Mahmoud; Jayyousi, Amin; Badii, Ramin; Al-Marri, Ajayeb Al-Nabet; Chouchane, Lotfi; Stadler, Dora J.; Hunter-Zinck, Haley; Mezey, Jason G.; Crystal, Ronald G.

2013-01-01

Exome sequencing of families of related individuals has been highly successful in identifying genetic polymorphisms responsible for Mendelian disorders. Here, we demonstrate the value of the reverse approach, where we use exome sequencing of a sample of unrelated individuals to analyze allele frequencies of known causal mutations for Mendelian diseases. We sequenced the exomes of 100 individuals representing the three major genetic subgroups of the Qatari population (Q1 Bedouin, Q2 Persian-South Asian, Q3 African) and identified 37 variants in 33 genes with effects on 36 clinically significant Mendelian diseases. These include variants not present in 1000 Genomes and variants at high frequency when compared to 1000 Genomes populations. Several of these Mendelian variants were only segregating in one Qatari subpopulation, where the observed subpopulation specificity trends were confirmed in an independent population of 386 Qataris. Pre-marital genetic screening in Qatar tests for only 4 out of the 37, such that this study provides a set of Mendelian disease variants with potential impact on the epidemiological profile of the population that could be incorporated into the testing program if further experimental and clinical characterization confirms high penetrance. PMID:24123366

Pleiotropic analysis of cancer risk loci on esophageal adenocarcinoma risk

PubMed Central

Lee, Eunjung; Stram, Daniel O.; Ek, Weronica E.; Onstad, Lynn E; MacGregor, Stuart; Gharahkhani, Puya; Ye, Weimin; Lagergren, Jesper; Shaheen, Nicholas J.; Murray, Liam J.; Hardie, Laura J; Gammon, Marilie D.; Chow, Wong-Ho; Risch, Harvey A.; Corley, Douglas A.; Levine, David M; Whiteman, David C.; Bernstein, Leslie; Bird, Nigel C.; Vaughan, Thomas L.; Wu, Anna H.

2015-01-01

Background Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus (BE). Methods We examined the associations between risks of EA and BE and 387 single nucleotide polymorphisms (SNPs) that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 BE) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. Results After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or BE. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. Conclusions Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or BE. Impact To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and BE. PMID:26364162

Novel whole blood assay for phenotyping platelet reactivity in mice identifies ICAM-1 as a mediator of platelet-monocyte interaction

PubMed Central

Kirkby, Nicholas S.; Chan, Melissa V.; Finsterbusch, Michaela; Hogg, Nancy; Nourshargh, Sussan; Warner, Timothy D.

2015-01-01

Testing of platelet function is central to the cardiovascular phenotyping of genetically modified mice. Traditional platelet function tests have been developed primarily for testing human samples and the volumes required make them highly unsuitable for the testing of mouse platelets. This limits research in this area. To address this problem, we have developed a miniaturized whole blood aggregometry assay, based on a readily accessible 96-well plate format coupled with quantification of single platelet depletion by flow cytometric analysis. Using this approach, we observed a concentration-dependent loss of single platelets in blood exposed to arachidonic acid, collagen, U46619 or protease activated receptor 4 activating peptide. This loss was sensitive to well-established antiplatelet agents and genetic manipulation of platelet activation pathways. Observations were more deeply analyzed by flow cytometric imaging, confocal imaging, and measurement of platelet releasates. Phenotypic analysis of the reactivity of platelets taken from mice lacking intercellular adhesion molecule (ICAM)-1 identified a marked decrease in fibrinogen-dependent platelet-monocyte interactions, especially under inflammatory conditions. Such findings exemplify the value of screening platelet phenotypes of genetically modified mice and shed further light upon the roles and interactions of platelets in inflammation. PMID:26215112

Improving Decision Making about Genetic Testing in the Clinic: An Overview of Effective Knowledge Translation Interventions.

PubMed

Légaré, France; Robitaille, Hubert; Gane, Claire; Hébert, Jessica; Labrecque, Michel; Rousseau, François

2016-01-01

Knowledge translation (KT) interventions are attempts to change behavior in keeping with scientific evidence. While genetic tests are increasingly available to healthcare consumers in the clinic, evidence about their benefits is unclear and decisions about genetic testing are thus difficult for all parties. We sought to identify KT interventions that involved decisions about genetic testing in the clinical context and to assess their effectiveness for improving decision making in terms of behavior change, increased knowledge and wellbeing. We searched for trials assessing KT interventions in the context of genetic testing up to March 2014 in all systematic reviews (n = 153) published by two Cochrane review groups: Effective Practice and Organisation of Care (EPOC) and Consumers and Communication. We retrieved 2473 unique trials of which we retained only 28 (1%). Two EPOC reviews yielded two trials of KT interventions: audit and feedback (n = 1) and educational outreach (n = 1). Both targeted health professionals and the KT intervention they assessed was found to be effective. Four Consumers and Communication reviews yielded 26 trials: decision aids (n = 15), communication of DNA-based disease risk estimates (n = 7), personalized risk communication (n = 3) and mobile phone messaging (n = 1). Among these, 25 trials targeted only health consumers or patients and the KT interventions were found to be effective in four trials, partly effective in seven, and ineffective in four. Lastly, only one trial targeted both physicians and patients and was found to be effective. More research on the effectiveness of KT interventions regarding genetic testing in the clinical context may contribute to patients making informed value-based decisions and drawing the maximum benefit from clinical applications of genetic and genomic innovations.

Interest in Genetic Counseling and Testing for Adolescent Nicotine Addiction Susceptibility among a Sample of Adolescent Medicine Providers Attending a Scientific Conference on Adolescent Health

PubMed Central

Tercyak, Kenneth P.; Peshkin, Beth N.; Abraham, Anisha; Wine, Lauren; Walker, Leslie R.

2007-01-01

Purpose Preventing adolescents from smoking and becoming addicted to nicotine is an important public health issue. New research on the genetics of susceptibility to nicotine addition is emerging and may someday help identify adolescents at high risk. Over time, genetic counseling and testing for nicotine addiction susceptibility may become incorporated into tobacco control practice, and providers in primary care settings are likely to be at the forefront of these services. As such, it is important to understand the attitudes and practices of adolescent medicine providers toward tobacco control and genetic testing to better anticipate their needs and interests and prepare for the future. This study describes adolescent medicine providers’ interest, and correlates of their interest, in genetic counseling and testing for nicotine addiction susceptibility among their adolescent patients--a test which is not yet clinically available. Methods Adolescent medicine providers attending a national scientific conference (N = 232) completed a survey about their patient tobacco control and other screening behaviors, perceptions of their patients’ attitudes and beliefs toward tobacco control, and their own attitudes and beliefs about smoking and genetics. Results Providers who engaged in more regular tobacco screening behaviors with their adolescent patients (Odds Ratio [OR] = 4.07, 95% Confidence Interval [CI] = 2.20, 7.751, p = .00) and those who were more optimistic that biobehavioral research would lead to significant improvements in adolescent smoking prevention and treatment (OR = 2.47, 95% CI = 1.40, 4.37, p = .00), were more interested in counseling and testing. Conclusions Someday, adolescent wellness visits may present an opportunity to offer genetic counseling and testing for nicotine addiction susceptibility. Implementation at the provider level may depend on tobacco screening behavior and research optimism. Educating providers about safe and effective adolescent tobacco control strategies incorporating genetics will be essential. PMID:17577533

Exceptions to the rule: case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes.

PubMed

Rosenthal, E T; Bowles, K R; Pruss, D; van Kan, A; Vail, P J; McElroy, H; Wenstrup, R J

2015-12-01

Based on current consensus guidelines and standard practice, many genetic variants detected in clinical testing are classified as disease causing based on their predicted impact on the normal expression or function of the gene in the absence of additional data. However, our laboratory has identified a subset of such variants in hereditary cancer genes for which compelling contradictory evidence emerged after the initial evaluation following the first observation of the variant. Three representative examples of variants in BRCA1, BRCA2 and MSH2 that are predicted to disrupt splicing, prematurely truncate the protein, or remove the start codon were evaluated for pathogenicity by analyzing clinical data with multiple classification algorithms. Available clinical data for all three variants contradicts the expected pathogenic classification. These variants illustrate potential pitfalls associated with standard approaches to variant classification as well as the challenges associated with monitoring data, updating classifications, and reporting potentially contradictory interpretations to the clinicians responsible for translating test outcomes to appropriate clinical action. It is important to address these challenges now as the model for clinical testing moves toward the use of large multi-gene panels and whole exome/genome analysis, which will dramatically increase the number of genetic variants identified. © 2015 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tracing Technological Development Trajectories: A Genetic Knowledge Persistence-Based Main Path Approach.

PubMed

Park, Hyunseok; Magee, Christopher L

2017-01-01

The aim of this paper is to propose a new method to identify main paths in a technological domain using patent citations. Previous approaches for using main path analysis have greatly improved our understanding of actual technological trajectories but nonetheless have some limitations. They have high potential to miss some dominant patents from the identified main paths; nonetheless, the high network complexity of their main paths makes qualitative tracing of trajectories problematic. The proposed method searches backward and forward paths from the high-persistence patents which are identified based on a standard genetic knowledge persistence algorithm. We tested the new method by applying it to the desalination and the solar photovoltaic domains and compared the results to output from the same domains using a prior method. The empirical results show that the proposed method can dramatically reduce network complexity without missing any dominantly important patents. The main paths identified by our approach for two test cases are almost 10x less complex than the main paths identified by the existing approach. The proposed approach identifies all dominantly important patents on the main paths, but the main paths identified by the existing approach miss about 20% of dominantly important patents.

Tracing Technological Development Trajectories: A Genetic Knowledge Persistence-Based Main Path Approach

PubMed Central

2017-01-01

The aim of this paper is to propose a new method to identify main paths in a technological domain using patent citations. Previous approaches for using main path analysis have greatly improved our understanding of actual technological trajectories but nonetheless have some limitations. They have high potential to miss some dominant patents from the identified main paths; nonetheless, the high network complexity of their main paths makes qualitative tracing of trajectories problematic. The proposed method searches backward and forward paths from the high-persistence patents which are identified based on a standard genetic knowledge persistence algorithm. We tested the new method by applying it to the desalination and the solar photovoltaic domains and compared the results to output from the same domains using a prior method. The empirical results show that the proposed method can dramatically reduce network complexity without missing any dominantly important patents. The main paths identified by our approach for two test cases are almost 10x less complex than the main paths identified by the existing approach. The proposed approach identifies all dominantly important patents on the main paths, but the main paths identified by the existing approach miss about 20% of dominantly important patents. PMID:28135304

Using a genetic test result in the care of family members: how does the duty of confidentiality apply?

PubMed

Parker, Michael; Lucassen, Anneke

2018-04-27

The use of genetic and genomic testing is becoming more widespread in healthcare and more inherited explanations for family history of diseases or conditions are being uncovered. Currently, relevant genetic information is not always used in the care of family members who might benefit from it, because of health professionals' fears of inappropriately breaching another family member's confidence. Such examples are likely to increase as testing possibilities expand. Here we present the case for use of familial information in the care and treatment of family members. We argue that whilst a clinical diagnosis in person A is confidential, the discovery of a familial factor that led to this diagnosis should be available for use in depersonalised form by health professionals to inform the testing and clinical care of other family members. The possibility of such use should be made clear in clinical practice at the time of initial testing, but should not require consent from the person in whom the familial factor was first identified. We call for further debate on these questions in the wake of high profile non-disclosure of genetic information cases, and forthcoming Data Protection legislation changes.

Prematurity and Genetic Testing for Neonatal Diabetes.

PubMed

Besser, Rachel E J; Flanagan, Sarah E; Mackay, Deborah G J; Temple, I K; Shepherd, Maggie H; Shields, Beverley M; Ellard, Sian; Hattersley, Andrew T

2016-09-01

Hyperglycemia in premature infants is usually thought to reflect inadequate pancreatic development rather than monogenic neonatal diabetes. No studies, to our knowledge, have investigated the prevalence of monogenic forms of diabetes in preterm infants. We studied 750 patients with diabetes diagnosed before 6 months of age. We compared the genetic etiology and clinical characteristics of 146 preterm patients born <37 weeks and compared them with 604 born ≥37 weeks. A genetic etiology was found in 97/146 (66%) preterm infants compared with 501/604 (83%) born ≥37weeks, P < .0001. Chromosome 6q24 imprinting abnormalities (27% vs 12%, P = .0001) and GATA6 mutations (9% vs 2%, P = .003) occurred more commonly in preterm than term infants while mutations in KCNJ11 were less common (21 vs 34%, P = .008). Preterm patients with an identified mutation were diagnosed later than those without an identified mutation (median [interquartile range] 35 [34 to 36] weeks vs 31 [28 to 36] weeks, P < .0001). No difference was seen in other clinical characteristics of preterm patients with and without an identified mutation including age of presentation, birth weight, and time to referral. Patients with neonatal diabetes due to a monogenic etiology can be born preterm, especially those with 6q24 abnormalities or GATA6 mutations. A genetic etiology is more likely in patients with less severe prematurity (>32 weeks). Prematurity should not prevent referral for genetic testing as 37% have a potassium channel mutation and as a result can get improved control by replacing insulin with sulphonylurea therapy. Copyright © 2016 by the American Academy of Pediatrics.

A genotyping protocol for multiple tissue types from the polyploid tree species Sequoia sempervirens (Cupressaceae)1

PubMed Central

Narayan, Lakshmi; Dodd, Richard S.; O’Hara, Kevin L.

2015-01-01

Premise of the study: Identifying clonal lineages in asexually reproducing plants using microsatellite markers is complicated by the possibility of nonidentical genotypes from the same clonal lineage due to somatic mutations, null alleles, and scoring errors. We developed and tested a clonal identification protocol that is robust to these issues for the asexually reproducing hexaploid tree species coast redwood (Sequoia sempervirens). Methods: Microsatellite data from four previously published and two newly developed primers were scored using a modified protocol, and clones were identified using Bruvo genetic distances. The effectiveness of this clonal identification protocol was assessed using simulations and by genotyping a test set of paired samples of different tissue types from the same trees. Results: Data from simulations showed that our protocol allowed us to accurately identify clonal lineages. Multiple test samples from the same trees were identified correctly, although certain tissue type pairs had larger genetic distances on average. Discussion: The methods described in this paper will allow for the accurate identification of coast redwood clones, facilitating future studies of the reproductive ecology of this species. The techniques used in this paper can be applied to studies of other clonal organisms as well. PMID:25798341

A genotyping protocol for multiple tissue types from the polyploid tree species Sequoia sempervirens (Cupressaceae).

PubMed

Narayan, Lakshmi; Dodd, Richard S; O'Hara, Kevin L

2015-03-01

Identifying clonal lineages in asexually reproducing plants using microsatellite markers is complicated by the possibility of nonidentical genotypes from the same clonal lineage due to somatic mutations, null alleles, and scoring errors. We developed and tested a clonal identification protocol that is robust to these issues for the asexually reproducing hexaploid tree species coast redwood (Sequoia sempervirens). Microsatellite data from four previously published and two newly developed primers were scored using a modified protocol, and clones were identified using Bruvo genetic distances. The effectiveness of this clonal identification protocol was assessed using simulations and by genotyping a test set of paired samples of different tissue types from the same trees. Data from simulations showed that our protocol allowed us to accurately identify clonal lineages. Multiple test samples from the same trees were identified correctly, although certain tissue type pairs had larger genetic distances on average. The methods described in this paper will allow for the accurate identification of coast redwood clones, facilitating future studies of the reproductive ecology of this species. The techniques used in this paper can be applied to studies of other clonal organisms as well.

DNA barcoding and the identification of tree frogs (Amphibia: Anura: Rhacophoridae).

PubMed

Dang, Ning-Xin; Sun, Feng-Hui; Lv, Yun-Yun; Zhao, Bo-Han; Wang, Ji-Chao; Murphy, Robert W; Wang, Wen-Zhi; Li, Jia-Tang

2016-07-01

The DNA barcoding gene COI (cytochrome c oxidase subunit I) effectively identifies many species. Herein, we barcoded 172 individuals from 37 species belonging to nine genera in Rhacophoridae to test if the gene serves equally well to identify species of tree frogs. Phenetic neighbor joining and phylogenetic Bayesian inference were used to construct phylogenetic trees, which resolved all nine genera as monophyletic taxa except for Rhacophorus, two new matrilines for Liuixalus, and Polypedates leucomystax species complex. Intraspecific genetic distances ranged from 0.000 to 0.119 and interspecific genetic distances ranged from 0.015 to 0.334. Within Rhacophorus and Kurixalus, the intra- and interspecific genetic distances did not reveal an obvious barcode gap. Notwithstanding, we found that COI sequences unambiguously identified rhacophorid species and helped to discover likely new cryptic species via the synthesis of genealogical relationships and divergence patterns. Our results supported that COI is an effective DNA barcoding marker for Rhacophoridae.

Looking at genes in the workplace.

PubMed

Holden, C

1982-07-23

The Office of Technology Assessment recently testified at a congressional hearing that many corporations are considering genetic screening of employees. Biochemical genetic screening of "susceptible" workers is aimed at identifying individuals unsuitable for specific jobs, and cytogenic monitoring involves the testing of groups of workers for chromosome aberrations that might occur as a result of exposure to chemicals. The apparent surge of interest in such testing requires that several legal, ethical, and policy issues be addressed, including the potential for discrimination, the misuse of screening as an alternative to cleaning up the workplace, the predictive capability of the tests, and the necessity for the development of guidelines for screening programs.

Germline genetic variants with implications for disease risk and therapeutic outcomes.

PubMed

Pasternak, Amy L; Ward, Kristen M; Luzum, Jasmine A; Ellingrod, Vicki L; Hertz, Daniel L

2017-10-01

Genetic testing has multiple clinical applications including disease risk assessment, diagnosis, and pharmacogenomics. Pharmacogenomics can be utilized to predict whether a pharmacologic therapy will be effective or to identify patients at risk for treatment-related toxicity. Although genetic tests are typically ordered for a distinct clinical purpose, the genetic variants that are found may have additional implications for either disease or pharmacology. This review will address multiple examples of germline genetic variants that are informative for both disease and pharmacogenomics. The discussed relationships are diverse. Some of the agents are targeted for the disease-causing genetic variant, while others, although not targeted therapies, have implications for the disease they are used to treat. It is also possible that the disease implications of a genetic variant are unrelated to the pharmacogenomic implications. Some of these examples are considered clinically actionable pharmacogenes, with evidence-based, pharmacologic treatment recommendations, while others are still investigative as areas for additional research. It is important that clinicians are aware of both the disease and pharmacogenomic associations of these germline genetic variants to ensure patients are receiving comprehensive personalized care. Copyright © 2017 the American Physiological Society.

How Well Do Customers of Direct-to-Consumer Personal Genomic Testing Services Comprehend Genetic Test Results? Findings from the Impact of Personal Genomics Study.

PubMed

Ostergren, Jenny E; Gornick, Michele C; Carere, Deanna Alexis; Kalia, Sarah S; Uhlmann, Wendy R; Ruffin, Mack T; Mountain, Joanna L; Green, Robert C; Roberts, J Scott

2015-01-01

To assess customer comprehension of health-related personal genomic testing (PGT) results. We presented sample reports of genetic results and examined responses to comprehension questions in 1,030 PGT customers (mean age: 46.7 years; 59.9% female; 79.0% college graduates; 14.9% non-White; 4.7% of Hispanic/Latino ethnicity). Sample reports presented a genetic risk for Alzheimer's disease and type 2 diabetes, carrier screening summary results for >30 conditions, results for phenylketonuria and cystic fibrosis, and drug response results for a statin drug. Logistic regression was used to identify correlates of participant comprehension. Participants exhibited high overall comprehension (mean score: 79.1% correct). The highest comprehension (range: 81.1-97.4% correct) was observed in the statin drug response and carrier screening summary results, and lower comprehension (range: 63.6-74.8% correct) on specific carrier screening results. Higher levels of numeracy, genetic knowledge, and education were significantly associated with greater comprehension. Older age (≥ 60 years) was associated with lower comprehension scores. Most customers accurately interpreted the health implications of PGT results; however, comprehension varied by demographic characteristics, numeracy and genetic knowledge, and types and format of the genetic information presented. Results suggest a need to tailor the presentation of PGT results by test type and customer characteristics. © 2015 S. Karger AG, Basel.

How Well Do Customers of Direct-to-Consumer Personal Genomic Testing Services Comprehend Genetic Test Results? Findings from the Impact of Personal Genomics Study

PubMed Central

Ostergren, Jenny E.; Gornick, Michele C.; Carere, Deanna Alexis; Kalia, Sarah S.; Uhlmann, Wendy R.; Ruffin, Mack T.; Mountain, Joanna L.; Green, Robert C.; Roberts, J. Scott

2016-01-01

Aim To assess customer comprehension of health-related personal genomic testing (PGT) results. Methods We presented sample reports of genetic results and examined responses to comprehension questions in 1,030 PGT customers (mean age: 46.7 years; 59.9% female; 79.0% college graduates; 14.9% non-White; 4.7% of Hispanic/Latino ethnicity). Sample reports presented a genetic risk for Alzheimer’s disease and type 2 diabetes, carrier screening summary results for >30 conditions, results for phenylketonuria and cystic fibrosis, and drug response results for a statin drug. Logistic regression was used to identify correlates of participant comprehension. Results Participants exhibited high overall comprehension (mean score: 79.1% correct). The highest comprehension (range: 81.1–97.4% correct) was observed in the statin drug response and carrier screening summary results, and lower comprehension (range: 63.6–74.8% correct) on specific carrier screening results. Higher levels of numeracy, genetic knowledge, and education were significantly associated with greater comprehension. Older age (≥ 60 years) was associated with lower comprehension scores. Conclusions Most customers accurately interpreted the health implications of PGT results; however, comprehension varied by demographic characteristics, numeracy and genetic knowledge, and types and format of the genetic information presented. Results suggest a need to tailor the presentation of PGT results by test type and customer characteristics. PMID:26087778

Engagement with genetic discrimination: concerns and experiences in the context of Huntington disease

PubMed Central

Bombard, Yvonne; Penziner, Elizabeth; Suchowersky, Oksana; Guttman, Mark; Paulsen, Jane S; Bottorff, Joan L; Hayden, Michael R

2013-01-01

It has been over 20 years since the inception of predictive testing for Huntington disease (HD), yet the social implications of knowing one's genetic risk for HD have not been fully explored. Genetic discrimination (GD) is a potential risk associated with predictive testing. Although anecdotal reports of GD have been documented, there is a paucity of research on the nature and experiences of GD in the context of HD. The purpose of this study was to describe the concerns and experiences of GD in the HD community. Semistructured interviews were conducted with 45 genetically tested and 10 untested individuals and analyzed using grounded theory methods. Our findings demonstrate that a majority of individuals were concerned about (37/55) and experienced GD (32/55) across a variety of contexts that extend beyond the traditionally examined contexts of insurance and employment to include family, social, government, and health-care domains. We describe a process of engagement with GD in which individuals formed meaningful interpretations of GD and personalized its risk and consequences in their lives. Our findings provide an insight into some of the specific processes and factors influencing engagement with GD. These results help identify areas where more education and support is needed and provide direction to genetic professionals supporting their clients as they confront issues of GD and genetic testing. PMID:17957229

Utilizing Remote Real-Time Videoconferencing to Expand Access to Cancer Genetic Services in Community Practices: A Multicenter Feasibility Study.

PubMed

Bradbury, Angela; Patrick-Miller, Linda; Harris, Diana; Stevens, Evelyn; Egleston, Brian; Smith, Kyle; Mueller, Rebecca; Brandt, Amanda; Stopfer, Jill; Rauch, Shea; Forman, Andrea; Kim, Rebecca; Fetzer, Dominique; Fleisher, Linda; Daly, Mary; Domchek, Susan

2016-02-01

Videoconferencing has been used to expand medical services to low-access populations and could increase access to genetic services at community sites where in-person visits with genetic providers are not available. To evaluate the feasibility of, patient feedback of, and cognitive and affective responses to remote two-way videoconferencing (RVC) telegenetic services at multiple sociodemographically diverse community practices without access to genetic providers. Patients at 3 community sites in 2 US states outside the host center completed RVC pretest (visit 1, V1) and post-test (visit 2, V2) genetic counseling for cancer susceptibility. Surveys evaluated patient experiences, knowledge, satisfaction with telegenetic and cancer genetics services, anxiety, depression, and cancer worry. A total of 82 out of 100 (82.0%) approached patients consented to RVC services. A total of 61 out of 82 patients (74%) completed pretest counseling and 41 out of 61 (67%) proceeded with testing and post-test counseling. A total of 4 out of 41 (10%) mutation carriers were identified: BRCA2, MSH2, and PMS2. Patients reported many advantages (eg, lower travel burden and convenience) and few disadvantages to RVC telegenetic services. Most patients reported feeling comfortable with the video camera--post-V1: 52/57 (91%); post-V2: 39/41 (95%)--and that their privacy was respected--post-V1: 56/57 (98%); post-V2: 40/41 (98%); however, some reported concerns that RVC might increase the risk of a confidentiality breach of their health information--post-V1: 14/57 (25%); post-V2: 12/41 (29%). While the majority of patients reported having no trouble seeing or hearing the genetic counselor--post-V1: 47/57 (82%); post-V2: 39/41 (95%)--51 out of 98 (52%) patients reported technical difficulties. Nonetheless, all patients reported being satisfied with genetic services. Compared to baseline, knowledge increased significantly after pretest counseling (+1.11 mean score, P=.005); satisfaction with telegenetic (+1.74 mean score, P=.02) and genetic services (+2.22 mean score, P=.001) increased after post-test counseling. General anxiety and depression decreased after pretest (-0.97 mean anxiety score, P=.003; -0.37 mean depression score, P=.046) and post-test counseling (-1.13 mean anxiety score, P=.003; -0.75 mean depression score, P=.01); state anxiety and cancer-specific worry did not significantly increase. Remote videoconferencing telegenetic services are feasible, identify genetic carriers in community practices, and are associated with high patient satisfaction and favorable cognitive and affective outcomes, suggesting an innovative delivery model for further study to improve access to genetic providers and services. Potential barriers to dissemination include technology costs, unclear billing and reimbursement, and state requirements for provider licensure.

Genetic structure of lake whitefish, Coregonus clupeaformis, populations in the northern main basin of Lake Huron

USGS Publications Warehouse

Stott, Wendylee; Ebener, Mark P.; Mohr, Lloyd; Schaeffer, Jeff; Roseman, Edward F.; Harford, William J.; Johnson, James E.; Fietsch, Cherie-Lee

2012-01-01

Genetic analysis of spawning lake whitefish (Coregonus clupeaformis) from six sites in the main basin of Lake Huron was conducted to determine population structure. Samples from fisheryindependent assessment surveys in the northwest main basin were analyzed to determine the relative contributions of lake whitefish genetic populations. Genetic population structure was identified using data from seven microsatellite DNA loci. One population was identified at Manitoulin Island, one to two were observed in the east-central main basin (Fishing Island and Douglas Point), and one to two populations were found in the northwest (Thunder Bay and Duncan Bay). The genetic identity of collections from Duncan Bay and Thunder Bay was not consistent among methods used to analyze population structure. Low genetic distances suggested that they comprised one population, but genic differences indicated that they may constitute separate populations. Simulated data indicated that the genetic origins of samples from a mixed-fishery could be accurately identified, but accuracy could be improved by incorporating additional microsatellite loci. Mixture analysis and individual assignment tests performed on mixed-stock samples collected from the western main basin suggested that genetic populations from the east-central main basin contributed less than those from the western main basin and that the proportional contribution of each baseline population was similar in each assessment sample. Analysis of additional microsatellite DNA loci may be useful to help improve the precision of the estimates, thus increasing our ability to manage and protect this valuable resource.

Information needs of mothers regarding communicating BRCA1/2 cancer genetic test results to their children.

PubMed

Tercyak, Kenneth P; Peshkin, Beth N; Demarco, Tiffani A; Patenaude, Andrea Farkas; Schneider, Katherine A; Garber, Judy E; Valdimarsdottir, Heiddis B; Schwartz, Marc D

2007-01-01

Mothers who participate in genetic testing for hereditary breast/ovarian cancer risk must decide if, when, and how to ultimately share their BRCA1 and BRCA2 (BRCA1/2) test results with their minor-age children. One of the primary aides for mothers in making this decision is cancer genetic counseling. However, counseling is limited in how well it can educate mothers about such decisions without the availability of resources that are specific to family communication and genetic testing per se. In an effort to fill this gap and identify mothers most likely to benefit from such resources, surveys were conducted with 187 mothers undergoing BRCA1/2 testing who had children 8-21 years old. Data were collected weeks after genetic testing but prior to mothers' learning of their test results; quantitative assessments of informational resource needs (i.e., speaking with previous BRCA1/2 testing participants who are parents regarding their experiences, reading educational literature about options and what to expect, speaking with a family counselor, attending a family support group, and self-nominated other resources), testing motivations, decision making vigilance, and decisional conflict regarding communicating test results to children were included. Mothers' most-to-least frequently cited information resource needs were: literature (93.4%), family counseling (85.8%), prior participants (79.0%), support groups (53.9%), and other (28.9%; e.g., pediatricians and psychologists). Seventy-eight percent of mothers were interested in accessing three or more resources. In multivariate regression analyses, testing motivations (beta = 0.35, p = 0.03), decision-making vigilance (beta = 0.16, p = 0.00), and decisional conflict (beta = 0.10, p = 0.00) were associated with mothers' need level; mothers with a greater interest in testing to learn about their children's risks, those with more vigilant decision-making styles, and those with higher decisional conflict had the greatest need. In conjunction with enhanced genetic counseling focusing on family disclosure, educational literature, and psychosocial support may promote improved outcomes.

Genetic signatures of natural selection in a model invasive ascidian

NASA Astrophysics Data System (ADS)

Lin, Yaping; Chen, Yiyong; Yi, Changho; Fong, Jonathan J.; Kim, Won; Rius, Marc; Zhan, Aibin

2017-03-01

Invasive species represent promising models to study species’ responses to rapidly changing environments. Although local adaptation frequently occurs during contemporary range expansion, the associated genetic signatures at both population and genomic levels remain largely unknown. Here, we use genome-wide gene-associated microsatellites to investigate genetic signatures of natural selection in a model invasive ascidian, Ciona robusta. Population genetic analyses of 150 individuals sampled in Korea, New Zealand, South Africa and Spain showed significant genetic differentiation among populations. Based on outlier tests, we found high incidence of signatures of directional selection at 19 loci. Hitchhiking mapping analyses identified 12 directional selective sweep regions, and all selective sweep windows on chromosomes were narrow (~8.9 kb). Further analyses indentified 132 candidate genes under selection. When we compared our genetic data and six crucial environmental variables, 16 putatively selected loci showed significant correlation with these environmental variables. This suggests that the local environmental conditions have left significant signatures of selection at both population and genomic levels. Finally, we identified “plastic” genomic regions and genes that are promising regions to investigate evolutionary responses to rapid environmental change in C. robusta.

Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma

PubMed Central

Reis, Linda M.; Semina, Elena V.

2016-01-01

The human eye is a complex organ whose development requires extraordinary coordination of developmental processes. The conservation of ocular developmental steps in vertebrates suggests possible common genetic mechanisms. Genetic diseases involving the eye represent a leading cause of blindness in children and adults. During the last decades, there has been an exponential increase in genetic studies of ocular disorders. In this review, we summarize current success in identification of genes responsible for microphthalmia, anophthalmia and coloboma (MAC) phenotypes, which are associated with early defects in embryonic eye development. Studies in animal models for the orthologous genes identified overlapping phenotypes for most factors confirming the conservation of their function in vertebrate development. These animal models allow for further investigation of the mechanisms of MAC, integration of various identified genes into common developmental pathways and, finally, provide an avenue for the development and testing of therapeutic interventions. PMID:26046913

Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma.

PubMed

Reis, Linda M; Semina, Elena V

2015-06-01

The human eye is a complex organ whose development requires extraordinary coordination of developmental processes. The conservation of ocular developmental steps in vertebrates suggests possible common genetic mechanisms. Genetic diseases involving the eye represent a leading cause of blindness in children and adults. During the last decades, there has been an exponential increase in genetic studies of ocular disorders. In this review, we summarize current success in identification of genes responsible for microphthalmia, anophthalmia, and coloboma (MAC) phenotypes, which are associated with early defects in embryonic eye development. Studies in animal models for the orthologous genes identified overlapping phenotypes for most factors, confirming the conservation of their function in vertebrate development. These animal models allow for further investigation of the mechanisms of MAC, integration of various identified genes into common developmental pathways and finally, provide an avenue for the development and testing of therapeutic interventions. © 2015 Wiley Periodicals, Inc.

Systems genetics for drug target discovery

PubMed Central

Penrod, Nadia M.; Cowper-Sal_lari, Richard; Moore, Jason H.

2011-01-01

The collection and analysis of genomic data has the potential to reveal novel druggable targets by providing insight into the genetic basis of disease. However, the number of drugs, targeting new molecular entities, approved by the US Food and Drug Administration (FDA) has not increased in the years since the collection of genomic data has become commonplace. The paucity of translatable results can be partly attributed to conventional analysis methods that test one gene at a time in an effort to identify disease-associated factors as candidate drug targets. By disengaging genetic factors from their position within the genetic regulatory system, much of the information stored within the genomic data set is lost. Here we discuss how genomic data is used to identify disease-associated genes or genomic regions, how disease-associated regions are validated as functional targets, and the role network analysis can play in bridging the gap between data generation and effective drug target identification. PMID:21862141

Clinical and Mechanistic Insights into the Genetics of Cardiomyopathy

PubMed Central

Burke, Michael A.; Cook, Stuart A.; Seidman, Jonathan G.; Seidman, Christine E.

2018-01-01

Over the last quarter-century, there has been tremendous progress in genetics research that has defined molecular causes for cardiomyopathies. More than a thousand mutations have been identified in many genes with varying ontologies, therein indicating the diverse molecules and pathways that cause hypertrophic, dilated, restrictive, and arrhythmogenic cardiomyopathies. Translation of this research to the clinic via genetic testing can precisely group affected patients according to molecular etiology, and identify individuals without evidence of disease who are at high risk for developing cardiomyopathy. These advances provide insights into the earliest manifestations of cardiomyopathy and help to define the molecular pathophysiological basis for cardiac remodeling. Although these efforts remain incomplete, new genomic technologies and analytic strategies provide unparalleled opportunities to fully explore the genetic architecture of cardiomyopathies. Such data hold the promise that mutation-specific pathophysiology will uncover novel therapeutic targets, and herald the beginning of precision therapy for cardiomyopathy patients. PMID:28007147

The role of disease characteristics in the ethical debate on personal genome testing.

PubMed

Bunnik, Eline M; Schermer, Maartje Hn; Janssens, A Cecile J W

2012-01-19

Companies are currently marketing personal genome tests directly-to-consumer that provide genetic susceptibility testing for a range of multifactorial diseases simultaneously. As these tests comprise multiple risk analyses for multiple diseases, they may be difficult to evaluate. Insight into morally relevant differences between diseases will assist researchers, healthcare professionals, policy-makers and other stakeholders in the ethical evaluation of personal genome tests. In this paper, we identify and discuss four disease characteristics--severity, actionability, age of onset, and the somatic/psychiatric nature of disease--and show how these lead to specific ethical issues. By way of illustration, we apply this framework to genetic susceptibility testing for three diseases: type 2 diabetes, age-related macular degeneration and clinical depression. For these three diseases, we point out the ethical issues that are relevant to the question whether it is morally justifiable to offer genetic susceptibility testing to adults or to children or minors, and on what conditions. We conclude that the ethical evaluation of personal genome tests is challenging, for the ethical issues differ with the diseases tested for. An understanding of the ethical significance of disease characteristics will improve the ethical, legal and societal debate on personal genome testing.

Polygenic risk accelerates the developmental progression to heavy, persistent smoking and nicotine dependence: Evidence from a 4-Decade Longitudinal Study

PubMed Central

Moffitt, Terrie E; Baker, Timothy B; Biddle, Andrea K; Evans, James P; Harrington, HonaLee; Houts, Renate; Meier, Madeline; Sugden, Karen; Williams, Benjamin; Poulton, Richie; Caspi, Avshalom

2013-01-01

OBJECTIVE To test how genomic loci identified in genome-wide association studies (GWAS) influence the developmental progression of smoking behavior. DESIGN A 38-year prospective longitudinal study of a representative birth-cohort. SETTING The Dunedin Multidisciplinary Health and Development Study, New Zealand. PARTICIPANTS N=1037 male and female study members. MAIN EXPOSURES We assessed genetic risk with a multi-locus genetic risk score (GRS). The GRS was composed of single-nucleotide polymorphisms identified in three meta-analyses of GWAS of smoking quantity phenotypes. OUTCOME MEASURES Smoking initiation, conversion to daily smoking, progression to heavy smoking, nicotine dependence (Fagerstrom Test of Nicotine Dependence), and cessation difficulties were evaluated at eight assessments spanning ages 11-38 years. RESULTS Genetic risk score was unrelated to smoking initiation. However, individuals at higher genetic risk were more likely to convert to daily smoking as teenagers, progressed more rapidly from smoking initiation to heavy smoking, persisted longer in smoking heavily, developed nicotine dependence more frequently, were more reliant on smoking to cope with stress, and were more likely to fail in their cessation attempts. Further analysis revealed that two adolescent developmental phenotypes—early conversion to daily smoking and rapid progression to heavy smoking--mediated associations between the genetic risk score and mature phenotypes of persistent heavy smoking, nicotine dependence, and cessation failure. The genetic risk score predicted smoking risk over and above family history. CONCLUSIONS Initiatives that disrupt the developmental progression of smoking behavior among adolescents may mitigate genetic risks for developing adult smoking problems. Future genetic research may maximize discovery potential by focusing on smoking behavior soon after smoking initiation and by studying young smokers. PMID:23536134

History, geography and host use shape genomewide patterns of genetic variation in the redheaded pine sawfly (Neodiprion lecontei).

PubMed

Bagley, Robin K; Sousa, Vitor C; Niemiller, Matthew L; Linnen, Catherine R

2017-02-01

Divergent host use has long been suspected to drive population differentiation and speciation in plant-feeding insects. Evaluating the contribution of divergent host use to genetic differentiation can be difficult, however, as dispersal limitation and population structure may also influence patterns of genetic variation. In this study, we use double-digest restriction-associated DNA (ddRAD) sequencing to test the hypothesis that divergent host use contributes to genetic differentiation among populations of the redheaded pine sawfly (Neodiprion lecontei), a widespread pest that uses multiple Pinus hosts throughout its range in eastern North America. Because this species has a broad range and specializes on host plants known to have migrated extensively during the Pleistocene, we first assess overall genetic structure using model-based and model-free clustering methods and identify three geographically distinct genetic clusters. Next, using a composite-likelihood approach based on the site frequency spectrum and a novel strategy for maximizing the utility of linked RAD markers, we infer the population topology and date divergence to the Pleistocene. Based on existing knowledge of Pinus refugia, estimated demographic parameters and patterns of diversity among sawfly populations, we propose a Pleistocene divergence scenario for N. lecontei. Finally, using Mantel and partial Mantel tests, we identify a significant relationship between genetic distance and geography in all clusters, and between genetic distance and host use in two of three clusters. Overall, our results indicate that Pleistocene isolation, dispersal limitation and ecological divergence all contribute to genomewide differentiation in this species and support the hypothesis that host use is a common driver of population divergence in host-specialized insects. © 2016 John Wiley & Sons Ltd.

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

PubMed

Yurgelun, Matthew B; Allen, Brian; Kaldate, Rajesh R; Bowles, Karla R; Judkins, Thaddeus; Kaushik, Praveen; Roa, Benjamin B; Wenstrup, Richard J; Hartman, Anne-Renee; Syngal, Sapna

2015-09-01

Multigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome. We performed germline analysis with a 25-gene, next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All patients had a history of Lynch syndrome-associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain clinical significance (VUS). We also analyzed data on patients' personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing. Of the 1260 patients, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing (88%; 95% confidence interval [CI], 86%-90%). Multigene panel testing identified 114 probands with Lynch syndrome mutations (9.0%; 95% CI, 7.6%-10.8%) and 71 with mutations in other cancer predisposition genes (5.6%; 95% CI, 4.4%-7.1%). Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis (P = .0017). An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. A total of 479 individuals had 1 or more VUS (38%; 95% CI, 35%-41%). In individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many of which were unexpected based on patients' histories. Parallel sequencing also detected a high number of potentially uninformative germline findings, including VUS. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer.

PubMed

Scarbrough, Peter M; Weber, Rachel Palmieri; Iversen, Edwin S; Brhane, Yonathan; Amos, Christopher I; Kraft, Peter; Hung, Rayjean J; Sellers, Thomas A; Witte, John S; Pharoah, Paul; Henderson, Brian E; Gruber, Stephen B; Hunter, David J; Garber, Judy E; Joshi, Amit D; McDonnell, Kevin; Easton, Doug F; Eeles, Ros; Kote-Jarai, Zsofia; Muir, Kenneth; Doherty, Jennifer A; Schildkraut, Joellen M

2016-01-01

DNA damage is an established mediator of carcinogenesis, although genome-wide association studies (GWAS) have identified few significant loci. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility. We conducted a cross-cancer analysis of 60,297 single nucleotide polymorphisms, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Because of the unavailability of individual data, data were analyzed at the aggregate level. Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling. We identified three susceptibility DNA repair genes, RAD51B (P < 5.09 × 10(-6)), MSH5 (P < 5.09 × 10(-6)), and BRCA2 (P = 5.70 × 10(-6)). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways. Only three susceptibility loci were identified, which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways. Results suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria. ©2015 American Association for Cancer Research.

Genetic diversity analysis of cultivated and wild grapevine (Vitis vinifera L.) accessions around the Mediterranean basin and Central Asia.

PubMed

Riaz, Summaira; De Lorenzis, Gabriella; Velasco, Dianne; Koehmstedt, Anne; Maghradze, David; Bobokashvili, Zviad; Musayev, Mirza; Zdunic, Goran; Laucou, Valerie; Andrew Walker, M; Failla, Osvaldo; Preece, John E; Aradhya, Mallikarjuna; Arroyo-Garcia, Rosa

2018-06-27

The mountainous region between the Caucasus and China is considered to be the center of domestication for grapevine. Despite the importance of Central Asia in the history of grape growing, information about the extent and distribution of grape genetic variation in this region is limited in comparison to wild and cultivated grapevines from around the Mediterranean basin. The principal goal of this work was to survey the genetic diversity and relationships among wild and cultivated grape germplasm from the Caucasus, Central Asia, and the Mediterranean basin collectively to understand gene flow, possible domestication events and adaptive introgression. A total of 1378 wild and cultivated grapevines collected around the Mediterranean basin and from Central Asia were tested with a set of 20 nuclear SSR markers. Genetic data were analyzed (Cluster analysis, Principal Coordinate Analysis and STRUCTURE) to identify groups, and the results were validated by Nei's genetic distance, pairwise F ST analysis and assignment tests. All of these analyses identified three genetic groups: G1, wild accessions from Croatia, France, Italy and Spain; G2, wild accessions from Armenia, Azerbaijan and Georgia; and G3, cultivars from Spain, France, Italy, Georgia, Iran, Pakistan and Turkmenistan, which included a small group of wild accessions from Georgia and Croatia. Wild accessions from Georgia clustered with cultivated grape from the same area (proles pontica), but also with Western Europe (proles occidentalis), supporting Georgia as the ancient center of grapevine domestication. In addition, cluster analysis indicated that Western European wild grapes grouped with cultivated grapes from the same area, suggesting that the cultivated proles occidentalis contributed more to the early development of wine grapes than the wild vines from Eastern Europe. The analysis of genetic relationships among the tested genotypes provided evidence of genetic relationships between wild and cultivated accessions in the Mediterranean basin and Central Asia. The genetic structure indicated a considerable amount of gene flow, which limited the differentiation between the two subspecies. The results also indicated that grapes with mixed ancestry occur in the regions where wild grapevines were domesticated.

Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia.

PubMed

Wen, Wei Xiong; Allen, Jamie; Lai, Kah Nyin; Mariapun, Shivaani; Hasan, Siti Norhidayu; Ng, Pei Sze; Lee, Daphne Shin-Chi; Lee, Sheau Yee; Yoon, Sook-Yee; Lim, Joanna; Lau, Shao Yan; Decker, Brennan; Pooley, Karen; Dorling, Leila; Luccarini, Craig; Baynes, Caroline; Conroy, Don M; Harrington, Patricia; Simard, Jacques; Yip, Cheng Har; Mohd Taib, Nur Aishah; Ho, Weang Kee; Antoniou, Antonis C; Dunning, Alison M; Easton, Douglas F; Teo, Soo Hwang

2018-02-01

Genetic testing for BRCA1 and BRCA2 is offered typically to selected women based on age of onset and family history of cancer. However, current internationally accepted genetic testing referral guidelines are built mostly on data from cancer genetics clinics in women of European descent. To evaluate the appropriateness of such guidelines in Asians, we have determined the prevalence of germ line variants in an unselected cohort of Asian patients with breast cancer and healthy controls. Germ line DNA from a hospital-based study of 2575 unselected patients with breast cancer and 2809 healthy controls were subjected to amplicon-based targeted sequencing of exonic and proximal splice site junction regions of BRCA1 and BRCA2 using the Fluidigm Access Array system, with sequencing conducted on a Illumina HiSeq2500 platform. Variant calling was performed with GATK UnifiedGenotyper and were validated by Sanger sequencing. Fifty-five (2.1%) BRCA1 and 66 (2.6%) BRCA2 deleterious mutations were identified among patients with breast cancer and five (0.18%) BRCA1 and six (0.21%) BRCA2 mutations among controls. One thousand one hundred and eighty-six (46%) patients and 97 (80%) carriers fulfilled the National Comprehensive Cancer Network guidelines for genetic testing. Five per cent of unselected Asian patients with breast cancer carry deleterious variants in BRCA1 or BRCA2 . While current referral guidelines identified the majority of carriers, one in two patients would be referred for genetic services. Given that such services are largely unavailable in majority of low-resource settings in Asia, our study highlights the need for more efficient guidelines to identify at-risk individuals in Asia. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Diagnosis of Fanconi Anemia: Mutation Analysis by Multiplex Ligation-Dependent Probe Amplification and PCR-Based Sanger Sequencing

PubMed Central

Gille, Johan J. P.; Floor, Karijn; Kerkhoven, Lianne; Ameziane, Najim; Joenje, Hans; de Winter, Johan P.

2012-01-01

Fanconi anemia (FA) is a rare inherited disease characterized by developmental defects, short stature, bone marrow failure, and a high risk of malignancies. FA is heterogeneous: 15 genetic subtypes have been distinguished so far. A clinical diagnosis of FA needs to be confirmed by testing cells for sensitivity to cross-linking agents in a chromosomal breakage test. As a second step, DNA testing can be employed to elucidate the genetic subtype of the patient and to identify the familial mutations. This knowledge allows preimplantation genetic diagnosis (PGD) and enables prenatal DNA testing in future pregnancies. Although simultaneous testing of all FA genes by next generation sequencing will be possible in the near future, this technique will not be available immediately for all laboratories. In addition, in populations with strong founder mutations, a limited test using Sanger sequencing and MLPA will be a cost-effective alternative. We describe a strategy and optimized conditions for the screening of FANCA, FANCB, FANCC, FANCE, FANCF, and FANCG and present the results obtained in a cohort of 54 patients referred to our diagnostic service since 2008. In addition, the follow up with respect to genetic counseling and carrier screening in the families is discussed. PMID:22778927

Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy.

PubMed

Shaw, Kaitlyn; Amstutz, Ursula; Kim, Richard B; Lesko, Lawrence J; Turgeon, Jacques; Michaud, Veronique; Hwang, Soomi; Ito, Shinya; Ross, Colin; Carleton, Bruce C

2015-08-01

To systematically review evidence on genetic variants influencing outcomes during warfarin therapy and provide practice recommendations addressing the key questions: (1) Should genetic testing be performed in patients with an indication for warfarin therapy to improve achievement of stable anticoagulation and reduce adverse effects? (2) Are there subgroups of patients who may benefit more from genetic testing compared with others? (3) How should patients with an indication for warfarin therapy be managed based on their genetic test results? A systematic literature search was performed for VKORC1 and CYP2C9 and their association with warfarin therapy. Evidence was critically appraised, and clinical practice recommendations were developed based on expert group consensus. Testing of VKORC1 (-1639G>A), CYP2C9*2, and CYP2C9*3 should be considered for all patients, including pediatric patients, within the first 2 weeks of therapy or after a bleeding event. Testing for CYP2C9*5, *6, *8, or *11 and CYP4F2 (V433M) is currently not recommended. Testing should also be considered for all patients who are at increased risk of bleeding complications, who consistently show out-of-range international normalized ratios, or suffer adverse events while receiving warfarin. Genotyping results should be interpreted using a pharmacogenetic dosing algorithm to estimate the required dose. This review provides the latest update on genetic markers for warfarin therapy, clinical practice recommendations as a basis for informed decision making regarding the use of genotype-guided dosing in patients with an indication for warfarin therapy, and identifies knowledge gaps to guide future research.

A probabilistic method for testing and estimating selection differences between populations.

PubMed

He, Yungang; Wang, Minxian; Huang, Xin; Li, Ran; Xu, Hongyang; Xu, Shuhua; Jin, Li

2015-12-01

Human populations around the world encounter various environmental challenges and, consequently, develop genetic adaptations to different selection forces. Identifying the differences in natural selection between populations is critical for understanding the roles of specific genetic variants in evolutionary adaptation. Although numerous methods have been developed to detect genetic loci under recent directional selection, a probabilistic solution for testing and quantifying selection differences between populations is lacking. Here we report the development of a probabilistic method for testing and estimating selection differences between populations. By use of a probabilistic model of genetic drift and selection, we showed that logarithm odds ratios of allele frequencies provide estimates of the differences in selection coefficients between populations. The estimates approximate a normal distribution, and variance can be estimated using genome-wide variants. This allows us to quantify differences in selection coefficients and to determine the confidence intervals of the estimate. Our work also revealed the link between genetic association testing and hypothesis testing of selection differences. It therefore supplies a solution for hypothesis testing of selection differences. This method was applied to a genome-wide data analysis of Han and Tibetan populations. The results confirmed that both the EPAS1 and EGLN1 genes are under statistically different selection in Han and Tibetan populations. We further estimated differences in the selection coefficients for genetic variants involved in melanin formation and determined their confidence intervals between continental population groups. Application of the method to empirical data demonstrated the outstanding capability of this novel approach for testing and quantifying differences in natural selection. © 2015 He et al.; Published by Cold Spring Harbor Laboratory Press.

Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications.

PubMed

Girolami, Francesca; Frisso, Giulia; Benelli, Matteo; Crotti, Lia; Iascone, Maria; Mango, Ruggiero; Mazzaccara, Cristina; Pilichou, Kalliope; Arbustini, Eloisa; Tomberli, Benedetta; Limongelli, Giuseppe; Basso, Cristina; Olivotto, Iacopo

2018-01-01

: Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype-phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, 'real-world' experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines.

Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications

PubMed Central

Girolami, Francesca; Frisso, Giulia; Benelli, Matteo; Crotti, Lia; Iascone, Maria; Mango, Ruggiero; Mazzaccara, Cristina; Pilichou, Kalliope; Arbustini, Eloisa; Tomberli, Benedetta; Limongelli, Giuseppe; Basso, Cristina; Olivotto, Iacopo

2018-01-01

Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype–phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, ‘real-world’ experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines. PMID:29176389

Personal Factors Associated with Reported Benefits of Huntington Disease Family History or Genetic Testing

PubMed Central

Williams, Janet K.; Erwin, Cheryl; Juhl, Andrew; Mills, James; Brossman, Bradley

2010-01-01

Aims: A family history of Huntington disease (HD) or receiving results of HD predictive genetic testing can influence individual well-being, family relationships, and social interactions in positive and negative ways. The aim of this study was to examine benefits reported by people with an HD family history or those who have undergone predictive HD testing, as well as the personal variables associated with perceived benefits. Methods: Seventy-four of 433 people completing the International Response of a Sample Population to HD risk (I-RESPOND-HD) survey reported benefits. Knowledge and understanding was perceived as the most common benefit from participants in both groups. The next most frequent perceived benefits from a family history were connecting with others and achieving life meaning and insights. The next most common perceived benefits from genetic testing were life planning and social support. The least common perceived benefit for both groups was renewed hope and optimism. Older age and spirituality were significantly associated with benefits in both groups. Conclusions: Perceptions of benefit may not be as likely until later years in people with prodromal HD. A developed sense of spirituality is identified as a personal resource associated with the perception of benefit from genetic testing for HD. Associations among spirituality, perceived benefits, and other indicators of personal and family well-being may be useful in genetic counseling and health care of people with prodromal HD. PMID:20722493

National Estimates of Genetic Testing in Women With a History of Breast or Ovarian Cancer.

PubMed

Childers, Christopher P; Childers, Kimberly K; Maggard-Gibbons, Melinda; Macinko, James

2017-12-01

Purpose In the United States, 3.8 million women have a history of breast (BC) or ovarian cancer (OC). Up to 15% of cases are attributable to heritable mutations, which, if identified, provide critical knowledge for treatment and preventive care. It is unknown how many patients who are at high risk for these mutations have not been tested and how rates vary by risk criteria. Methods We used pooled cross-sectional data from three Cancer Control Modules (2005, 2010, 2015) of the National Health Interview Survey, a national in-person household interview survey. Eligible patients were adult females with a history of BC and/or OC meeting select 2017 National Comprehensive Cancer Network eligibility criteria on the basis of age of diagnosis and family history. Outcomes included the proportion of individuals reporting a history of discussing genetic testing with a health professional, being advised to undergo genetic testing, or undergoing genetic testing for BC or OC. Results Of 47,218 women, 2.7% had a BC history and 0.4% had an OC history. For BC, 35.6% met one or more select eligibility criteria; of those, 29.0% discussed, 20.2% were advised to undergo, and 15.3% underwent genetic testing. Testing rates for individual eligibility criteria ranged from 6.2% (relative with OC) to 18.2% (diagnosis ≤ 45 years of age). For OC, 15.1% discussed, 13.1% were advised to undergo, and 10.5% underwent testing. Using only four BC eligibility criteria and all patients with OC, an estimated 1.2 to 1.3 million individuals failed to receive testing. Conclusion Fewer than one in five individuals with a history of BC or OC meeting select National Cancer Comprehensive Network criteria have undergone genetic testing. Most have never discussed testing with a health care provider. Large national efforts are warranted to address this unmet need.

Genetic basis of arrhythmogenic cardiomyopathy.

PubMed

Karmouch, Jennifer; Protonotarios, Alexandros; Syrris, Petros

2018-05-01

To date 16 genes have been associated with arrhythmogenic cardiomyopathy (ACM). Mutations in these genes can lead to a broad spectrum of phenotypic expression ranging from disease affecting predominantly the right or left ventricle, to biventricular subtypes. Understanding the genetic causes of ACM is important in diagnosis and management of the disorder. This review summarizes recent advances in molecular genetics and discusses the application of next-generation sequencing technology in genetic testing in ACM. Use of next-generation sequencing methods has resulted in the identification of novel causative variants and genes for ACM. The involvement of filamin C in ACM demonstrates the genetic overlap between ACM and other types of cardiomyopathy. Putative pathogenic variants have been detected in cadherin 2 gene, a protein involved in cell adhesion. Large genomic rearrangements in desmosome genes have been systematically investigated in a cohort of ACM patients. Recent studies have identified novel causes of ACM providing new insights into the genetic spectrum of the disease and highlighting an overlapping phenotype between ACM and dilated cardiomyopathy. Next-generation sequencing is a useful tool for research and genetic diagnostic screening but interpretation of identified sequence variants requires caution and should be performed in specialized centres.

Neurocognitive Endophenotypes for Bipolar Disorder Identified in Multiplex Multigenerational Families

PubMed Central

Glahn, David C.; Almasy, Laura; Barguil, Marcela; Hare, Elizabeth; Peralta, Juan Manuel; Kent, Jack W.; Dassori, Alabana; Contreras, Javier; Pacheco, Adriana; Lanzagorta, Nuria; Nicolini, Humberto; Raventós, Henriette; Escamilla, Michael A.

2012-01-01

Context Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, one strategy for identifying risk genes is the use of quantitative endophenotypes. Objective The goal of the current study is to adjudicate neurocognitive endophenotypes for bipolar disorder. Design, Setting, and Participants 709 Latino individuals from the central valley of Costa Rica, Mexico City, Mexico, or San Antonio, Texas participated in the study. 660 of these persons were members of extended pedigrees with at least two siblings diagnosed with bipolar disorder (n=230). The remaining subjects were community controls drawn from each site and without personal or family history of bipolar disorder or schizophrenia. All subjects received psychodiagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which tests are impaired in affected individuals, sensitive to genetic liability for the illness and genetically correlated with affection status. Main Outcome Measures The main outcome measure was neurocognitive test performance. Results Two of the 21 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 of these cognitive measures compared to non-related healthy subjects. Non-bipolar first-degree relatives were impaired on five of these and three tests were genetically correlated with affection status: digit symbol coding, object delayed response, and immediate facial memory. Conclusions This large-scale extended pedigree study of cognitive functioning in bipolar disorder identified measures of processing speed, working memory and declarative (facial) memory as candidate endophenotypes for bipolar disorder. PMID:20124116

Contribution of Large Region Joint Associations to Complex Traits Genetics

PubMed Central

Paré, Guillaume; Asma, Senay; Deng, Wei Q.

2015-01-01

A polygenic model of inheritance, whereby hundreds or thousands of weakly associated variants contribute to a trait’s heritability, has been proposed to underlie the genetic architecture of complex traits. However, relatively few genetic variants have been positively identified so far and they collectively explain only a small fraction of the predicted heritability. We hypothesized that joint association of multiple weakly associated variants over large chromosomal regions contributes to complex traits variance. Confirmation of such regional associations can help identify new loci and lead to a better understanding of known ones. To test this hypothesis, we first characterized the ability of commonly used genetic association models to identify large region joint associations. Through theoretical derivation and simulation, we showed that multivariate linear models where multiple SNPs are included as independent predictors have the most favorable association profile. Based on these results, we tested for large region association with height in 3,740 European participants from the Health and Retirement Study (HRS) study. Adjusting for SNPs with known association with height, we demonstrated clustering of weak associations (p = 2x10-4) in regions extending up to 433.0 Kb from known height loci. The contribution of regional associations to phenotypic variance was estimated at 0.172 (95% CI 0.063-0.279; p < 0.001), which compared favorably to 0.129 explained by known height variants. Conversely, we showed that suggestively associated regions are enriched for known height loci. To extend our findings to other traits, we also tested BMI, HDLc and CRP for large region associations, with consistent results for CRP. Our results demonstrate the presence of large region joint associations and suggest these can be used to pinpoint weakly associated SNPs. PMID:25856144

Genetic Misdiagnoses and the Potential for Health Disparities.

PubMed

Manrai, Arjun K; Funke, Birgit H; Rehm, Heidi L; Olesen, Morten S; Maron, Bradley A; Szolovits, Peter; Margulies, David M; Loscalzo, Joseph; Kohane, Isaac S

2016-08-18

For more than a decade, risk stratification for hypertrophic cardiomyopathy has been enhanced by targeted genetic testing. Using sequencing results, clinicians routinely assess the risk of hypertrophic cardiomyopathy in a patient's relatives and diagnose the condition in patients who have ambiguous clinical presentations. However, the benefits of genetic testing come with the risk that variants may be misclassified. Using publicly accessible exome data, we identified variants that have previously been considered causal in hypertrophic cardiomyopathy and that are overrepresented in the general population. We studied these variants in diverse populations and reevaluated their initial ascertainments in the medical literature. We reviewed patient records at a leading genetic-testing laboratory for occurrences of these variants during the near-decade-long history of the laboratory. Multiple patients, all of whom were of African or unspecified ancestry, received positive reports, with variants misclassified as pathogenic on the basis of the understanding at the time of testing. Subsequently, all reported variants were recategorized as benign. The mutations that were most common in the general population were significantly more common among black Americans than among white Americans (P<0.001). Simulations showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications. We identified methodologic shortcomings that contributed to these errors in the medical literature. The misclassification of benign variants as pathogenic that we found in our study shows the need for sequencing the genomes of diverse populations, both in asymptomatic controls and the tested patient population. These results expand on current guidelines, which recommend the use of ancestry-matched controls to interpret variants. As additional populations of different ancestry backgrounds are sequenced, we expect variant reclassifications to increase, particularly for ancestry groups that have historically been less well studied. (Funded by the National Institutes of Health.).

Eliciting preferences for priority setting in genetic testing: a pilot study comparing best-worst scaling and discrete-choice experiments.

PubMed

Severin, Franziska; Schmidtke, Jörg; Mühlbacher, Axel; Rogowski, Wolf H

2013-11-01

Given the increasing number of genetic tests available, decisions have to be made on how to allocate limited health-care resources to them. Different criteria have been proposed to guide priority setting. However, their relative importance is unclear. Discrete-choice experiments (DCEs) and best-worst scaling experiments (BWSs) are methods used to identify and weight various criteria that influence orders of priority. This study tests whether these preference eliciting techniques can be used for prioritising genetic tests and compares the empirical findings resulting from these two approaches. Pilot DCE and BWS questionnaires were developed for the same criteria: prevalence, severity, clinical utility, alternatives to genetic testing available, infrastructure for testing and care established, and urgency of care. Interview-style experiments were carried out among different genetics professionals (mainly clinical geneticists, researchers and biologists). A total of 31 respondents completed the DCE and 26 completed the BWS experiment. Weights for the levels of the six attributes were estimated by conditional logit models. Although the results derived from the DCE and BWS experiments differed in detail, we found similar valuation patterns in the DCE and BWS experiments. The respondents attached greatest value to tests with high clinical utility (defined by the availability of treatments that reduce mortality and morbidity) and to testing for highly prevalent conditions. The findings from this study exemplify how decision makers can use quantitative preference eliciting methods to measure aggregated preferences in order to prioritise alternative clinical interventions. Further research is necessary to confirm the survey results.

Validation of Version 3.0 of the Breast Cancer Genetics Referral Screening Tool (B-RST™).

PubMed

Bellcross, Cecelia; Hermstad, April; Tallo, Christine; Stanislaw, Christine

2018-05-08

Despite increased awareness of hereditary breast and ovarian cancer among clinicians and the public, many BRCA1/2 mutation carriers remain unaware of their risk status. The Breast Cancer Genetics Referral Screening Tool (B-RST™) was created and validated to easily identify individuals at increased risk for hereditary breast and ovarian cancer for referral to cancer genetics services. The purpose of this study was to revise B-RST™ to maximize sensitivity against BRCA1/2 mutation status. We analyzed pedigrees of 277 individuals who had undergone BRCA1/2 testing to determine modifications to the B-RST™ 2.0 algorithm that would maximize sensitivity for mutations, while maintaining simplicity. We used McNemar's chi-square test to compare validation measures between the revised version (3.0) and the 2.0 version. Algorithmic changes made to B-RST™ 2.0 increased the sensitivity against BRCA1/2 mutation analysis from 71.1 to 94.0% (P < 0.0001). While specificity decreased, all screen-positive individuals were appropriate for cancer genetics referral, the primary purpose of the tool. Despite calls for BRCA1/2 population screening, there remains a critical need to identify those most at risk who should receive cancer genetics services. B-RST™ version 3.0 demonstrates high sensitivity for BRCA1/2 mutations, yet remains a simple and quick screening tool for at-risk individuals.

Antagonistic Pleiotropy at the Human "IL6" Promoter Confers Genetic Resilience to the Pro-Inflammatory Effects of Adverse Social Conditions in Adolescence

ERIC Educational Resources Information Center

Cole, Steven W.; Arevalo, Jesusa M. G.; Manu, Kavya; Telzer, Eva H.; Kiang, Lisa; Bower, Julienne E.; Irwin, Michael R.; Fuligni, Andrew J.

2011-01-01

The authors tested the evolutionary genetic hypothesis that the functional form of an asymmetrically risky Gene x Environment interaction will differ as a function of age-related antagonistic pleiotropy (i.e., show opposite effects in young vs. old individuals). Previous studies have identified a polymorphism in the human "IL6" promoter…

The micropolitics of responsibility vis-à-vis autonomy: parental accounts of childhood genetic testing and (non)disclosure.

PubMed

Arribas-Ayllon, Michael; Sarangi, Srikant; Clarke, Angus

2008-03-01

Genetic testing and (non)disclosure of genetic information present ethical and moral dilemmas for the management of parental responsibility vis-à-vis the child's autonomy. Ethical guidelines aimed at professionals currently seek to defer childhood testing where there is no clear medical or psychosocial benefit. This version of autonomy is derived from a bioethical paradigm which brackets the individual rights and capacities of the child. In this paper we focus on situated parental accounts of responsibility/autonomy to understand the complex forms of relational work -i.e. the micropolitics of balancing rights and responsibilities - involving a range of inherited genetic disorders. Interviews (n= 20) were conducted with parents whose genetic condition may have had consequences for their children. Using rhetorical discourse analysis, we show how parents draw upon a number of rhetorical/discoursal devices to produce accounts where genetic responsibility is actually or potentially transmitted to the child. We identify three kinds of accounting practice: (1) aligned responsibility; (2) deferred responsibility; and (3) misaligned responsibility. Each of these practices demonstrates how parents position themselves responsibly by foregrounding figures and events onto which the child's autonomy is selectively mapped. Rather than simple representations, we regard these accounts as complex moral performances that seek alignment with broader bioethical discourses.

Detection of genetic variants affecting cattle behaviour and their impact on milk production: a genome-wide association study.

PubMed

Friedrich, Juliane; Brand, Bodo; Ponsuksili, Siriluck; Graunke, Katharina L; Langbein, Jan; Knaust, Jacqueline; Kühn, Christa; Schwerin, Manfred

2016-02-01

Behaviour traits of cattle have been reported to affect important production traits, such as meat quality and milk performance as well as reproduction and health. Genetic predisposition is, together with environmental stimuli, undoubtedly involved in the development of behaviour phenotypes. Underlying molecular mechanisms affecting behaviour in general and behaviour and productions traits in particular still have to be studied in detail. Therefore, we performed a genome-wide association study in an F2 Charolais × German Holstein cross-breed population to identify genetic variants that affect behaviour-related traits assessed in an open-field and novel-object test and analysed their putative impact on milk performance. Of 37,201 tested single nucleotide polymorphism (SNPs), four showed a genome-wide and 37 a chromosome-wide significant association with behaviour traits assessed in both tests. Nine of the SNPs that were associated with behaviour traits likewise showed a nominal significant association with milk performance traits. On chromosomes 14 and 29, six SNPs were identified to be associated with exploratory behaviour and inactivity during the novel-object test as well as with milk yield traits. Least squares means for behaviour and milk performance traits for these SNPs revealed that genotypes associated with higher inactivity and less exploratory behaviour promote higher milk yields. Whether these results are due to molecular mechanisms simultaneously affecting behaviour and milk performance or due to a behaviour predisposition, which causes indirect effects on milk performance by influencing individual reactivity, needs further investigation. © 2015 Stichting International Foundation for Animal Genetics.

BRCA1 genetic mutation and its link to ovarian cancer: implications for advanced practice nurses.

PubMed

Brunsvold, Amy N; Wung, Shu-Fen; Merkle, Carrie J

2005-12-01

The purpose of this paper is to review (a) the linkage between the BRCA1 gene and ovarian cancer and (b) BRCA1 testing and its related issues. This review is aimed for nurse practitioners (NPs), who may be in positions to identify those at risk for BRCA1-associated ovarian cancer and to assist patients with related issues. Data sources include reviews and original research from scholarly journals and Internet sites. Ovarian cancer is a deadly disease. Identification of those at risk because of BRCA1 mutation is possible through genetic testing. Testing for BRCA1 gene mutations has many implications whether results are positive or negative. Those with positive results will be faced with decisions regarding the best management strategies. Negative results do not completely eliminate ovarian cancer risk. Current management options for carriers of the BRCA1 mutation include taking no action, increasing surveillance for ovarian cancer, and chemoprevention with oral contraceptives or prophylactic oophorectomy for those who have completed childbearing. It is essential that NPs have knowledge underlying the issues and concerns of patients and their families at risk for BRCA1-associated ovarian cancer. NPs are in a unique position to help identify BRCA1 mutation carriers and to assist them and their families with the complex issues involving genetic testing and management options. Understanding these issues will allow NPs to give appropriate care that may include making appropriate referrals to certified genetic counselors and having balanced discussions on treatment options. Such measurements may improve early diagnosis of ovarian cancer and increase survival from this disease.

The effect of genetic test-based risk information on behavioral outcomes: A critical examination of failed trials and a call to action.

PubMed

Austin, Jehannine

2015-12-01

Encouraging individuals at risk for common complex disease like heart disease, cancer, and diabetes to adopt lifestyle changes (e.g., smoking cessation, exercise, proper nutrition, increased screening) could be powerful public health tools to decrease the enormous personal and economic burden of these conditions. Theoretically, genetic risk information appears to be a compelling tool that could be used to provoke at-risk individuals to adopt these lifestyle changes. Unfortunately, however, numerous studies now have shown that providing individuals with genetic test-based risk information has little to no impact on their behavior. In this article (a commentary not a systematic review), the failed trials in which genetic information has been used as a tool to induce behavior change will be critically examined in order to identify new and potentially more effective ways forward. © 2015 Wiley Periodicals, Inc.

Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype.

PubMed

Cooper-Knock, Johnathan; Robins, Henry; Niedermoser, Isabell; Wyles, Matthew; Heath, Paul R; Higginbottom, Adrian; Walsh, Theresa; Kazoka, Mbombe; Ince, Paul G; Hautbergue, Guillaume M; McDermott, Christopher J; Kirby, Janine; Shaw, Pamela J

2017-01-01

Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72 . We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes ( n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72 . We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies ( p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression ( t -test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course ( t -test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.

Developing genetic competency in undergraduate nursing students through the context of human disease and the constructivist framework

NASA Astrophysics Data System (ADS)

Tribble, Leta Meole

Nowhere is the influence of genetics more extensively seen than in medicine. More precise diagnostic testing, prevention methods, and risk counseling have resulted from recent decades of genetics research, including the Human Genome Project (HGP). The expansion in genetics knowledge and related technologies will drive a major paradigm shift from diagnosis and treatment to preventive medicine. Resulting from this predicted shift are educational challenges for healthcare professionals including both physicians and nurses. The largest group of healthcare providers is registered professional nurses whose work allows a unique and holistic view of patients and families, often caring for patients throughout the life span. Nurses need to understand basic genetic concepts including the role of genes in common diseases, to identify individuals at risk through the collection of informed family histories, to provide information about genetic testing and informed consent, and to know when and how to make appropriate referrals to genetic specialists. The purpose of this study was to expand the clinical application and use of genetic principles in patient management and care. To do this, a survey of South Carolina nursing educators from twenty two nursing programs was conducted to determine the extent of genetic content in the curriculum. The second part of the study was teaching a semester course in human genetics to undergraduate nursing students, a need identified in the literature review and supported by results of the nursing programs survey. Through the use of clinical case studies, PBL activities, and "shrink wrapped" lectures, all congruent with the constructivist viewpoint of learning, student's objective post-intervention measurements indicated significant improvement in content knowledge with an effect size of 1.6 and significant improvement in their ability to analyze and draw the family history in a pedigree format. An attitudinal tool used to assess student preferences of teaching approaches indicated preference for all three constructivist methods over traditional lecture.

Professional challenges in cancer genetic testing: who is the patient?

PubMed

Chan-Smutko, Gayun; Patel, Devanshi; Shannon, Kristen M; Ryan, Paula D

2008-03-01

In the genetic counseling setting, the health care provider can be challenged by opposing duties to members of the same family: protecting the privacy of the patient identified with a gene mutation and the ethical obligation to warn at-risk relatives. In a situation of nondisclosure between members of a family with a known disease-predisposing mutation, this type of dilemma can present in acute form for the provider who cares for different members of the family. This can hinder effective medical decision making. To minimize this effect, we recommend detailed pretest genetic counseling steps to empower the patient to communicate with their at-risk relatives their intent to pursue testing and willingness to share information. In addition, post-test counseling should reiterate the implications of a positive result for at-risk relatives and conclude with a written summary that patients can share with their family.

Genetics of coronary artery disease: discovery, biology and clinical translation

PubMed Central

Khera, Amit V.; Kathiresan, Sekar

2018-01-01

Coronary artery disease is the leading global cause of mortality. Long recognized to be heritable, recent advances have started to unravel the genetic architecture of the disease. Common variant association studies have linked about 60 genetic loci to coronary risk. Large-scale gene sequencing efforts and functional studies have facilitated a better understanding of causal risk factors, elucidated underlying biology and informed the development of new therapeutics. Moving forward, genetic testing could enable precision medicine approaches, by identifying subgroups of patients at increased risk of CAD or those with a specific driving pathophysiology in whom a therapeutic or preventive approach is most useful. PMID:28286336

Clinical characterization and mutation spectrum in Hispanic families with adenomatous polyposis syndromes.

PubMed

Cruz-Correa, Marcia; Diaz-Algorri, Yaritza; Mendez, Vanessa; Vazquez, Pedro Juan; Lozada, Maria Eugenia; Freyre, Katerina; Lathroum, Liselle; Gonzalez-Pons, Maria; Hernandez-Marrero, Jessica; Giardiello, Francis; Rodriguez-Quilichini, Segundo

2013-09-01

Several genetically defined hereditary colorectal cancer (CRC) syndromes are associated with colonic polyposis including familial adenomatous polyposis (FAP) and MUTYH adenomatous polyposis (MAP). Limited data exists on the clinical characterization and genotypic spectrum of polyposis syndromes among Hispanics. To describe the phenotype and genotype of Puerto Rican Hispanic patients with FAP and MUTYH and compare with other ethnic and racial groups. Probands were identified from the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). Recruited individuals completed risk factors, medical, and family history questionnaires and underwent genetic testing for genotype analysis. Frequency analysis, Chi square, Fisher's exact and Wilcoxon rank-sum tests were used for statistical analysis methods. A total of 31 FAP (from 19 families) and 13 MAP (from 13 families) Hispanic patients recruited from the PURIFICAR were evaluated. Among the FAP cases, mean age at diagnosis was 27.6 (range 9-71 years); 67.7 % cases had more than 100 polyps and 41.9 % had upper gastrointestinal polyps. Among the 19 FAP families, there were 77 affected FAP individuals and 26 colorectal cancer cases. Genetic mutations were available for 42.2 % of FAP families; all mutations identified were unique. Surgeries were reported in 31 cases; 14 (45.2 %) prophylactic surgeries and 6 (19.4 %) therapeutic surgeries for management of CRC. Among MAP cases, mean age at diagnosis was 53 (range 34-76 years). Genetic analysis revealed homozygous biallelic mutations (G382D) in 53.8 %, compound heterozygous mutations (G382/Y165C) in 23 %, and non-G382/Y165C monoallelic mutations in 23 %. Familial cancer registries should be promoted as vehicles for detection, education and follow up of families at-risk of acquiring familial cancers. PURIFICAR is the first and only familial cancer registry in Puerto Rico providing these services to families affected with familial cancer syndromes promoting education, testing and surveillance of at-risk family members, and focusing on cancer prevention efforts. The fact that only 40 % of FAP patients had access to genetic testing stresses the need to promote the establishment of policies supporting genetic testing coverage by medical insurance companies in order to provide patients with the highest standard of care to prevent cancer. Furthermore, our results suggest that Hispanics may have uncommon mutations in adenomatous polyposis related genes, which emphasize the need for full gene sequencing to establish genetic diagnosis.

Genetic characterization of Spinocerebellar ataxia 1 in a South Indian cohort.

PubMed

Kumaran, Dhanya; Balagopal, Krishnan; Tharmaraj, Reginald George Alex; Aaron, Sanjith; George, Kuryan; Muliyil, Jayaprakash; Sivadasan, Ajith; Danda, Sumita; Alexander, Mathew; Hasan, Gaiti

2014-10-25

Spinocerebellar ataxia type 1 (SCA1) is a late onset autosomal dominant cerebellar ataxia, caused by CAG triplet repeat expansion in the ATXN1 gene. The frequency of SCA1 occurrence is more in Southern India than in other regions as observed from hospital-based studies. However there are no reports on variability of CAG repeat expansion, phenotype-genotype association and founder mutations in a homogenous population from India. Genomic DNA isolated from buccal mouthwash of the individuals in the cohort was used for PCR-based diagnosis of SCA1. Subsequently SNP's found within the ATXN1 loci were identified by Taqman allelic discrimination assays. Significance testing of the genotype-phenotype associations was calculated by Kruskal-Wallis ANOVA test with post-hoc Dunnett's test and Pearson's correlation coefficient. By genetic analysis of an affected population in Southern India we identified 21 pre-symptomatic individuals including four that were well past the average age of disease onset of 44 years, 16 symptomatic and 63 normal individuals. All pre-symptomatic cases harbor "pure" expansions of greater than 40 CAGs. Genotyping to test for the presence of two previously identified SNPs showed a founder effect of the same repeat carrying allele as in the general Indian population. We show that SCA1 disease onset is significantly delayed when transmission of the disease is maternal. Our finding of early disease onset in individuals with a paternally inherited allele could serve as valuable information for clinicians towards early detection of SCA1 in patients with affected fathers. Identification of older pre-symptomatic individuals (n = 4) in our cohort among individuals with a shared genetic and environmental background, suggests that second site genetic or epigenetic modifiers might significantly affect SCA1 disease progression. Moreover, such undetected SCA1 cases could underscore the true prevalence of SCA1 in India.

Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol.

PubMed

Meric-Bernstam, F; Brusco, L; Daniels, M; Wathoo, C; Bailey, A M; Strong, L; Shaw, K; Lu, K; Qi, Y; Zhao, H; Lara-Guerra, H; Litton, J; Arun, B; Eterovic, A K; Aytac, U; Routbort, M; Subbiah, V; Janku, F; Davies, M A; Kopetz, S; Mendelsohn, J; Mills, G B; Chen, K

2016-05-01

Next-generation sequencing in cancer research may reveal germline variants of clinical significance. We report patient preferences for return of results and the prevalence of incidental pathogenic germline variants (PGVs). Targeted exome sequencing of 202 genes was carried out in 1000 advanced cancers using tumor and normal DNA in a research laboratory. Pathogenic variants in 18 genes, recommended for return by The American College of Medical Genetics and Genomics, as well as PALB2, were considered actionable. Patient preferences of return of incidental germline results were collected. Return of results was initiated with genetic counseling and repeat CLIA testing. Of the 1000 patients who underwent sequencing, 43 had likely PGVs: APC (1), BRCA1 (11), BRCA2 (10), TP53 (10), MSH2 (1), MSH6 (4), PALB2 (2), PTEN (2), TSC2 (1), and RB1 (1). Twenty (47%) of 43 variants were previously known based on clinical genetic testing. Of the 1167 patients who consented for a germline testing protocol, 1157 (99%) desired to be informed of incidental results. Twenty-three previously unrecognized mutations identified in the research environment were confirmed with an orthogonal CLIA platform. All patients approached decided to proceed with formal genetic counseling; in all cases where formal genetic testing was carried out, the germline variant of concern validated with clinical genetic testing. In this series, 2.3% patients had previously unrecognized pathogenic germline mutations in 19 cancer-related genes. Thus, genomic sequencing must be accompanied by a plan for return of germline results, in partnership with genetic counseling. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Value of genetic profiling for the prediction of coronary heart disease.

PubMed

van der Net, Jeroen B; Janssens, A Cecile J W; Sijbrands, Eric J G; Steyerberg, Ewout W

2009-07-01

Advances in high-throughput genomics facilitate the identification of novel genetic susceptibility variants for coronary heart disease (CHD). This may improve CHD risk prediction. The aim of the present simulation study was to investigate to what degree CHD risk can be predicted by testing multiple genetic variants (genetic profiling). We simulated genetic profiles for a population of 100,000 individuals with a 10-year CHD incidence of 10%. For each combination of model parameters (number of variants, genotype frequency and odds ratio [OR]), we calculated the area under the receiver operating characteristic curve (AUC) to indicate the discrimination between individuals who will and will not develop CHD. The AUC of genetic profiles could rise to 0.90 when 100 hypothetical variants with ORs of 1.5 and genotype frequencies of 50% were simulated. The AUC of a genetic profile consisting of 10 established variants, with ORs ranging from 1.13 to 1.42, was 0.59. When 2, 5, and 10 times as many identical variants would be identified, the AUCs were 0.63, 0.69, and 0.76. To obtain AUCs similar to those of conventional CHD risk predictors, a considerable number of additional common genetic variants need to be identified with preferably strong effects.

Genetic homogeneity of the invasive lionfish across the Northwestern Atlantic and the Gulf of Mexico based on Single Nucleotide Polymorphisms.

PubMed

Pérez-Portela, R; Bumford, A; Coffman, B; Wedelich, S; Davenport, M; Fogg, A; Swenarton, M K; Coleman, F; Johnston, M A; Crawford, D L; Oleksiak, M F

2018-03-22

Despite the devastating impact of the lionfish (Pterois volitans) invasion on NW Atlantic ecosystems, little genetic information about the invasion process is available. We applied Genotyping by Sequencing techniques to identify 1,220 single nucleotide polymorphic sites (SNPs) from 162 lionfish samples collected between 2013 and 2015 from two areas chronologically identified as the first and last invaded areas in US waters: the east coast of Florida and the Gulf of Mexico. We used population genomic analyses, including phylogenetic reconstruction, Bayesian clustering, genetic distances, Discriminant Analyses of Principal Components, and coalescence simulations for detection of outlier SNPs, to understand genetic trends relevant to the lionfish's long-term persistence. We found no significant differences in genetic structure or diversity between the two areas (F ST p-values > 0.01, and t-test p-values > 0.05). In fact, our genomic analyses showed genetic homogeneity, with enough gene flow between the east coast of Florida and Gulf of Mexico to erase previous signals of genetic divergence detected between these areas, secondary spreading, and bottlenecks in the Gulf of Mexico. These findings suggest rapid genetic changes over space and time during the invasion, resulting in one panmictic population with no signs of divergence between areas due to local adaptation.

Modeling of genetic gain for single traits from marker-assisted seedling selection in clonally propagated crops

PubMed Central

Ru, Sushan; Hardner, Craig; Carter, Patrick A; Evans, Kate; Main, Dorrie; Peace, Cameron

2016-01-01

Seedling selection identifies superior seedlings as candidate cultivars based on predicted genetic potential for traits of interest. Traditionally, genetic potential is determined by phenotypic evaluation. With the availability of DNA tests for some agronomically important traits, breeders have the opportunity to include DNA information in their seedling selection operations—known as marker-assisted seedling selection. A major challenge in deploying marker-assisted seedling selection in clonally propagated crops is a lack of knowledge in genetic gain achievable from alternative strategies. Existing models based on additive effects considering seed-propagated crops are not directly relevant for seedling selection of clonally propagated crops, as clonal propagation captures all genetic effects, not just additive. This study modeled genetic gain from traditional and various marker-based seedling selection strategies on a single trait basis through analytical derivation and stochastic simulation, based on a generalized seedling selection scheme of clonally propagated crops. Various trait-test scenarios with a range of broad-sense heritability and proportion of genotypic variance explained by DNA markers were simulated for two populations with different segregation patterns. Both derived and simulated results indicated that marker-based strategies tended to achieve higher genetic gain than phenotypic seedling selection for a trait where the proportion of genotypic variance explained by marker information was greater than the broad-sense heritability. Results from this study provides guidance in optimizing genetic gain from seedling selection for single traits where DNA tests providing marker information are available. PMID:27148453

Precision medicine: does ethnicity information complement genotype-based prescribing decisions?

PubMed Central

Shah, Rashmi R.; Gaedigk, Andrea

2017-01-01

Inter-ethnic differences in drug response are all too well known. These are underpinned by a number of factors, including pharmacogenetic differences across various ethnic populations. Precision medicine relies on genotype-based prescribing decisions with the aim of maximizing efficacy and mitigating the risks. When there is no access to genotyping tests, ethnicity is frequently regarded as a proxy of the patient’s probable genotype on the basis of overall population-based frequency of genetic variations in the ethnic group the patient belongs to, with some variations being ethnicity-specific. However, ever-increasing transcontinental migration of populations and the resulting admixing of populations have undermined the utility of self-identified ethnicity in predicting the genetic ancestry, and therefore the genotype, of the patient. An example of the relevance of genetic ancestry of a patient is the inadequate performance of European-derived pharmacogenetic dosing algorithms of warfarin in African Americans, Brazilians and Caribbean Hispanics. Consequently, genotyping a patient potentially requires testing for all known clinically actionable variants that the patient may harbour, and new variants that are likely to be identified using state-of the art next-generation sequencing-based methods. Furthermore, self-identified ethnicity is associated with a number of ethnicity-related attributes and non-genetic factors that potentially influence the risk of phenoconversion (genotype–phenotype discordance), which may adversely impact the success of genotype-based prescribing decisions. Therefore, while genotype-based prescribing decisions are important in implementing precision medicine, ethnicity should not be disregarded. PMID:29318005

Meta-analysis of gene-level tests for rare variant association.

PubMed

Liu, Dajiang J; Peloso, Gina M; Zhan, Xiaowei; Holmen, Oddgeir L; Zawistowski, Matthew; Feng, Shuang; Nikpay, Majid; Auer, Paul L; Goel, Anuj; Zhang, He; Peters, Ulrike; Farrall, Martin; Orho-Melander, Marju; Kooperberg, Charles; McPherson, Ruth; Watkins, Hugh; Willer, Cristen J; Hveem, Kristian; Melander, Olle; Kathiresan, Sekar; Abecasis, Gonçalo R

2014-02-01

The majority of reported complex disease associations for common genetic variants have been identified through meta-analysis, a powerful approach that enables the use of large sample sizes while protecting against common artifacts due to population structure and repeated small-sample analyses sharing individual-level data. As the focus of genetic association studies shifts to rare variants, genes and other functional units are becoming the focus of analysis. Here we propose and evaluate new approaches for performing meta-analysis of rare variant association tests, including burden tests, weighted burden tests, variable-threshold tests and tests that allow variants with opposite effects to be grouped together. We show that our approach retains useful features from single-variant meta-analysis approaches and demonstrate its use in a study of blood lipid levels in ∼18,500 individuals genotyped with exome arrays.

Genetic counselors' views and experiences with the clinical integration of genome sequencing.

PubMed

Machini, Kalotina; Douglas, Jessica; Braxton, Alicia; Tsipis, Judith; Kramer, Kate

2014-08-01

In recent years, new sequencing technologies known as next generation sequencing (NGS) have provided scientists the ability to rapidly sequence all known coding as well as non-coding sequences in the human genome. As the two emerging approaches, whole exome (WES) and whole genome (WGS) sequencing, have started to be integrated in the clinical arena, we sought to survey health care professionals who are likely to be involved in the implementation process now and/or in the future (e.g., genetic counselors, geneticists and nurse practitioners). Two hundred twenty-one genetic counselors- one third of whom currently offer WES/WGS-participated in an anonymous online survey. The aims of the survey were first, to identify barriers to the implementation of WES/WGS, as perceived by survey participants; second, to provide the first systematic report of current practices regarding the integration of WES/WGS in clinic and/or research across the US and Canada and to illuminate the roles and challenges of genetic counselors participating in this process; and third to evaluate the impact of WES/WGS on patient care. Our results showed that genetic counseling practices with respect to WES/WGS are consistent with the criteria set forth in the ACMG 2012 policy statement, which highlights indications for testing, reporting, and pre/post test considerations. Our respondents described challenges related to offering WES/WGS, which included billing issues, the duration and content of the consent process, result interpretation and disclosure of incidental findings and variants of unknown significance. In addition, respondents indicated that specialty area (i.e., prenatal and cancer), lack of clinical utility of WES/WGS and concerns about interpretation of test results were factors that prevented them from offering this technology to patients. Finally, study participants identified the aspects of their professional training which have been most beneficial in aiding with the integration of WES/WGS into the clinical setting (molecular/clinical genetics, counseling and bioethics) and suggested that counseling aids (to assist them when explaining aspects of these tests to patients) and webinars focused on WES/WGS (for genetic counselors and other health care professionals) would be useful educational tools. Future research should permit us to further enhance our knowledge of pitfalls and benefits associated with the introduction of these powerful technologies in patient care and to further explore the roles and opportunities for genetic counselors in this rapidly evolving field.

Metabologenomics of Phaeochromocytoma and Paraganglioma: An Integrated Approach for Personalised Biochemical and Genetic Testing

PubMed Central

Eisenhofer, Graeme; Klink, Barbara; Richter, Susan; Lenders, Jacques WM; Robledo, Mercedes

2017-01-01

The tremendous advances over the past two decades in both clinical genetics and biochemical testing of chromaffin cell tumours have led to new considerations about how these aspects of laboratory medicine can be integrated to improve diagnosis and management of affected patients. With germline mutations in 15 genes now identified to be responsible for over a third of all cases of phaeochromocytomas and paragangliomas, these tumours are recognised to have one of the richest hereditary backgrounds among all neoplasms. Depending on the mutation, tumours show distinct differences in metabolic pathways that relate to or even directly impact clinical presentation. At the same time, there has been improved understanding about how catecholamines are synthesised, stored, secreted and metabolised by chromaffin cell tumours. Although the tumours may not always secrete catecholamines it has become clear that almost all continuously produce and metabolise catecholamines. This has not only fuelled changes in laboratory medicine, but has also assisted in recognition of genotype-biochemical phenotype relationships important for diagnostics and clinical care. In particular, differences in catecholamine and energy pathway metabolomes can guide genetic testing, assist with test interpretation and provide predictions about the nature, behaviour and imaging characteristics of the tumours. Conversely, results of genetic testing are important for guiding how routine biochemical testing should be employed and interpreted in surveillance programmes for at-risk patients. In these ways there are emerging needs for modern laboratory medicine to seamlessly integrate biochemical and genetic testing into the diagnosis and management of patients with chromaffin cell tumours. PMID:29332973

Gene panel testing for hereditary breast cancer.

PubMed

Winship, Ingrid; Southey, Melissa C

2016-03-21

Inherited predisposition to breast cancer is explained only in part by mutations in the BRCA1 and BRCA2 genes. Most families with an apparent familial clustering of breast cancer who are investigated through Australia's network of genetic services and familial cancer centres do not have mutations in either of these genes. More recently, additional breast cancer predisposition genes, such as PALB2, have been identified. New genetic technology allows a panel of multiple genes to be tested for mutations in a single test. This enables more women and their families to have risk assessment and risk management, in a preventive approach to predictable breast cancer. Predictive testing for a known family-specific mutation in a breast cancer predisposition gene provides personalised risk assessment and evidence-based risk management. Breast cancer predisposition gene panel tests have a greater diagnostic yield than conventional testing of only the BRCA1 and BRCA2 genes. The clinical validity and utility of some of the putative breast cancer predisposition genes is not yet clear. Ethical issues warrant consideration, as multiple gene panel testing has the potential to identify secondary findings not originally sought by the test requested. Multiple gene panel tests may provide an affordable and effective way to investigate the heritability of breast cancer.

Genetic determinants of leucocyte telomere length in children: a neglected and challenging field.

PubMed

Stathopoulou, Maria G; Petrelis, Alexandros M; Buxton, Jessica L; Froguel, Philippe; Blakemore, Alexandra I F; Visvikis-Siest, Sophie

2015-03-01

Telomere length is associated with a large range of human diseases. Genome-wide association studies (GWAS) have identified genetic variants that are associated with leucocyte telomere length (LTL). However, these studies are limited to adult populations. Nevertheless, childhood is a crucial period for the determination of LTL, and the assessment of age-specific genetic determinants, although neglected, could be of great importance. Our aim was to provide insights and preliminary results on genetic determinants of LTL in children. Healthy children (n = 322, age range = 6.75-17 years) with available GWAS data (Illumina Human CNV370-Duo array) were included. The LTL was measured using multiplex quantitative real-time polymerase chain reaction. Linear regression models adjusted for age, gender, parental age at child's birth, and body mass index were used to test the associations of LTL with polymorphisms identified in adult GWAS and to perform a discovery-only GWAS. The previously GWAS-identified variants in adults were not associated with LTL in our paediatric sample. This lack of association was not due to possible interactions with age or gene × gene interactions. Furthermore, a discovery-only GWAS approach demonstrated six novel variants that reached the level of suggestive association (P ≤ 5 × 10(-5)) and explain a high percentage of children's LTL. The study of genetic determinants of LTL in children may identify novel variants not previously identified in adults. Studies in large-scale children populations are needed for the confirmation of these results, possibly through a childhood consortium that could better handle the methodological challenges of LTL genetic epidemiology field. © 2015 John Wiley & Sons Ltd.

Variable approaches to genetic counseling for microarray regions of homozygosity associated with parental relatedness.

PubMed

Grote, Lauren; Myers, Melanie; Lovell, Anne; Saal, Howard; Sund, Kristen Lipscomb

2014-01-01

SNP microarrays are capable of detecting regions of homozygosity (ROH) which can suggest parental relatedness. This study was designed to describe pre- and post-test counseling practices of genetics professionals regarding ROH, explore perceived comfort and ethical concerns in the follow-up of such results, demonstrate awareness of laws surrounding duty to report consanguinity and incest, and allow respondents to share their personal experiences with results suggesting a parental relationship. A 35 question survey was administered to 240 genetic counselors and geneticists who had ordered or counseled for SNP microarray. The results are presented using descriptive statistics. There was variation in both pre- and post-test counseling practices of genetics professionals. Twenty-five percent of respondents reported pre-test counseling that ROH can indicate parental relatedness. The most commonly reported ethical concern was disclosure of findings suggesting parental relatedness to parents of the patient; only 48.4% reported disclosing parental relatedness when indicated. Fifty-seven percent felt comfortable receiving results suggesting parental consanguinity while 17% felt comfortable receiving results suggesting parental incest. Twenty percent of respondents were extremely/moderately familiar with the laws about duty to report incest. Personal experiences in post-test counseling included both parental acknowledgement and denial of relatedness. This study highlights the differences in genetics professionals' pre- and post-test counseling practices, comfort, and experiences surrounding parental relatedness suggested by SNP microarray results. It identifies a need for professional organizations to offer guidance to genetics professionals about how to respond to and counsel for molecular results suggesting parental consanguinity or incest. © 2013 Wiley Periodicals, Inc.

Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients.

PubMed

Jóri, Balazs; Kamps, Rick; Xanthoulea, Sofia; Delvoux, Bert; Blok, Marinus J; Van de Vijver, Koen K; de Koning, Bart; Oei, Felicia Trups; Tops, Carli M; Speel, Ernst Jm; Kruitwagen, Roy F; Gomez-Garcia, Encarna B; Romano, Andrea

2015-12-01

The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer. A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis. A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype. A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.

Multilocus Phylogeography of the Treefrog Scinax eurydice (Anura, Hylidae) Reveals a Plio-Pleistocene Diversification in the Atlantic Forest.

PubMed

Menezes, Lucas; Canedo, Clarissa; Batalha-Filho, Henrique; Garda, Adrian Antonio; Gehara, Marcelo; Napoli, Marcelo Felgueiras

2016-01-01

We aim to evaluate the genetic structure of an Atlantic Forest amphibian species, Scinax eurydice, testing the congruence among patterns identified and proposed by the literature for Pleistocene refugia, microrefugia, and geographic barriers to gene flow such as major rivers. Furthermore, we aim to evaluate predictions of such barriers and refugia on the genetic structure of the species, such as presence/absence of dispersal, timing since separation, and population expansions/contractions. We sequenced mitochondrial and nuclear genetic markers on 94 tissue samples from 41 localities. We inferred a gene tree and estimated genetic distances using mtDNA sequences. We then ran population clustering and assignment methods, AMOVA, and estimated migration rates among populations identified through mtDNA and nDNA analyses. We used a dated species tree, skyline plots, and summary statistics to evaluate concordance between population's distributions and geographic barriers and Pleistocene refugia. Scinax eurydice showed high mtDNA divergences and four clearly distinct mtDNA lineages. Species tree and population assignment tests supported the existence of two major clades corresponding to northeastern and southeastern Atlantic Forest in Brazil, each one composed of two other clades. Lineage splitting events occurred from late Pliocene to Pleistocene. We identified demographic expansions in two clades, and inexistent to low levels of migrations among different populations. Genetic patterns and demographic data support the existence of two northern Refuge and corroborate microrefugia south of the Doce/Jequitinhonha Rivers biogeographic divide. The results agree with a scenario of recent demographic expansion of lowland taxa. Scinax eurydice comprises a species complex, harboring undescribed taxa consistent with Pleistocene refugia. Two rivers lie at the boundaries among populations and endorse their role as secondary barriers to gene flow.

Multilocus Phylogeography of the Treefrog Scinax eurydice (Anura, Hylidae) Reveals a Plio-Pleistocene Diversification in the Atlantic Forest

PubMed Central

Menezes, Lucas; Canedo, Clarissa; Batalha-Filho, Henrique; Garda, Adrian Antonio; Gehara, Marcelo; Napoli, Marcelo Felgueiras

2016-01-01

We aim to evaluate the genetic structure of an Atlantic Forest amphibian species, Scinax eurydice, testing the congruence among patterns identified and proposed by the literature for Pleistocene refugia, microrefugia, and geographic barriers to gene flow such as major rivers. Furthermore, we aim to evaluate predictions of such barriers and refugia on the genetic structure of the species, such as presence/absence of dispersal, timing since separation, and population expansions/contractions. We sequenced mitochondrial and nuclear genetic markers on 94 tissue samples from 41 localities. We inferred a gene tree and estimated genetic distances using mtDNA sequences. We then ran population clustering and assignment methods, AMOVA, and estimated migration rates among populations identified through mtDNA and nDNA analyses. We used a dated species tree, skyline plots, and summary statistics to evaluate concordance between population’s distributions and geographic barriers and Pleistocene refugia. Scinax eurydice showed high mtDNA divergences and four clearly distinct mtDNA lineages. Species tree and population assignment tests supported the existence of two major clades corresponding to northeastern and southeastern Atlantic Forest in Brazil, each one composed of two other clades. Lineage splitting events occurred from late Pliocene to Pleistocene. We identified demographic expansions in two clades, and inexistent to low levels of migrations among different populations. Genetic patterns and demographic data support the existence of two northern Refuge and corroborate microrefugia south of the Doce/Jequitinhonha Rivers biogeographic divide. The results agree with a scenario of recent demographic expansion of lowland taxa. Scinax eurydice comprises a species complex, harboring undescribed taxa consistent with Pleistocene refugia. Two rivers lie at the boundaries among populations and endorse their role as secondary barriers to gene flow. PMID:27248688

Inherited behavioral susceptibility to adiposity in infancy: a multivariate genetic analysis of appetite and weight in the Gemini birth cohort.

PubMed

Llewellyn, Clare H; van Jaarsveld, Cornelia H M; Plomin, Robert; Fisher, Abigail; Wardle, Jane

2012-03-01

The behavioral susceptibility model proposes that inherited differences in traits such as appetite confer differential risk of weight gain and contribute to the heritability of weight. Evidence that the FTO gene may influence weight partly through its effects on appetite supports this model, but testing the behavioral pathways for multiple genes with very small effects is not feasible. Twin analyses make it possible to get a broad-based estimate of the extent of shared genetic influence between appetite and weight. The objective was to use multivariate twin analyses to test the hypothesis that associations between appetite and weight are underpinned by shared genetic effects. Data were from Gemini, a population-based birth cohort of twins (n = 4804) born in 2007. Infant weights at 3 mo were taken from the records of health professionals. Appetite was assessed at 3 mo for the milk-feeding period by using the Baby Eating Behaviour Questionnaire (BEBQ), a parent-reported measure of appetite [enjoyment of food, food responsiveness, slowness in eating (SE), satiety responsiveness (SR), and appetite size (AS)]. Multivariate quantitative genetic modeling was used to test for shared genetic influences. Significant correlations were found between all BEBQ traits and weight. Significant shared genetic influence was identified for weight with SE, SR, and AS; genetic correlations were between 0.22 and 0.37. Shared genetic effects explained 41-45% of these phenotypic associations. Differences in weight in infancy may be due partly to genetically determined differences in appetitive traits that confer differential susceptibility to obesogenic environments.

Genome-Wide Association Analysis to Identify Loci for Milk Yield in Gyr Breed

USDA-ARS?s Scientific Manuscript database

A genome scan was conducted to identify QTL affecting milk yield in a Brazilian Gyr population of progeny test bulls (N=319). Data used in this study was derived from traditional genetic evaluation records computed by the Embrapa Dairy Cattleand released in May/2009 (http://www.cnpgl.embrapa.br/nova...

Gene flow in complex landscapes: Testing multiple hypotheses with causal modeling

Treesearch

Samuel A. Cushman; Kevin S. McKelvey; Jim Hayden; Michael K. Schwartz

2006-01-01

Predicting population-level effects of landscape change depends on identifying factors that influence population connectivity in complex landscapes. However, most putative movement corridors and barriers have not been based on empirical data. In this study, we identify factors that influence connectivity by comparing patterns of genetic similarity among 146 black bears...

Whole-genome association studies of alcoholism with loci linked to schizophrenia susceptibility.

PubMed

Namkung, Junghyun; Kim, Youngchul; Park, Taesung

2005-12-30

Alcoholism is a complex disease. There have been many reports on significant comorbidity between alcoholism and schizophrenia. For the genetic study of complex diseases, association analysis has been recommended because of its higher power than that of the linkage analysis for detecting genes with modest effects on disease. To identify alcoholism susceptibility loci, we performed genome-wide single-nucleotide polymorphisms (SNP) association tests, which yielded 489 significant SNPs at the 1% significance level. The association tests showed that tsc0593964 (P-value 0.000013) on chromosome 7 was most significantly associated with alcoholism. From 489 SNPs, 74 genes were identified. Among these genes, GABRA1 is a member of the same gene family with GABRA2 that was recently reported as alcoholism susceptibility gene. By comparing 74 genes to the published results of various linkage studies of schizophrenia, we identified 13 alcoholism associated genes that were located in the regions reported to be linked to schizophrenia. These 13 identified genes can be important candidate genes to study the genetic mechanism of co-occurrence of both diseases.

A practical guide to environmental association analysis in landscape genomics.

PubMed

Rellstab, Christian; Gugerli, Felix; Eckert, Andrew J; Hancock, Angela M; Holderegger, Rolf

2015-09-01

Landscape genomics is an emerging research field that aims to identify the environmental factors that shape adaptive genetic variation and the gene variants that drive local adaptation. Its development has been facilitated by next-generation sequencing, which allows for screening thousands to millions of single nucleotide polymorphisms in many individuals and populations at reasonable costs. In parallel, data sets describing environmental factors have greatly improved and increasingly become publicly accessible. Accordingly, numerous analytical methods for environmental association studies have been developed. Environmental association analysis identifies genetic variants associated with particular environmental factors and has the potential to uncover adaptive patterns that are not discovered by traditional tests for the detection of outlier loci based on population genetic differentiation. We review methods for conducting environmental association analysis including categorical tests, logistic regressions, matrix correlations, general linear models and mixed effects models. We discuss the advantages and disadvantages of different approaches, provide a list of dedicated software packages and their specific properties, and stress the importance of incorporating neutral genetic structure in the analysis. We also touch on additional important aspects such as sampling design, environmental data preparation, pooled and reduced-representation sequencing, candidate-gene approaches, linearity of allele-environment associations and the combination of environmental association analyses with traditional outlier detection tests. We conclude by summarizing expected future directions in the field, such as the extension of statistical approaches, environmental association analysis for ecological gene annotation, and the need for replication and post hoc validation studies. © 2015 John Wiley & Sons Ltd.

Genetic Testing of Maturity-Onset Diabetes of the Young Current Status and Future Perspectives

PubMed Central

Firdous, Parveena; Nissar, Kamran; Ali, Sajad; Ganai, Bashir Ahmad; Shabir, Uzma; Hassan, Toyeeba; Masoodi, Shariq Rashid

2018-01-01

Diabetes is a global epidemic problem growing exponentially in Asian countries posing a serious threat. Among diabetes, maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders that occurs due to β cell dysfunction. Genetic defects in the pancreatic β-cells result in the decrease of insulin production required for glucose utilization thereby lead to early-onset diabetes (often <25 years). It is generally considered as non-insulin dependent form of diabetes and comprises of 1–5% of total diabetes. Till date, 14 genes have been identified and mutation in them may lead to MODY. Different genetic testing methodologies like linkage analysis, restriction fragment length polymorphism, and DNA sequencing are used for the accurate and correct investigation of gene mutations associated with MODY. The next-generation sequencing has emerged as one of the most promising and effective tools to identify novel mutated genes related to MODY. Diagnosis of MODY is mainly relying on the sequential screening of the three marker genes like hepatocyte nuclear factor 1 alpha (HNF1α), hepatocyte nuclear factor 4 alpha (HNF4α), and glucokinase (GCK). Interestingly, MODY patients can be managed by diet alone for many years and may also require minimal doses of sulfonylureas. The primary objective of this article is to provide a review on current status of MODY, its prevalence, genetic testing/diagnosis, possible treatment, and future perspective. PMID:29867778

Genetics in primary health care and the National Policy on Comprehensive Care for People with Rare Diseases in Brazil: opportunities and challenges for professional education.

PubMed

Melo, Débora Gusmão; de Paula, Pamela Karen; de Araujo Rodrigues, Stephania; da Silva de Avó, Lucimar Retto; Germano, Carla Maria Ramos; Demarzo, Marcelo Marcos Piva

2015-07-01

As discoveries regarding the genetic contribution to disease have grown rapidly, health care professionals are expected to incorporate genetic and genomic perspectives into health education and practice. Genetic competencies common to all health professionals have been identified by the US National Coalition for Health Professional Education in Genetics (NCHPEG), which defined the knowledge, skills, and attitudes required to achieve these competencies. The aim of this study is to analyze genetic competencies of primary health care professionals in Brazil. It is a descriptive survey study, whereby doctors, nurses, and dentists were invited to participate by answering a questionnaire including 11 issues based on competencies established by the NCHPEG. Data were presented as percentages. Differences between groups of participants were assessed by the Fisher exact test, with the level of significance set at p < 0.05. Results showed that concerning knowledge, about 80 % of the participants recognized basic genetics terminology, but practitioners had difficulty in identifying patterns of inheritance. Regarding clinical skills, practitioners were able to recognize facial dysmorphias and identify situations where referral of patients to specialists was necessary. Nevertheless, there were challenges in the process of valuing and gathering information about family history. Regarding attitudes, 68.9 % of the participants thought about the comprehensiveness of care but faced challenges in counselling parents. The results of this study may contribute to developing an ongoing education program for primary health care professionals, leading to a strategy to overcome the challenges of including genetics in the Brazilian Unified Health System.

Deleterious BRCA1/2 mutations in an urban population of Black women

PubMed Central

Smith, Karen Lisa; Stein, Julie; DeMarco, Tiffani; Wang, Yiru; Wang, Hongkun; Fries, Melissa; Peshkin, Beth N.; Isaacs, Claudine

2018-01-01

Information on the prevalence of deleterious BRCA1 and BRCA2 (BRCA1/2) mutations in clinic-based populations of Black women is limited. In order to address this gap, we performed a retrospective study to determine the prevalence of deleterious BRCA1/2 mutations, predictors of having a mutation, and acceptance of risk-reducing surgeries in Black women. In an urban unselected clinic-based population, we evaluated 211 self-identified Black women who underwent genetic counseling for hereditary breast–ovarian cancer syndrome. BRCA1/2 mutations were identified in 13.4 % of the participants who received genetic testing. Younger age at diagnosis, higher BRCA-PRO score, significant family history, and diagnosis of triple-negative breast cancer were associated with identification of a BRCA1/2 mutation. Of the affected patients found to have a deleterious mutation, almost half underwent prophylactic measures. In our study population, 1 in 7 Black women who underwent genetic testing harbored a deleterious BRCA1/2 mutation independent of age at diagnosis or family history. PMID:26250392

Influence of Genetic Counseling Graduate Program Websites on Student Application Decisions.

PubMed

Ivan, Kristina M; Hassed, Susan; Darden, Alix G; Aston, Christopher E; Guy, Carrie

2017-12-01

This study investigated how genetic counseling educational program websites affect application decisions via an online survey sent to current students and recent graduates. Program leadership: directors, assistant directors, associate directors, were also surveyed to determine where their opinions coincided or differed from those reported by students and recent graduates. Chi square analysis and t-tests were used to determine significance of results. A two-sample t-test was used to compare factors students identified as important on a 5-point Likert scale with those identified by directors. Thematic analysis revealed three major themes students consider important for program websites: easy navigation, website content, and website impression. Directors were interested in how prospective students use their program website and what information they found most useful. Students indicated there were specific programs they chose not to apply to due to the difficulty of using the website for that program. Directors significantly underestimated how important information about application requirements was to students in making application decisions. The information reported herein will help individual genetic counseling graduate programs improve website functionality and retain interested applicants.

Adaptive divergence despite strong genetic drift: genomic analysis of the evolutionary mechanisms causing genetic differentiation in the island fox (Urocyon littoralis)

PubMed Central

FUNK, W. CHRIS; LOVICH, ROBERT E.; HOHENLOHE, PAUL A.; HOFMAN, COURTNEY A.; MORRISON, SCOTT A.; SILLETT, T. SCOTT; GHALAMBOR, CAMERON K.; MALDONADO, JESUS E.; RICK, TORBEN C.; DAY, MITCH D.; POLATO, NICHOLAS R.; FITZPATRICK, SARAH W.; COONAN, TIMOTHY J.; CROOKS, KEVIN R.; DILLON, ADAM; GARCELON, DAVID K.; KING, JULIE L.; BOSER, CHRISTINA L.; GOULD, NICHOLAS; ANDELT, WILLIAM F.

2016-01-01

The evolutionary mechanisms generating the tremendous biodiversity of islands have long fascinated evolutionary biologists. Genetic drift and divergent selection are predicted to be strong on islands and both could drive population divergence and speciation. Alternatively, strong genetic drift may preclude adaptation. We conducted a genomic analysis to test the roles of genetic drift and divergent selection in causing genetic differentiation among populations of the island fox (Urocyon littoralis). This species consists of 6 subspecies, each of which occupies a different California Channel Island. Analysis of 5293 SNP loci generated using Restriction-site Associated DNA (RAD) sequencing found support for genetic drift as the dominant evolutionary mechanism driving population divergence among island fox populations. In particular, populations had exceptionally low genetic variation, small Ne (range = 2.1–89.7; median = 19.4), and significant genetic signatures of bottlenecks. Moreover, islands with the lowest genetic variation (and, by inference, the strongest historical genetic drift) were most genetically differentiated from mainland gray foxes, and vice versa, indicating genetic drift drives genome-wide divergence. Nonetheless, outlier tests identified 3.6–6.6% of loci as high FST outliers, suggesting that despite strong genetic drift, divergent selection contributes to population divergence. Patterns of similarity among populations based on high FST outliers mirrored patterns based on morphology, providing additional evidence that outliers reflect adaptive divergence. Extremely low genetic variation and small Ne in some island fox populations, particularly on San Nicolas Island, suggest that they may be vulnerable to fixation of deleterious alleles, decreased fitness, and reduced adaptive potential. PMID:26992010

Non-small cell lung cancer: current treatment and future advances

PubMed Central

Zappa, Cecilia

2016-01-01

Lung cancer has a poor prognosis; over half of people diagnosed with lung cancer die within one year of diagnosis and the 5-year survival is less than 18%. Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancer cases. Risk factors for developing NSCLC have been identified, with cigarette smoking being a major factor along with other environmental and genetic risk factors. Depending on the staging of lung cancer, patients are eligible for certain treatments ranging from surgery to radiation to chemotherapy as well as targeted therapy. With the advancement of genetics and biomarkers testing, specific mutations have been identified to better target treatment for individual patients. This review discusses current treatments including surgery, chemotherapy, radiotherapy, and immunotherapy as well as how biomarker testing has helped improve survival in patients with NSCLC. PMID:27413711

Development of a molecular diagnostic test for Retinitis Pigmentosa in the Japanese population.

PubMed

Maeda, Akiko; Yoshida, Akiko; Kawai, Kanako; Arai, Yuki; Akiba, Ryutaro; Inaba, Akira; Takagi, Seiji; Fujiki, Ryoji; Hirami, Yasuhiko; Kurimoto, Yasuo; Ohara, Osamu; Takahashi, Masayo

2018-05-21

Retinitis Pigmentosa (RP) is the most common form of inherited retinal dystrophy caused by different genetic variants. More than 60 causative genes have been identified to date. The establishment of cost-effective molecular diagnostic tests with high sensitivity and specificity can be beneficial for patients and clinicians. Here, we developed a clinical diagnostic test for RP in the Japanese population. Evaluation of diagnostic technology, Prospective, Clinical and experimental study. A panel of 39 genes reported to cause RP in Japanese patients was established. Next generation sequence (NGS) technology was applied for the analyses of 94 probands with RP and RP-related diseases. After interpretation of detected genetic variants, molecular diagnosis based on a study of the genetic variants and a clinical phenotype was made by a multidisciplinary team including clinicians, researchers and genetic counselors. NGS analyses found 14,343 variants from 94 probands. Among them, 189 variants in 83 probands (88.3% of all cases) were selected as pathogenic variants and 64 probands (68.1%) have variants which can cause diseases. After the deliberation of these 64 cases, molecular diagnosis was made in 43 probands (45.7%). The final molecular diagnostic rate with the current system combining supplemental Sanger sequencing was 47.9% (45 of 94 cases). The RP panel provides the significant advantage of detecting genetic variants with a high molecular diagnostic rate. This type of race-specific high-throughput genotyping allows us to conduct a cost-effective and clinically useful genetic diagnostic test.

Genetic testing facilitates prepubertal diagnosis of congenital hypogonadotropic hypogonadism.

PubMed

Xu, C; Lang-Muritano, M; Phan-Hug, F; Dwyer, A A; Sykiotis, G P; Cassatella, D; Acierno, J; Mohammadi, M; Pitteloud, N

2017-08-01

Neonatal micropenis and cryptorchidism raise the suspicion of congenital hypogonadotropic hypogonadism (CHH), a rare genetic disorder caused by gonadotropin-releasing hormone deficiency. Low plasma testosterone levels and low gonadotropins during minipuberty provide a clinical diagnostic clue, yet these tests are seldomly performed in general practice. We report a male neonate with no family history of reproductive disorders who was born with micropenis and cryptorchidism. Hormonal testing at age 2.5 months showed low testosterone (0.3 nmol/L) and undetectable gonadotropins (luteinizing hormone and follicle-stimulating hormone both <0.5 U/L), suggestive of CHH. Genetic testing identified a de novo, heterozygous mutation in fibroblast growth factor receptor 1 (FGFR1 p.L630P). L630 resides on the ATP binding cleft of the FGFR1 tyrosine kinase domain, and L630P is predicted to cause a complete loss of receptor function. Cell-based assays confirmed that L630P abolishes FGF8 signaling activity. Identification of a loss-of-function de novo FGFR1 mutation in this patient confirms the diagnosis of CHH, allowing for a timely hormonal treatment to induce pubertal development. Therefore, genetic testing can complement clinical and hormonal assessment for a timely diagnosis of CHH in childhood. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

No Association between Personality and Candidate Gene Polymorphisms in a Wild Bird Population

PubMed Central

Durieux, Gillian; Burke, Terry; Dugdale, Hannah L.

2015-01-01

Consistency of between-individual differences in behaviour or personality is a phenomenon in populations that can have ecological consequences and evolutionary potential. One way that behaviour can evolve is to have a genetic basis. Identifying the molecular genetic basis of personality could therefore provide insight into how and why such variation is maintained, particularly in natural populations. Previously identified candidate genes for personality in birds include the dopamine receptor D4 (DRD4), and serotonin transporter (SERT). Studies of wild bird populations have shown that exploratory and bold behaviours are associated with polymorphisms in both DRD4 and SERT. Here we tested for polymorphisms in DRD4 and SERT in the Seychelles warbler (Acrocephalus sechellensis) population on Cousin Island, Seychelles, and then investigated correlations between personality and polymorphisms in these genes. We found no genetic variation in DRD4, but identified four polymorphisms in SERT that clustered into five haplotypes. There was no correlation between bold or exploratory behaviours and SERT polymorphisms/haplotypes. The null result was not due to lack of power, and indicates that there was no association between these behaviours and variation in the candidate genes tested in this population. These null findings provide important data to facilitate representative future meta-analyses on candidate personality genes. PMID:26473495

The birds and the bees and the flowers and the trees: lessons from genetic mapping of sex determination in plants and animals.

PubMed

Charlesworth, Deborah; Mank, Judith E

2010-09-01

The ability to identify genetic markers in nonmodel systems has allowed geneticists to construct linkage maps for a diversity of species, and the sex-determining locus is often among the first to be mapped. Sex determination is an important area of study in developmental and evolutionary biology, as well as ecology. Its importance for organisms might suggest that sex determination is highly conserved. However, genetic studies have shown that sex determination mechanisms, and the genes involved, are surprisingly labile. We review studies using genetic mapping and phylogenetic inferences, which can help reveal evolutionary pattern within this lability and potentially identify the changes that have occurred among different sex determination systems. We define some of the terminology, particularly where confusion arises in writing about such a diverse range of organisms, and highlight some major differences between plants and animals, and some important similarities. We stress the importance of studying taxa suitable for testing hypotheses, and the need for phylogenetic studies directed to taxa where the patterns of changes can be most reliably inferred, if the ultimate goal of testing hypotheses regarding the selective forces that have led to changes in such an essential trait is to become feasible.

Ehlers-Danlos syndrome, classical type.

PubMed

Bowen, Jessica M; Sobey, Glenda J; Burrows, Nigel P; Colombi, Marina; Lavallee, Mark E; Malfait, Fransiska; Francomano, Clair A

2017-03-01

Classical EDS is a heritable disorder of connective tissue. Patients are affected with joint hypermobility, skin hyperextensibilty, and skin fragility leading to atrophic scarring and significant bruising. These clinical features suggest consideration of the diagnosis which then needs to be confirmed, preferably by genetic testing. The most recent criteria for the diagnosis of EDS were devised in Villefranche in 1997. [Beighton et al. (1998); Am J Med Genet 77:31-37]. The aims set out in the Villefranche Criteria were: to enable diagnostic uniformity for clinical and research purposes, to understand the natural history of each subtype of EDS, to inform management and genetic counselling, and to identify potential areas of research. The authors recognized that the criteria would need updating, but viewed the Villefranche nosology as a good starting point. Since 1997, there have been major advances in the molecular understanding of classical EDS. Previous question marks over genetic heterogeneity have been largely surpassed by evidence that abnormalities in type V collagen are the cause. Advances in molecular testing have made it possible to identify the causative mutation in the majority of patients. This has aided the further clarification of this diagnosis. The aim of this literature review is to summarize the current knowledge and highlight areas for future research. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.

PubMed

Power, Robert A; Tansey, Katherine E; Buttenschøn, Henriette Nørmølle; Cohen-Woods, Sarah; Bigdeli, Tim; Hall, Lynsey S; Kutalik, Zoltán; Lee, S Hong; Ripke, Stephan; Steinberg, Stacy; Teumer, Alexander; Viktorin, Alexander; Wray, Naomi R; Arolt, Volker; Baune, Bernard T; Boomsma, Dorret I; Børglum, Anders D; Byrne, Enda M; Castelao, Enrique; Craddock, Nick; Craig, Ian W; Dannlowski, Udo; Deary, Ian J; Degenhardt, Franziska; Forstner, Andreas J; Gordon, Scott D; Grabe, Hans J; Grove, Jakob; Hamilton, Steven P; Hayward, Caroline; Heath, Andrew C; Hocking, Lynne J; Homuth, Georg; Hottenga, Jouke J; Kloiber, Stefan; Krogh, Jesper; Landén, Mikael; Lang, Maren; Levinson, Douglas F; Lichtenstein, Paul; Lucae, Susanne; MacIntyre, Donald J; Madden, Pamela; Magnusson, Patrik K E; Martin, Nicholas G; McIntosh, Andrew M; Middeldorp, Christel M; Milaneschi, Yuri; Montgomery, Grant W; Mors, Ole; Müller-Myhsok, Bertram; Nyholt, Dale R; Oskarsson, Hogni; Owen, Michael J; Padmanabhan, Sandosh; Penninx, Brenda W J H; Pergadia, Michele L; Porteous, David J; Potash, James B; Preisig, Martin; Rivera, Margarita; Shi, Jianxin; Shyn, Stanley I; Sigurdsson, Engilbert; Smit, Johannes H; Smith, Blair H; Stefansson, Hreinn; Stefansson, Kari; Strohmaier, Jana; Sullivan, Patrick F; Thomson, Pippa; Thorgeirsson, Thorgeir E; Van der Auwera, Sandra; Weissman, Myrna M; Breen, Gerome; Lewis, Cathryn M

2017-02-15

Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease. We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10 -11 ). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Comparing population structure as inferred from genealogical versus genetic information.

PubMed

Colonna, Vincenza; Nutile, Teresa; Ferrucci, Ronald R; Fardella, Giulio; Aversano, Mario; Barbujani, Guido; Ciullo, Marina

2009-12-01

Algorithms for inferring population structure from genetic data (ie, population assignment methods) have shown to effectively recognize genetic clusters in human populations. However, their performance in identifying groups of genealogically related individuals, especially in scanty-differentiated populations, has not been tested empirically thus far. For this study, we had access to both genealogical and genetic data from two closely related, isolated villages in southern Italy. We found that nearly all living individuals were included in a single pedigree, with multiple inbreeding loops. Despite F(st) between villages being a low 0.008, genetic clustering analysis identified two clusters roughly corresponding to the two villages. Average kinship between individuals (estimated from genealogies) increased at increasing values of group membership (estimated from the genetic data), showing that the observed genetic clusters represent individuals who are more closely related to each other than to random members of the population. Further, average kinship within clusters and F(st) between clusters increases with increasingly stringent membership threshold requirements. We conclude that a limited number of genetic markers is sufficient to detect structuring, and that the results of genetic analyses faithfully mirror the structuring inferred from detailed analyses of population genealogies, even when F(st) values are low, as in the case of the two villages. We then estimate the impact of observed levels of population structure on association studies using simulated data.

Comparing population structure as inferred from genealogical versus genetic information

PubMed Central

Colonna, Vincenza; Nutile, Teresa; Ferrucci, Ronald R; Fardella, Giulio; Aversano, Mario; Barbujani, Guido; Ciullo, Marina

2009-01-01

Algorithms for inferring population structure from genetic data (ie, population assignment methods) have shown to effectively recognize genetic clusters in human populations. However, their performance in identifying groups of genealogically related individuals, especially in scanty-differentiated populations, has not been tested empirically thus far. For this study, we had access to both genealogical and genetic data from two closely related, isolated villages in southern Italy. We found that nearly all living individuals were included in a single pedigree, with multiple inbreeding loops. Despite Fst between villages being a low 0.008, genetic clustering analysis identified two clusters roughly corresponding to the two villages. Average kinship between individuals (estimated from genealogies) increased at increasing values of group membership (estimated from the genetic data), showing that the observed genetic clusters represent individuals who are more closely related to each other than to random members of the population. Further, average kinship within clusters and Fst between clusters increases with increasingly stringent membership threshold requirements. We conclude that a limited number of genetic markers is sufficient to detect structuring, and that the results of genetic analyses faithfully mirror the structuring inferred from detailed analyses of population genealogies, even when Fst values are low, as in the case of the two villages. We then estimate the impact of observed levels of population structure on association studies using simulated data. PMID:19550436

Genotype-Phenotype Characterization of Novel Variants in Six Italian Patients with Familial Exudative Vitreoretinopathy.

PubMed

Iarossi, Giancarlo; Bertelli, Matteo; Maltese, Paolo Enrico; Gusson, Elena; Marchini, Giorgio; Bruson, Alice; Benedetti, Sabrina; Volpetti, Sabrina; Catena, Gino; Buzzonetti, Luca; Ziccardi, Lucia

2017-01-01

Familial exudative vitreoretinopathy (FEVR) is a complex disorder characterized by incomplete development of the retinal vasculature. Here, we report the results obtained on the spectrum of genetic variations and correlated phenotypes found in a cohort of Italian FEVR patients. Eight probands (age range 7-19 years) were assessed by genetic analysis and comprehensive age-appropriate ophthalmic examination. Genetic testing investigated the genes most widely associated in literature with FEVR: FZD4 , LRP5 , TSPAN12 , and NDP . Clinical and genetic evaluations were extended to relatives of probands positive to genetic testing. Six out of eight probands (75%) showed a genetic variation probably related to the phenotype. We identified four novel genetic variants, one variant already described in association with Norrie disease and one previously described linked to autosomal dominant FEVR. Pedigree analysis of patients led to the classification of four autosomal dominant cases of FEVR (caused by FZD4 and TSPAN12 variants) and two X-linked FEVR probands ( NDP variants). None of the patients showed variants in the LRP5 gene. This study represents the largest cohort study in Italian FEVR patients. Our findings are in agreement with the previous literature confirming that FEVR is a clinically and genetically heterogeneous retinal disorder, even when it manifests in the same family.

Genotype-Phenotype Characterization of Novel Variants in Six Italian Patients with Familial Exudative Vitreoretinopathy

PubMed Central

Marchini, Giorgio; Volpetti, Sabrina; Catena, Gino

2017-01-01

Familial exudative vitreoretinopathy (FEVR) is a complex disorder characterized by incomplete development of the retinal vasculature. Here, we report the results obtained on the spectrum of genetic variations and correlated phenotypes found in a cohort of Italian FEVR patients. Eight probands (age range 7–19 years) were assessed by genetic analysis and comprehensive age-appropriate ophthalmic examination. Genetic testing investigated the genes most widely associated in literature with FEVR: FZD4, LRP5, TSPAN12, and NDP. Clinical and genetic evaluations were extended to relatives of probands positive to genetic testing. Six out of eight probands (75%) showed a genetic variation probably related to the phenotype. We identified four novel genetic variants, one variant already described in association with Norrie disease and one previously described linked to autosomal dominant FEVR. Pedigree analysis of patients led to the classification of four autosomal dominant cases of FEVR (caused by FZD4 and TSPAN12 variants) and two X-linked FEVR probands (NDP variants). None of the patients showed variants in the LRP5 gene. This study represents the largest cohort study in Italian FEVR patients. Our findings are in agreement with the previous literature confirming that FEVR is a clinically and genetically heterogeneous retinal disorder, even when it manifests in the same family. PMID:28758032

Optimality models in the age of experimental evolution and genomics.

PubMed

Bull, J J; Wang, I-N

2010-09-01

Optimality models have been used to predict evolution of many properties of organisms. They typically neglect genetic details, whether by necessity or design. This omission is a common source of criticism, and although this limitation of optimality is widely acknowledged, it has mostly been defended rather than evaluated for its impact. Experimental adaptation of model organisms provides a new arena for testing optimality models and for simultaneously integrating genetics. First, an experimental context with a well-researched organism allows dissection of the evolutionary process to identify causes of model failure--whether the model is wrong about genetics or selection. Second, optimality models provide a meaningful context for the process and mechanics of evolution, and thus may be used to elicit realistic genetic bases of adaptation--an especially useful augmentation to well-researched genetic systems. A few studies of microbes have begun to pioneer this new direction. Incompatibility between the assumed and actual genetics has been demonstrated to be the cause of model failure in some cases. More interestingly, evolution at the phenotypic level has sometimes matched prediction even though the adaptive mutations defy mechanisms established by decades of classic genetic studies. Integration of experimental evolutionary tests with genetics heralds a new wave for optimality models and their extensions that does not merely emphasize the forces driving evolution.

Molecular diagnosis of putative Stargardt disease probands by exome sequencing

PubMed Central

2012-01-01

Background The commonest genetic form of juvenile or early adult onset macular degeneration is Stargardt Disease (STGD) caused by recessive mutations in the gene ABCA4. However, high phenotypic and allelic heterogeneity and a small but non-trivial amount of locus heterogeneity currently impede conclusive molecular diagnosis in a significant proportion of cases. Methods We performed whole exome sequencing (WES) of nine putative Stargardt Disease probands and searched for potentially disease-causing genetic variants in previously identified retinal or macular dystrophy genes. Follow-up dideoxy sequencing was performed for confirmation and to screen for mutations in an additional set of affected individuals lacking a definitive molecular diagnosis. Results Whole exome sequencing revealed seven likely disease-causing variants across four genes, providing a confident genetic diagnosis in six previously uncharacterized participants. We identified four previously missed mutations in ABCA4 across three individuals. Likely disease-causing mutations in RDS/PRPH2, ELOVL, and CRB1 were also identified. Conclusions Our findings highlight the enormous potential of whole exome sequencing in Stargardt Disease molecular diagnosis and research. WES adequately assayed all coding sequences and canonical splice sites of ABCA4 in this study. Additionally, WES enables the identification of disease-related alleles in other genes. This work highlights the importance of collecting parental genetic material for WES testing as the current knowledge of human genome variation limits the determination of causality between identified variants and disease. While larger sample sizes are required to establish the precision and accuracy of this type of testing, this study supports WES for inherited early onset macular degeneration disorders as an alternative to standard mutation screening techniques. PMID:22863181

Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas.

PubMed

Sun, Xiangqing; Elston, Robert; Falk, Gary W; Grady, William M; Faulx, Ashley; Mittal, Sumeet K; Canto, Marcia I; Shaheen, Nicholas J; Wang, Jean S; Iyer, Prasad G; Abrams, Julian A; Willis, Joseph E; Guda, Kishore; Markowitz, Sanford; Barnholtz-Sloan, Jill S; Chandar, Apoorva; Brock, Wendy; Chak, Amitabh

2016-07-01

Familial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barrett's esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC). We genotyped 144 individuals in 42 multiplex pedigrees chosen from 1000 singly ascertained BE/EAC pedigrees, and performed both model-based and model-free linkage analyses, using S.A.G.E. and other software. Segregation models were fitted, from the data on both the 42 pedigrees and the 1000 pedigrees, to determine parameters for performing model-based linkage analysis. Model-based and model-free linkage analyses were conducted in two sets of pedigrees: the 42 pedigrees and a subset of 18 pedigrees with female affected members that are expected to be more genetically homogeneous. Genome-wide associations were also tested in these families. Linkage analyses on the 42 pedigrees identified several regions consistently suggestive of linkage by different linkage analysis methods on chromosomes 2q31, 12q23, and 4p14. A linkage on 15q26 is the only consistent linkage region identified in the 18 female-affected pedigrees, in which the linkage signal is higher than in the 42 pedigrees. Other tentative linkage signals are also reported. Our linkage study of BE/EAC pedigrees identified linkage regions on chromosomes 2, 4, 12, and 15, with some reported associations located within our linkage peaks. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to BE and EAC.

Patient reported outcomes and patient empowerment in clinical genetics services.

PubMed

McAllister, M; Dearing, A

2015-08-01

Evaluation of clinical genetics services (CGS), including genetic counseling and genetic testing, has been problematic. Patient mortality and morbidity are unlikely to be directly improved by interventions offered in CGS. Patient-reported outcomes (PROs) are not routinely measured in CGS evaluation, but this may change as patient-reported outcome measures (PROMs) become a key part of how healthcare services are managed and funded across the world. However, there is no clear consensus about which PROMs are most useful for CGS evaluation. This review summarizes the published research on how PROs from CGS have been measured and how patients may benefit from using those services, with a focus on patient empowerment. Many patient benefits (PROs) identified repeatedly in the research literature can be re-interpreted within a patient empowerment framework. Other important PROs identified include family functioning, social functioning, altruism, sense of purpose, enabling development of future research and treatment/participating in research. Well-validated measures are available to capture (dimensions of) patient empowerment. Although generic measures of family functioning are available, suitable measures capturing social functioning, development of future treatments, and altruism were not identified in this review. Patient empowerment provides one useful approach to measuring PROs from CGS. © 2014 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Prevalence of the AMHR2 mutation in Miniature Schnauzers and genetic investigation of a Belgian Malinois with persistent Müllerian duct syndrome.

PubMed

Smit, M M; Ekenstedt, K J; Minor, K M; Lim, C K; Leegwater, Paj; Furrow, E

2018-04-01

Persistent Müllerian duct syndrome (PMDS) is a sex-limited disorder in which males develop portions of the female reproductive tract. Important consequences of PMDS are cryptorchidism and its sequelae of infertility and increased risk of testicular cancer. Anti-Müllerian hormone (AMH) and its receptor (AMHR2) induce the regression of the Müllerian ducts in male embryos. In Miniature Schnauzer dogs, the genetic basis has been identified as an autosomal recessive nonsense mutation in AMHR2, but the allele frequency of the mutation is unknown. Thus, the primary objective of this study was to estimate the prevalence of the AMHR2 mutation in North American Miniature Schnauzers, in order to ascertain the value of genetic testing in this breed. An additional objective was to determine whether mutations in AMH or AMHR2 were responsible for PMDS in a Belgian Malinois; this would aid development of a genetic test for the Belgian Malinois breed. Genomic DNA from 216 Miniature Schnauzers (including one known PMDS case) was genotyped for the AMHR2 mutation, and DNA from a single PMDS-affected Belgian Malinois was sequenced for all coding exons of AMH and AMHR2. The Miniature Schnauzer cohort had an AMHR2 mutation allele frequency of 0.16 and a carrier genotypic frequency of 0.27. The genetic basis for PMDS in the Belgian Malinois was not determined, as no coding or splicing mutations were identified in either AMH or AMHR2. These findings support a benefit to AMHR2 mutation testing Miniature Schnauzers used for breeding or with cryptorchidism. © 2017 Blackwell Verlag GmbH.

Permanent neonatal diabetes mellitus: prevalence and genetic diagnosis in the SEARCH for Diabetes in Youth Study.

PubMed

Kanakatti Shankar, Roopa; Pihoker, Catherine; Dolan, Lawrence M; Standiford, Debra; Badaru, Angela; Dabelea, Dana; Rodriguez, Beatriz; Black, Mary Helen; Imperatore, Giuseppina; Hattersley, Andrew; Ellard, Sian; Gilliam, Lisa K

2013-05-01

Neonatal diabetes mellitus (NDM) is defined as diabetes with onset before 6 months of age. Nearly half of individuals with NDM are affected by permanent neonatal diabetes mellitus (PNDM). Mutations in KATP channel genes (KCNJ11, ABCC8) and the insulin gene (INS) are the most common causes of PNDM. To estimate the prevalence of PNDM among SEARCH for Diabetes in Youth (SEARCH) study participants (2001-2008) and to identify the genetic mutations causing PNDM. SEARCH is a multicenter population-based study of diabetes in youth <20 yr of age. Participants diagnosed with diabetes before 6 months of age were invited for genetic testing for mutations in the KCNJ11, ABCC8, and INS genes. Of the 15,829 SEARCH participants with diabetes, 39 were diagnosed before 6 months of age. Thirty-five of them had PNDM (0.22% of all diabetes cases in SEARCH), 3 had transient neonatal diabetes that had remitted by 18 months and 1 was unknown. The majority of them (66.7%) had a clinical diagnosis of type1 diabetes by their health care provider. Population prevalence of PNDM in youth <20 yr was estimated at 1 in 252 000. Seven participants underwent genetic testing; mutations causing PNDM were identified in five (71%), (two KCNJ11, three INS). We report the first population-based frequency of PNDM in the US based on the frequency of PNDM in SEARCH. Patients with NDM are often misclassified as having type1 diabetes. Widespread education is essential to encourage appropriate genetic testing and treatment of NDM. © 2012 John Wiley & Sons A/S.

Critical Need for Family-Based, Quasi-Experimental Designs in Integrating Genetic and Social Science Research

PubMed Central

Lahey, Benjamin B.; Turkheimer, Eric; Lichtenstein, Paul

2013-01-01

Researchers have identified environmental risks that predict subsequent psychological and medical problems. Based on these correlational findings, researchers have developed and tested complex developmental models and have examined biological moderating factors (e.g., gene–environment interactions). In this context, we stress the critical need for researchers to use family-based, quasi-experimental designs when trying to integrate genetic and social science research involving environmental variables because these designs rigorously examine causal inferences by testing competing hypotheses. We argue that sibling comparison, offspring of twins or siblings, in vitro fertilization designs, and other genetically informed approaches play a unique role in bridging gaps between basic biological and social science research. We use studies on maternal smoking during pregnancy to exemplify these principles. PMID:23927516

Critical need for family-based, quasi-experimental designs in integrating genetic and social science research.

PubMed

D'Onofrio, Brian M; Lahey, Benjamin B; Turkheimer, Eric; Lichtenstein, Paul

2013-10-01

Researchers have identified environmental risks that predict subsequent psychological and medical problems. Based on these correlational findings, researchers have developed and tested complex developmental models and have examined biological moderating factors (e.g., gene-environment interactions). In this context, we stress the critical need for researchers to use family-based, quasi-experimental designs when trying to integrate genetic and social science research involving environmental variables because these designs rigorously examine causal inferences by testing competing hypotheses. We argue that sibling comparison, offspring of twins or siblings, in vitro fertilization designs, and other genetically informed approaches play a unique role in bridging gaps between basic biological and social science research. We use studies on maternal smoking during pregnancy to exemplify these principles.

Mutagenicity of fractionated test material from the synthetic fuel technology with bacterial systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rao, T.K.; Young, J.A.; Hardigree, A.A.

1978-01-01

The predictive value of short-term genetic tests, such as the Salmonella and Escherichia coli (K-12, 343/113) systems including microsomal activation, is well documented. We have applied the short-term testing to various crude products and effluents from the synthetic fuel technologies. Class fractionation and column chromatography of the test materials and the coupled bioassays can be used to identify the most active fractions (collaborative effort with Analytical Chemistry Division). Reversion at the histidine locus for Salmonella was assayed with each fraction and the results are expressed in units of revertants (strain TA98) per milligram of the starting material (organic content) includingmore » metabolic activation with a crude rat liver preparation. Results obtained with the Salmonella system were validated by employing E. coli strains auxotrophic for arginine. Genetic activity is seen with a variety of fractions, largely the basic and neutral (PAH) components. Total activity varies from process to process, thus, the short-term genetic test can be considered a useful prescreen for potential biohazard of various effluents both in plants and in the immediate plant environment.« less

Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC).

PubMed

Caudle, Kelly E; Dunnenberger, Henry M; Freimuth, Robert R; Peterson, Josh F; Burlison, Jonathan D; Whirl-Carrillo, Michelle; Scott, Stuart A; Rehm, Heidi L; Williams, Marc S; Klein, Teri E; Relling, Mary V; Hoffman, James M

2017-02-01

Reporting and sharing pharmacogenetic test results across clinical laboratories and electronic health records is a crucial step toward the implementation of clinical pharmacogenetics, but allele function and phenotype terms are not standardized. Our goal was to develop terms that can be broadly applied to characterize pharmacogenetic allele function and inferred phenotypes. Terms currently used by genetic testing laboratories and in the literature were identified. The Clinical Pharmacogenetics Implementation Consortium (CPIC) used the Delphi method to obtain a consensus and agree on uniform terms among pharmacogenetic experts. Experts with diverse involvement in at least one area of pharmacogenetics (clinicians, researchers, genetic testing laboratorians, pharmacogenetics implementers, and clinical informaticians; n = 58) participated. After completion of five surveys, a consensus (>70%) was reached with 90% of experts agreeing to the final sets of pharmacogenetic terms. The proposed standardized pharmacogenetic terms will improve the understanding and interpretation of pharmacogenetic tests and reduce confusion by maintaining consistent nomenclature. These standard terms can also facilitate pharmacogenetic data sharing across diverse electronic health care record systems with clinical decision support.Genet Med 19 2, 215-223.

Genetic Diversity and Structure of Managed and Semi-natural Populations of Cocoa (Theobroma cacao) in the Huallaga and Ucayali Valleys of Peru

PubMed Central

ZHANG, DAPENG; AREVALO-GARDINI, ENRIQUE; MISCHKE, SUE; ZÚÑIGA-CERNADES, LUIS; BARRETO-CHAVEZ, ALEJANDRO; AGUILA, JORGE ADRIAZOLA DEL

2006-01-01

• Background and Aims Cocoa (Theobroma cacao) is indigenous to the Amazon region of South America, and it is well known that the Peruvian Amazon harbours a large number of diverse cocoa populations. A small fraction of the diversity has been collected and maintained as an ex-situ germplasm repository in Peru. However, incorrect labelling of accessions and lack of information on genetic diversity have hindered efficient conservation and use of this germplasm. This study targeted assessment of genetic diversity and population structure in a managed and a semi-natural population. •Methods Using a capillary electrophoresis genotyping system, 105 cocoa accessions collected from the Huallaga and Ucayali valleys of Peru were fingerprinted. Based on 15 loci SSR profiles, genetic identity was examined for each accession and duplicates identified, population structure assessed and genetic diversity analysed in these two populations. •Key Results Ten synonymous mislabelled groups were identified among the 105 accessions. The germplasm group in the Huallaga valley was clearly separated from the group in Ucayali valley by the Bayesian assignment test. The Huallaga group has lower genetic diversity, both in terms of allelic richness and of gene diversity, than the Ucayali group. Analysis of molecular variance suggested genetic substructure in the Ucayali group. Significant spatial correlation between genetic distance and geographical distances was detected in the Ucayali group by Mantel tests. •Conclusions These results substantiate the hypothesis that the Peruvian Amazon hosts a high level of cocoa genetic diversity, and the diversity has a spatial structure. The introduction of exotic seed populations into the Peruvian Amazon is changing the cocoa germplasm spectrum in this region. The spatial structure of cocoa diversity recorded here highlights the need for additional collecting and conservation measures for natural and semi-natural cocoa populations. PMID:16845139

Strategies for identifying new prions in yeast

PubMed Central

MacLea, Kyle S

2011-01-01

The unexpected discovery of two prions, [URE3] and [PSI+], in Saccharomyces cerevisiae led to questions about how many other proteins could undergo similar prion-based structural conversions. However, [URE3] and [PSI+] were discovered by serendipity in genetic screens. Cataloging the full range of prions in yeast or in other organisms will therefore require more systematic search methods. Taking advantage of some of the unique features of prions, various researchers have developed bioinformatic and experimental methods for identifying novel prion proteins. These methods have generated long lists of prion candidates. The systematic testing of some of these prion candidates has led to notable successes; however, even in yeast, where rapid growth rate and ease of genetic manipulation aid in testing for prion activity, such candidate testing is laborious. Development of better methods to winnow the field of prion candidates will greatly aid in the discovery of new prions, both in yeast and in other organisms, and help us to better understand the role of prions in biology. PMID:22052351

Antidepressant-like Responses to Lithium in Genetically Diverse Mouse Strains

PubMed Central

Can, Adem; Blackwell, Robert A.; Piantadosi, Sean C.; Dao, David T.; O’Donnell, Kelley C.; Gould, Todd D.

2011-01-01

A mood stabilizing and antidepressant response to lithium is only found in a subgroup of bipolar disorder and depression patients. Identifying strains of mice that are responsive and non-responsive to lithium may elucidate genomic and other biological factors that play a role in lithium responsiveness. Mouse strains were tested in the forced swim, tail suspension, and open field tests after acute and chronic systemic, and intracerebroventricular and chronic lithium treatments. Serum and brain lithium levels were measured. Three (129S6/SvEvTac, C3H/HeNHsd, C57BL/6J) of the eight inbred strains tested, and one (CD-1) of the three outbred strains, showed an antidepressant-like response in the forced swim test following acute systemic administration of lithium. The three responsive inbred strains, as well as the DBA/2J strain, were also responsive in the forced swim test after chronic administration of lithium. However, in the tail suspension test, acute lithium resulted in an antidepressant-like effect only in C3H/HeNHsd mice. Only C57BL/6J and DBA/2J were responsive in the tail suspension test after chronic administration of lithium. Intracerebroventricular lithium administration resulted in a similar response profile in BALB/cJ (non-responsive) and C57BL/6J (responsive) strains. Serum and brain lithium concentrations demonstrated that behavioral results were not due to differential pharmacokinetics of lithium in individual strains, suggesting that genetic factors likely regulate responsiveness to lithium. Our results indicate that responsiveness to lithium in tests of antidepressant efficacy varies among genetically diverse mouse strains. These results will assist in identifying genomic factors associated with lithium responsiveness and the mechanisms of lithium action. PMID:21306560

Multi-variant study of obesity risk genes in African Americans: The Jackson Heart Study.

PubMed

Liu, Shijian; Wilson, James G; Jiang, Fan; Griswold, Michael; Correa, Adolfo; Mei, Hao

2016-11-30

Genome-wide association study (GWAS) has been successful in identifying obesity risk genes by single-variant association analysis. For this study, we designed steps of analysis strategy and aimed to identify multi-variant effects on obesity risk among candidate genes. Our analyses were focused on 2137 African American participants with body mass index measured in the Jackson Heart Study and 657 common single nucleotide polymorphisms (SNPs) genotyped at 8 GWAS-identified obesity risk genes. Single-variant association test showed that no SNPs reached significance after multiple testing adjustment. The following gene-gene interaction analysis, which was focused on SNPs with unadjusted p-value<0.10, identified 6 significant multi-variant associations. Logistic regression showed that SNPs in these associations did not have significant linear interactions; examination of genetic risk score evidenced that 4 multi-variant associations had significant additive effects of risk SNPs; and haplotype association test presented that all multi-variant associations contained one or several combinations of particular alleles or haplotypes, associated with increased obesity risk. Our study evidenced that obesity risk genes generated multi-variant effects, which can be additive or non-linear interactions, and multi-variant study is an important supplement to existing GWAS for understanding genetic effects of obesity risk genes. Copyright © 2016 Elsevier B.V. All rights reserved.

The role of disease characteristics in the ethical debate on personal genome testing

PubMed Central

2012-01-01

Background Companies are currently marketing personal genome tests directly-to-consumer that provide genetic susceptibility testing for a range of multifactorial diseases simultaneously. As these tests comprise multiple risk analyses for multiple diseases, they may be difficult to evaluate. Insight into morally relevant differences between diseases will assist researchers, healthcare professionals, policy-makers and other stakeholders in the ethical evaluation of personal genome tests. Discussion In this paper, we identify and discuss four disease characteristics - severity, actionability, age of onset, and the somatic/psychiatric nature of disease - and show how these lead to specific ethical issues. By way of illustration, we apply this framework to genetic susceptibility testing for three diseases: type 2 diabetes, age-related macular degeneration and clinical depression. For these three diseases, we point out the ethical issues that are relevant to the question whether it is morally justifiable to offer genetic susceptibility testing to adults or to children or minors, and on what conditions. Summary We conclude that the ethical evaluation of personal genome tests is challenging, for the ethical issues differ with the diseases tested for. An understanding of the ethical significance of disease characteristics will improve the ethical, legal and societal debate on personal genome testing. PMID:22260407

Complement Factor B Mutations in Atypical Hemolytic Uremic Syndrome—Disease-Relevant or Benign?

PubMed Central

Marinozzi, Maria Chiara; Vergoz, Laura; Rybkine, Tania; Ngo, Stephanie; Bettoni, Serena; Pashov, Anastas; Cayla, Mathieu; Tabarin, Fanny; Jablonski, Mathieu; Hue, Christophe; Smith, Richard J.; Noris, Marina; Halbwachs-Mecarelli, Lise; Donadelli, Roberta; Fremeaux-Bacchi, Veronique

2014-01-01

Atypical hemolytic uremic syndrome (aHUS) is a genetic ultrarare renal disease associated with overactivation of the alternative pathway of complement. Four gain-of-function mutations that form a hyperactive or deregulated C3 convertase have been identified in Factor B (FB) ligand binding sites. Here, we studied the functional consequences of 10 FB genetic changes recently identified from different aHUS cohorts. Using several tests for alternative C3 and C5 convertase formation and regulation, we identified two gain-of-function and potentially disease-relevant mutations that formed either an overactive convertase (M433I) or a convertase resistant to decay by FH (K298Q). One mutation (R178Q) produced a partially cleaved protein with no ligand binding or functional activity. Seven genetic changes led to near-normal or only slightly reduced ligand binding and functional activity compared with the most common polymorphism at position 7, R7. Notably, none of the algorithms used to predict the disease relevance of FB mutations agreed completely with the experimental data, suggesting that in silico approaches should be undertaken with caution. These data, combined with previously published results, suggest that 9 of 15 FB genetic changes identified in patients with aHUS are unrelated to disease pathogenesis. This study highlights that functional assessment of identified nucleotide changes in FB is mandatory to confirm disease association. PMID:24652797

Genetic signatures of natural selection in a model invasive ascidian

PubMed Central

Lin, Yaping; Chen, Yiyong; Yi, Changho; Fong, Jonathan J.; Kim, Won; Rius, Marc; Zhan, Aibin

2017-01-01

Invasive species represent promising models to study species’ responses to rapidly changing environments. Although local adaptation frequently occurs during contemporary range expansion, the associated genetic signatures at both population and genomic levels remain largely unknown. Here, we use genome-wide gene-associated microsatellites to investigate genetic signatures of natural selection in a model invasive ascidian, Ciona robusta. Population genetic analyses of 150 individuals sampled in Korea, New Zealand, South Africa and Spain showed significant genetic differentiation among populations. Based on outlier tests, we found high incidence of signatures of directional selection at 19 loci. Hitchhiking mapping analyses identified 12 directional selective sweep regions, and all selective sweep windows on chromosomes were narrow (~8.9 kb). Further analyses indentified 132 candidate genes under selection. When we compared our genetic data and six crucial environmental variables, 16 putatively selected loci showed significant correlation with these environmental variables. This suggests that the local environmental conditions have left significant signatures of selection at both population and genomic levels. Finally, we identified “plastic” genomic regions and genes that are promising regions to investigate evolutionary responses to rapid environmental change in C. robusta. PMID:28266616

New Approaches in International Guidelines for Genetic Toxicology Assays: Latest Updates on OECD Guidelines

EPA Science Inventory

In March 2010, the 22nd meeting of the Working Group of National Coordinators of the OECD Test Guidelines Programme (WNT) approved a project for updating the Test Guidelines on genotoxicity, with Canada, the Netherlands, France and the USA identified as lead countries for this wo...

Understanding Individual Differences in Spatial Ability within Females: A Nature/Nurture Interactionist Framework.

ERIC Educational Resources Information Center

Casey, M. Beth

1996-01-01

Identified subjects' handedness and family handedness (genetic variables) and college major (environmental variable); and tested subjects on the Vandenberg Mental Rotation Test. Found that right-handed females with non-right-handed relatives and with science or math majors outperformed other females and equaled the performance of males on the…

Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes

PubMed Central

Edmunds, Richard C.; Su, Baofeng; Balhoff, James P.; Eames, B. Frank; Dahdul, Wasila M.; Lapp, Hilmar; Lundberg, John G.; Vision, Todd J.; Dunham, Rex A.; Mabee, Paula M.; Westerfield, Monte

2016-01-01

Phenotypes resulting from mutations in genetic model organisms can help reveal candidate genes for evolutionarily important phenotypic changes in related taxa. Although testing candidate gene hypotheses experimentally in nonmodel organisms is typically difficult, ontology-driven information systems can help generate testable hypotheses about developmental processes in experimentally tractable organisms. Here, we tested candidate gene hypotheses suggested by expert use of the Phenoscape Knowledgebase, specifically looking for genes that are candidates responsible for evolutionarily interesting phenotypes in the ostariophysan fishes that bear resemblance to mutant phenotypes in zebrafish. For this, we searched ZFIN for genetic perturbations that result in either loss of basihyal element or loss of scales phenotypes, because these are the ancestral phenotypes observed in catfishes (Siluriformes). We tested the identified candidate genes by examining their endogenous expression patterns in the channel catfish, Ictalurus punctatus. The experimental results were consistent with the hypotheses that these features evolved through disruption in developmental pathways at, or upstream of, brpf1 and eda/edar for the ancestral losses of basihyal element and scales, respectively. These results demonstrate that ontological annotations of the phenotypic effects of genetic alterations in model organisms, when aggregated within a knowledgebase, can be used effectively to generate testable, and useful, hypotheses about evolutionary changes in morphology. PMID:26500251

Discovery of a novel dominant mutation in the REN gene after forty years of renal disease: a case report.

PubMed

Clissold, Rhian L; Clarke, Helen C; Spasic-Boskovic, Olivera; Brugger, Kim; Abbs, Stephen; Bingham, Coralie; Shaw-Smith, Charles

2017-07-12

Heterozygous mutations in the gene encoding renin (REN) cause autosomal dominant tubulointerstitial kidney disease (ADTKD), early-onset anaemia and hyperuricaemia; only four different mutations have been described in the published literature to date. We report a novel dominant REN mutation discovered in an individual after forty years of renal disease. A 57 year old Caucasian woman with chronic kidney disease stage five was reviewed in a regional joint renal genetics clinic. She had initially been diagnosed with chronic pyelonephritis in adolescence, around the same time that she was investigated for anaemia out of keeping with her degree of renal impairment. Hyperuricaemia was identified in her twenties following an episode of gout. A diagnosis of ADTKD was not made until the age of 37 years, when her mother was also found to have kidney disease and commenced haemodialysis. The patient's renal function continued to slowly deteriorate and, twenty years later, her sister was worked up as a potential donor for kidney transplantation. Revisiting the maternal family history during the transplant work up prompted a referral to clinical genetics and urgent REN genetic testing was requested for the patient, leading to discovery of a heterozygous mutation in the REN gene: c.49 T > C, p.(Trp17Arg). This variant was not identified in her otherwise healthy sister, allowing pre-emptive live renal transplantation to take place shortly afterwards. In an era where genetic testing is becoming much more readily available, this case highlights the importance of considering a genetic aetiology in all patients with long-standing renal disease and a relevant family history. Establishing a genetic diagnosis of ADTKD-REN in this individual with chronic anaemia, hyperuricaemia and slowly progressive renal impairment helped to identify a suitable live kidney donor and allowed successful pre-emptive transplantation to take place.

Social-group identity and population substructure in admixed populations in New Mexico and Latin America

PubMed Central

Healy, Meghan E.; Hill, Deirdre; Berwick, Marianne; Edgar, Heather; Gross, Jessica

2017-01-01

We examined the relationship between continental-level genetic ancestry and racial and ethnic identity in an admixed population in New Mexico with the goal of increasing our understanding of how racial and ethnic identity influence genetic substructure in admixed populations. Our sample consists of 98 New Mexicans who self-identified as Hispanic or Latino (NM-HL) and who further categorized themselves by race and ethnic subgroup membership. The genetic data consist of 270 newly-published autosomal microsatellites from the NM-HL sample and previously published data from 57 globally distributed populations, including 13 admixed samples from Central and South America. For these data, we 1) summarized the major axes of genetic variation using principal component analyses, 2) performed tests of Hardy Weinberg equilibrium, 3) compared empirical genetic ancestry distributions to those predicted under a model of admixture that lacked substructure, 4) tested the hypotheses that individuals in each sample had 100%, 0%, and the sample-mean percentage of African, European, and Native American ancestry. We found that most NM-HL identify themselves and their parents as belonging to one of two groups, conforming to a region-specific narrative that distinguishes recent immigrants from Mexico from individuals whose families have resided in New Mexico for generations and who emphasize their Spanish heritage. The “Spanish” group had significantly lower Native American ancestry and higher European ancestry than the “Mexican” group. Positive FIS values, PCA plots, and heterogeneous ancestry distributions suggest that most Central and South America admixed samples also contain substructure, and that this substructure may be related to variation in social identity. Genetic substructure appears to be common in admixed populations in the Americas and may confound attempts to identify disease-causing genes and to understand the social causes of variation in health outcomes and social inequality. PMID:28977000

Exome Array Analysis of Susceptibility to Pneumococcal Meningitis

PubMed Central

Kloek, Anne T.; van Setten, Jessica; van der Ende, Arie; Bots, Michiel L.; Asselbergs, Folkert W.; Serón, Mercedes Valls; Brouwer, Matthijs C.; van de Beek, Diederik; Ferwerda, Bart

2016-01-01

Host genetic variability may contribute to susceptibility of bacterial meningitis, but which genes contribute to the susceptibility to this complex disease remains undefined. We performed a genetic association study in 469 community-acquired pneumococcal meningitis cases and 2072 population-based controls from the Utrecht Health Project in order to find genetic variants associated with pneumococcal meningitis susceptibility. A HumanExome BeadChip was used to genotype 102,097 SNPs in the collected DNA samples. Associations were tested with the Fisher exact test. None of the genetic variants tested reached Bonferroni corrected significance (p-value <5 × 10−7). Our strongest signals associated with susceptibility to pneumococcal meningitis were rs139064549 on chromosome 1 in the COL11A1 gene (p = 1.51 × 10−6; G allele OR 3.21 [95% CI 2.05–5.02]) and rs9309464 in the EXOC6B gene on chromosome 2 (p = 6.01 × 10−5; G allele OR 0.66 [95% CI 0.54–0.81]). The sequence kernel association test (SKAT) tests for associations between multiple variants in a gene region and pneumococcal meningitis susceptibility yielded one significant associated gene namely COL11A1 (p = 1.03 × 10−7). Replication studies are needed to validate these results. If replicated, the functionality of these genetic variations should be further studied to identify by which means they influence the pathophysiology of pneumococcal meningitis. PMID:27389768

Illustrating, Quantifying, and Correcting for Bias in Post-hoc Analysis of Gene-Based Rare Variant Tests of Association

PubMed Central

Grinde, Kelsey E.; Arbet, Jaron; Green, Alden; O'Connell, Michael; Valcarcel, Alessandra; Westra, Jason; Tintle, Nathan

2017-01-01

To date, gene-based rare variant testing approaches have focused on aggregating information across sets of variants to maximize statistical power in identifying genes showing significant association with diseases. Beyond identifying genes that are associated with diseases, the identification of causal variant(s) in those genes and estimation of their effect is crucial for planning replication studies and characterizing the genetic architecture of the locus. However, we illustrate that straightforward single-marker association statistics can suffer from substantial bias introduced by conditioning on gene-based test significance, due to the phenomenon often referred to as “winner's curse.” We illustrate the ramifications of this bias on variant effect size estimation and variant prioritization/ranking approaches, outline parameters of genetic architecture that affect this bias, and propose a bootstrap resampling method to correct for this bias. We find that our correction method significantly reduces the bias due to winner's curse (average two-fold decrease in bias, p < 2.2 × 10−6) and, consequently, substantially improves mean squared error and variant prioritization/ranking. The method is particularly helpful in adjustment for winner's curse effects when the initial gene-based test has low power and for relatively more common, non-causal variants. Adjustment for winner's curse is recommended for all post-hoc estimation and ranking of variants after a gene-based test. Further work is necessary to continue seeking ways to reduce bias and improve inference in post-hoc analysis of gene-based tests under a wide variety of genetic architectures. PMID:28959274

Estimating connectivity in marine populations: an empirical evaluation of assignment tests and parentage analysis under different gene flow scenarios.

PubMed

Saenz-Agudelo, P; Jones, G P; Thorrold, S R; Planes, S

2009-04-01

The application of spatially explicit models of population dynamics to fisheries management and the design marine reserve network systems has been limited due to a lack of empirical estimates of larval dispersal. Here we compared assignment tests and parentage analysis for examining larval retention and connectivity under two different gene flow scenarios using panda clownfish (Amphiprion polymnus) in Papua New Guinea. A metapopulation of panda clownfish in Bootless Bay with little or no genetic differentiation among five spatially discrete locations separated by 2-6 km provided the high gene flow scenario. The low gene flow scenario compared the Bootless Bay metapopulation with a genetically distinct population (F(ST )= 0.1) located at Schumann Island, New Britain, 1500 km to the northeast. We used assignment tests and parentage analysis based on microsatellite DNA data to identify natal origins of 177 juveniles in Bootless Bay and 73 juveniles at Schumann Island. At low rates of gene flow, assignment tests correctly classified juveniles to their source population. On the other hand, parentage analysis led to an overestimate of self-recruitment within the two populations due to the significant deviation from panmixia when both populations were pooled. At high gene flow (within Bootless Bay), assignment tests underestimated self-recruitment and connectivity among subpopulations, and grossly overestimated self-recruitment within the overall metapopulation. However, the assignment tests did identify immigrants from distant (genetically distinct) populations. Parentage analysis clearly provided the most accurate estimates of connectivity in situations of high gene flow.

Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene-Environment Interactions

PubMed Central

Schoeps, Anja; Rudolph, Anja; Seibold, Petra; Dunning, Alison M.; Milne, Roger L.; Bojesen, Stig E.; Swerdlow, Anthony; Andrulis, Irene; Brenner, Hermann; Behrens, Sabine; Orr, Nicholas; Jones, Michael; Ashworth, Alan; Li, Jingmei; Cramp, Helen; Connley, Dan; Czene, Kamila; Darabi, Hatef; Chanock, Stephen J.; Lissowska, Jolanta; Figueroa, Jonine D.; Knight, Julia; Glendon, Gord; Mulligan, Anna M.; Dumont, Martine; Severi, Gianluca; Baglietto, Laura; Olson, Janet; Vachon, Celine; Purrington, Kristen; Moisse, Matthieu; Neven, Patrick; Wildiers, Hans; Spurdle, Amanda; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana M.; Hamann, Ute; Ko, Yon-Dschun; Dieffenbach, Aida K.; Arndt, Volker; Stegmaier, Christa; Malats, Núria; Arias Perez, JoséI.; Benítez, Javier; Flyger, Henrik; Nordestgaard, Børge G.; Truong, Théresè; Cordina-Duverger, Emilie; Menegaux, Florence; Silva, Isabel dos Santos; Fletcher, Olivia; Johnson, Nichola; Häberle, Lothar; Beckmann, Matthias W.; Ekici, Arif B.; Braaf, Linde; Atsma, Femke; van den Broek, Alexandra J.; Makalic, Enes; Schmidt, Daniel F.; Southey, Melissa C.; Cox, Angela; Simard, Jacques; Giles, Graham G.; Lambrechts, Diether; Mannermaa, Arto; Brauch, Hiltrud; Guénel, Pascal; Peto, Julian; Fasching, Peter A.; Hopper, John; Flesch-Janys, Dieter; Couch, Fergus; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Garcia-Closas, Montserrat; Schmidt, Marjanka K.; Hall, Per; Easton, Douglas F.; Chang-Claude, Jenny

2014-01-01

Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci. PMID:24248812

A Comprehensive Analysis of Common Genetic Variation Around Six Candidate Loci for Intrahepatic Cholestasis of Pregnancy

PubMed Central

Dixon, Peter H; Wadsworth, Christopher A; Chambers, Jennifer; Donnelly, Jennifer; Cooley, Sharon; Buckley, Rebecca; Mannino, Ramona; Jarvis, Sheba; Syngelaki, Argyro; Geenes, Victoria; Paul, Priyadarshini; Sothinathan, Meera; Kubitz, Ralf; Lammert, Frank; Tribe, Rachel M; Ch'ng, Chin Lye; Marschall, Hanns-Ulrich; Glantz, Anna; Khan, Shahid A; Nicolaides, Kypros; Whittaker, John; Geary, Michael; Williamson, Catherine

2014-01-01

OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19). METHODS: ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case–control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitage's trend test. RESULTS: Cochran–Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10−4 (rs3815676) and for ABCB4 it was 4.6×10−7(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings. CONCLUSIONS: Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility. PMID:24366234

Population genetic structure in a social landscape: barley in a traditional Ethiopian agricultural system

PubMed Central

Samberg, Leah H; Fishman, Lila; Allendorf, Fred W

2013-01-01

Conservation strategies are increasingly driven by our understanding of the processes and patterns of gene flow across complex landscapes. The expansion of population genetic approaches into traditional agricultural systems requires understanding how social factors contribute to that landscape, and thus to gene flow. This study incorporates extensive farmer interviews and population genetic analysis of barley landraces (Hordeum vulgare) to build a holistic picture of farmer-mediated geneflow in an ancient, traditional agricultural system in the highlands of Ethiopia. We analyze barley samples at 14 microsatellite loci across sites at varying elevations and locations across a contiguous mountain range, and across farmer-identified barley types and management strategies. Genetic structure is analyzed using population-based and individual-based methods, including measures of population differentiation and genetic distance, multivariate Principal Coordinate Analysis, and Bayesian assignment tests. Phenotypic analysis links genetic patterns to traits identified by farmers. We find that differential farmer management strategies lead to markedly different patterns of population structure across elevation classes and barley types. The extent to which farmer seed management appears as a stronger determinant of spatial structure than the physical landscape highlights the need for incorporation of social, landscape, and genetic data for the design of conservation strategies in human-influenced landscapes. PMID:24478796

Molecular genetic analysis of a cattle population to reconstitute the extinct Algarvia breed

PubMed Central

2010-01-01

Background Decisions to initiate conservation programmes need to account for extant variability, diversity loss and cultural and economic aspects. Molecular markers were used to investigate if putative Algarvia animals could be identified for use as progenitors in a breeding programme to recover this nearly extinct breed. Methods 46 individuals phenotypically representative of Algarvia cattle were genotyped for 27 microsatellite loci and compared with 11 Portuguese autochthonous and three imported breeds. Genetic distances and factorial correspondence analyses (FCA) were performed to investigate the relationship among Algarvia and related breeds. Assignment tests were done to identify representative individuals of the breed. Y chromosome and mtDNA analyses were used to further characterize Algarvia animals. Gene- and allelic-based conservation analyses were used to determine breed contributions to overall genetic diversity. Results Genetic distance and FCA results confirmed the close relationship between Algarvia and southern Portuguese breeds. Assignment tests without breed information classified 17 Algarvia animals in this cluster with a high probability (q > 0.95). With breed information, 30 cows and three bulls were identified (q > 0.95) that could be used to reconstitute the Algarvia breed. Molecular and morphological results were concordant. These animals showed intermediate levels of genetic diversity (MNA = 6.0 ± 1.6, Rt = 5.7 ± 1.4, Ho = 0.63 ± 0.19 and He = 0.69 ± 0.10) relative to other Portuguese breeds. Evidence of inbreeding was also detected (Fis = 0.083, P < 0.001). The four Algarvia bulls had Y-haplotypes H6Y2 and H11Y2, common in Portuguese cattle. The mtDNA composition showed prevalence of T3 matrilines and presence of the African-derived T1a haplogroup. This analysis confirmed the genetic proximity of Algarvia and Garvonesa breeds (Fst = 0.028, P > 0.05). Algarvia cattle provide an intermediate contribution (CB = 6.18, CW = -0.06 and D1 = 0.50) to the overall gene diversity of Portuguese cattle. Algarvia and seven other autochthonous breeds made no contribution to the overall allelic diversity. Conclusions Molecular analyses complemented previous morphological findings to identify 33 animals that can be considered remnants of the Algarvia breed. Results of genetic diversity and conservation analyses provide objective information to establish a management program to reconstitute the Algarvia breed. PMID:20540741

A clearing house for diagnostic testing: the solution to ensure access to and use of patented genetic inventions?

PubMed Central

van Zimmeren, Esther; Verbeure, Birgit; Matthijs, Gert; Van Overwalle, Geertrui

2006-01-01

In genetic diagnostics, the emergence of a so-called "patent thicket" is imminent. Such an overlapping set of patent rights may have restrictive effects on further research and development of diagnostic tests, and the provision of clinical diagnostic services. Currently, two models that may facilitate access to and use of patented genetic inventions are attracting much debate in various national and international fora: patent pools and clearing houses. In this article, we explore the concept of clearing houses. Several types of clearing houses are identified. First, we describe and discuss two types that would provide access to information on the patented inventions: the information clearing house and the technology exchange clearing house. Second, three types of clearing houses are analysed that not only offer access to information but also provide an instrument to facilitate the use of the patented inventions: the open access clearing house, the standardized licences clearing house and the royalty collection clearing house. A royalty collection clearing house for genetic diagnostic testing would be the most comprehensive as it would serve several functions: identifying patents and patent claims essential to diagnostic testing, matching licensees with licensors, developing and supplying standardized licences, collecting royalties, monitoring whether users respect licensing conditions, and providing dispute resolution services such as mediation and arbitration. In this way, it might function as an effective model for users to facilitate access to and use of the patented inventions. However, it remains to be seen whether patent holders with a strong patent portfolio will be convinced by the advantages of the royalty collection clearing house and be willing to participate. PMID:16710543

A place for genetic uncertainty: parents valuing an unknown in the meaning of disease.

PubMed

Whitmarsh, Ian; Davis, Arlene M; Skinner, Debra; Bailey, Donald B

2007-09-01

Klinefelter, Turner, and fragile X syndromes are conditions defined by a genetic or chromosomal variant. The timing of diagnosis, tests employed, specialists involved, symptoms evident, and prognoses available vary considerably within and across these syndromes, but all three share in common a diagnosis verified through a molecular or cytogenetic test. The genetic or chromosomal variant identified designates a syndrome, even when symptoms associated with the particular syndrome are absent. This article analyzes interviews conducted with parents and grandparents of children with these syndromes from across the USA to explore how they interpret a confirmed genetic diagnosis that is associated with a range of possible symptoms that may never be exhibited. Parents' responses indicate that they see the genetic aspects of the syndrome as stable, permanent, and authoritative. But they allow, and even embrace, uncertainty about the condition by focusing on variation between diagnosed siblings, the individuality of their diagnosed child, his or her accomplishments, and other positive aspects that go beyond the genetic diagnosis. Some families counter the genetic diagnosis by arguing that in the absence of symptoms, the syndrome does not exist. They use their own expertise to question the perceived certainty of the genetic diagnosis and to employ the diagnosis strategically. These multiple and often conflicting evaluations of the diagnostic label reveal the rich ways families make meaning of the authority attributed to genetic diagnosis.

The genetics of muscle atrophy and growth: the impact and implications of polymorphisms in animals and humans.

PubMed

Gordon, Erynn S; Gordish Dressman, Heather A; Hoffman, Eric P

2005-10-01

Much of the vast diversity we see in animals and people is governed by genetic loci that have quantitative effects of phenotype (quantitative trait loci; QTLs). Here we review the current knowledge of the genetics of atrophy and hypertrophy in both animal husbandry (meat quantity and quality), and humans (muscle size and performance). The selective breeding of animals for meat has apparently led to a few genetic loci with strong effects, with different loci in different animals. In humans, muscle quantitative trait loci (QTLs) appear to be more complex, with few "major" loci identified to date, although this is likely to change in the near future. We describe how the same phenotypic traits we see as positive, greater lean muscle mass in cattle or a better exercise results in humans, can also have negative "side effects" given specific environmental challenges. We also discuss the strength and limitations of single nucleotide polymorphisms (SNP) association studies; what the reader should look for and expect in a published study. Lastly we discuss the ethical and societal implications of this genetic information. As more and more research into the genetic loci that dictate phenotypic traits become available, the ethical implications of testing for these loci become increasingly important. As a society, most accept testing for genetic diseases or susceptibility, but do we as easily accept testing to determine one's athletic potential to be an Olympic endurance runner, or quarterback on the high school football team.

Genetically engineered mouse models for epithelial ovarian cancer: are we there yet?

PubMed

Howell, Viive M

2014-03-01

The development of preclinical spontaneous genetically engineered mouse models (GEMMs) requires an understanding of the genetic basis of the human disease. Such robust models have proven invaluable for increasing understanding of human malignancies as well as identifying new biomarkers and testing new therapies for these diseases. While GEMMs have been reported for ovarian cancer, the majority have proven disappointing overall in their recapitulation of paired genetic and histological features especially for serous ovarian epithelial cancer. This review describes GEMMs for ovarian cancer, in particular, high grade serous ovarian cancer and assesses these in light of recent changes in our understanding of the human malignancy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Hypokalemic periodic paralysis; two different genes responsible for similar clinical manifestations

PubMed Central

Kim, Hunmin; Hwang, Hee; Cheong, Hae Il

2011-01-01

Primary hypokalemic periodic paralysis (HOKPP) is an autosomal dominant disorder manifesting as recurrent periodic flaccid paralysis and concomitant hypokalemia. HOKPP is divided into type 1 and type 2 based on the causative gene. Although 2 different ion channels have been identified as the molecular genetic cause of HOKPP, the clinical manifestations between the 2 groups are similar. We report the cases of 2 patients with HOKPP who both presented with typical clinical manifestations, but with mutations in 2 different genes (CACNA1Sp.Arg528His and SCN4A p.Arg672His). Despite the similar clinical manifestations, there were differences in the response to acetazolamide treatment between certain genotypes of SCN4A mutations and CACNA1S mutations. We identified p.Arg672His in the SCN4A gene of patient 2 immediately after the first attack through a molecular genetic testing strategy. Molecular genetic diagnosis is important for genetic counseling and selecting preventive treatment. PMID:22253645

Developing single nucleotide polymorphism (SNP) markers from transcriptome sequences for identification of longan (Dimocarpus longan) germplasm

PubMed Central

Wang, Boyi; Tan, Hua-Wei; Fang, Wanping; Meinhardt, Lyndel W; Mischke, Sue; Matsumoto, Tracie; Zhang, Dapeng

2015-01-01

Longan (Dimocarpus longan Lour.) is an important tropical fruit tree crop. Accurate varietal identification is essential for germplasm management and breeding. Using longan transcriptome sequences from public databases, we developed single nucleotide polymorphism (SNP) markers; validated 60 SNPs in 50 longan germplasm accessions, including cultivated varieties and wild germplasm; and designated 25 SNP markers that unambiguously identified all tested longan varieties with high statistical rigor (P<0.0001). Multiple trees from the same clone were verified and off-type trees were identified. Diversity analysis revealed genetic relationships among analyzed accessions. Cultivated varieties differed significantly from wild populations (Fst=0.300; P<0.001), demonstrating untapped genetic diversity for germplasm conservation and utilization. Within cultivated varieties, apparent differences between varieties from China and those from Thailand and Hawaii indicated geographic patterns of genetic differentiation. These SNP markers provide a powerful tool to manage longan genetic resources and breeding, with accurate and efficient genotype identification. PMID:26504559

Ordering Molecular Genetic Tests and Reporting Results

PubMed Central

Lubin, Ira M.; Caggana, Michele; Constantin, Carolyn; Gross, Susan J.; Lyon, Elaine; Pagon, Roberta A.; Trotter, Tracy L.; Wilson, Jean Amos; McGovern, Margaret M.

2008-01-01

Previous studies have suggested that patient care may be compromised as a consequence of poor communication between clinicians and laboratory professionals in cases in which molecular genetic test results are reported. To understand better the contributing factors to such compromised care, we investigated both pre- and postanalytical processes using cystic fibrosis mutation analysis as our model. We found that although the majority of test requisition forms requested patient/family information that was necessary for the proper interpretation of test results, in many cases, these data were not provided by the individuals filling out the forms. We found instances in which result reports for simulated diagnostic testing described individuals as carriers where only a single mutation was found with no comment pertaining to a diagnosis of cystic fibrosis. Similarly, reports based on simulated scenarios for carrier testing were problematic when no mutations were identified, and the patient's race/ethnicity and family history were not discussed in reference to residual risk of disease. Remarkably, a pilot survey of obstetrician-gynecologists revealed that office staff, including secretaries, often helped order genetic tests and reported test results to patients, raising questions about what efforts are undertaken to ensure personnel competency. These findings are reviewed in light of what efforts should be taken to improve the quality of test-ordering and result-reporting practices. PMID:18669879

Impact of gene patents on the cost-effective delivery of care: the case of BRCA1 genetic testing.

PubMed

Sevilla, Christine; Julian-Reynier, Claire; Eisinger, François; Stoppa-Lyonnet, Dominique; Bressac-de Paillerets, Brigitte; Sobol, Hagay; Moatti, Jean-Paul

2003-01-01

In 1994/95, two genes, BRCA1/2, associated with a predisposition to breast or ovarian cancer were identified. Genetic testing of deleterious BRCA1/2 mutations consequently can be proposed to individuals with a family history of breast or ovarian cancer to identify who is at risk. The granting of U.S. patents on BRCA1/2 to a privately owned company has led to the monopoly use of a unique technique (Direct Sequencing of the gene, DS) for BRCA1/2 testing in this country. Alternative strategies using prescreening techniques, however, have been experienced worldwide. On the basis of data collected at three laboratories of French public hospitals, we carried out a cost-effectiveness study comparing DS to 19 alternative strategies with the number of deleterious BRCA1 mutations detected as the outcome. Results show that the DS strategy presents the highest average cost per mutation detected (9,882.5 Euro) and that there exist strategies using prescreening techniques that can reach similar effectiveness while reducing total costs. Moreover, other strategies can obtain a four- to sevenfold reduction in the average cost per mutation detected as soon as some rates of false negatives (2% to 13%) are deemed to be acceptable. Results suggest that gene patents with a very broad scope, covering all potential medical applications, may prevent health care systems from identifying and adopting the most efficient genetic testing strategies due to the monopoly granted for the exploitation of the gene. Policy implications for regulatory authorities, in the current context of the extension of BRCA1/2 patents in other countries, are discussed.

Comprehensive Mutation Scanning of LMNA in 268 Patients With Lone Atrial Fibrillation

PubMed Central

Brauch, Katharine M.; Chen, Lin Y.; Olson, Timothy M.

2009-01-01

Atrial fibrillation (AF) is a heritable, genetically heterogeneous disorder. To identify gene defects that cause or confer susceptibility to AF, a cohort of 268 unrelated patients with idiopathic forms of familial and sporadic AF was recruited. LMNA, encoding the nuclear membrane proteins, lamin A/C, was selected as a candidate gene for lone AF based on its established association with a syndrome of dilated cardiomyopathy, conduction system disease, and AF. Comprehensive mutation scanning identified only 1 potentially pathogenic mutation. In conclusion, LMNA mutations rarely cause lone AF and routine genetic testing of LMNA in these patients does not appear warranted. PMID:19427440

Ethical, legal and social issues in restoring genetic identity after forced disappearance and suppression of identity in Argentina.

PubMed

Penchaszadeh, Victor B

2015-07-01

Human genetic identification has been increasingly associated with the preservation, defence and reparation of human rights, in particular the right to genetic identity. The Argentinian military dictatorship of 1976-1983 engaged in a savage repression and egregious violations of human rights, including forced disappearance, torture, assassination and appropriation of children of the disappeared with suppression of their identity. The ethical, legal and social nuances in the use of forensic genetics to support the right to identity in Argentina included issues such as the best interest of children being raised by criminals, the right to learn the truth of one's origin and identity, rights of their biological families, the issue of voluntary versus compulsory testing of victims, as well as the duty of the state to investigate crimes against humanity, punish perpetrators and provide justice and reparation to the victims. In the 30 years following the return to democracy in 1984, the search, localization and DNA testing of disappeared children and young adults has led, so far, to the genetic identification of 116 persons who had been abducted as babies. The high value placed on DNA testing to identify victims of identity suppression did not conflict with the social consensus that personal identity is a complex and dynamic concept, attained by the interaction of genetics with historical, social, emotional, educational, cultural and other important environmental factors. The use of genetic identification as a tool to redress and repair human rights violations is a novel application of human genetics within a developing set of ethical and political circumstances.

Factor analysis in the Genetics of Asthma International Network family study identifies five major quantitative asthma phenotypes.

PubMed

Pillai, S G; Tang, Y; van den Oord, E; Klotsman, M; Barnes, K; Carlsen, K; Gerritsen, J; Lenney, W; Silverman, M; Sly, P; Sundy, J; Tsanakas, J; von Berg, A; Whyte, M; Ortega, H G; Anderson, W H; Helms, P J

2008-03-01

Asthma is a clinically heterogeneous disease caused by a complex interaction between genetic susceptibility and diverse environmental factors. In common with other complex diseases the lack of a standardized scheme to evaluate the phenotypic variability poses challenges in identifying the contribution of genes and environments to disease expression. To determine the minimum number of sets of features required to characterize subjects with asthma which will be useful in identifying important genetic and environmental contributors. Methods Probands aged 7-35 years with physician diagnosed asthma and symptomatic siblings were identified in 1022 nuclear families from 11 centres in six countries forming the Genetics of Asthma International Network. Factor analysis was used to identify distinct phenotypes from questionnaire, clinical, and laboratory data, including baseline pulmonary function, allergen skin prick test (SPT). Five distinct factors were identified:(1) baseline pulmonary function measures [forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)], (2) specific allergen sensitization by SPT, (3) self-reported allergies, (4) symptoms characteristic of rhinitis and (5) symptoms characteristic of asthma. Replication in symptomatic siblings was consistent with shared genetic and/or environmental effects, and was robust across age groups, gender, and centres. Cronbach's alpha ranged from 0.719 to 0.983 suggesting acceptable internal scale consistencies. Derived scales were correlated with serum IgE, methacholine PC(20), age and asthma severity (interrupted sleep). IgE correlated with all three atopy-related factors, the strongest with the SPT factor whereas severity only correlated with baseline lung function, and with symptoms characteristic of rhinitis and of asthma. In children and adolescents with established asthma, five distinct sets of correlated patient characteristics appear to represent important aspects of the disease. Factor scores as quantitative traits may be better phenotypes in epidemiological and genetic analyses than those categories derived from the presence or absence of combinations of +ve SPTs and/or elevated IgE.

First report of the Armillaria root-disease pathogen, Armillaria gallica, associated with several woody hosts in three states of Mexico

Treesearch

N. B. Klopfenstein; J. W. Hanna; P. G. Cannon; R. Medel-Ortiz; D. Alvarado-Rosales; F. Lorea-Hernandez; R. D. Elias-Roman; M. -S. Kim

2014-01-01

In September 2007, rhizomorphs with morphological characteristics of Armillaria were collected from woody hosts in forests of Mexico State, Veracruz, and Oaxaca, Mexico. Based on pairing tests, isolates were assigned to five somatically compatible genets or clones (MEX7R, MEX11R, MEX23R, MEX28R, and MEX30R). These genets were all identified as Armillaria gallica based...

To test, or not to test: time for a MODY calculator?

PubMed

Njølstad, P R; Molven, A

2012-05-01

To test, or not to test, that is often the question in diabetes genetics. This is why the paper of Shields et al in the current issue of Diabetologia is so warmly welcomed. MODY is the most common form of monogenic diabetes. Nevertheless, the optimal way of identifying MODY families still poses a challenge both for researchers and clinicians. Hattersley's group in Exeter, UK, have developed an easy-to-use MODY prediction model that can help to identify cases appropriate for genetic testing. By answering eight simple questions on the internet ( www.diabetesgenes.org/content/mody-probability-calculator ), the doctor receives a positive predictive value in return: the probability that the patient has MODY. Thus, the classical binary (yes/no) assessment provided by clinical diagnostic criteria has been substituted by a more rational, quantitative estimate. The model appears to discriminate well between MODY and type 1 and type 2 diabetes when diabetes is diagnosed before the age of 35 years. However, the performance of the MODY probability calculator should now be validated in other settings than where it was developed-and, as always, there is room for some improvements and modifications.

Familial ALS

PubMed Central

Boylan, Kevin

2015-01-01

Synopsis Genes linked to ALS susceptibility are being identified at an increasing rate owing to advances in molecular genetic technology. Genetic mechanisms in ALS pathogenesis appear to exert major effects in ~10% of patients, but genetic factors at some level may be important components of disease risk in most ALS patients. Identification of gene variants associated with ALS has informed concepts of the pathogenesis of ALS, aided the identification of therapeutic targets, facilitated research to develop new ALS biomarkers, and supported the establishment of clinical diagnostic tests for ALS-linked genes. Translation of this knowledge to ALS therapy development is ongoing. PMID:26515623

Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans.

PubMed

Keaton, Jacob M; Gao, Chuan; Guan, Meijian; Hellwege, Jacklyn N; Palmer, Nicholette D; Pankow, James S; Fornage, Myriam; Wilson, James G; Correa, Adolfo; Rasmussen-Torvik, Laura J; Rotter, Jerome I; Chen, Yii-Der I; Taylor, Kent D; Rich, Stephen S; Wagenknecht, Lynne E; Freedman, Barry I; Ng, Maggie C Y; Bowden, Donald W

2018-04-24

Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (P < 5 × 10 -8 ) interaction with MTNR1B and joint effects were detected for CMIP intronic SNP rs17197883 (P interaction  = 1.43 × 10 -8 ; P joint  = 4.70 × 10 -8 ). CMIP variants have been nominally associated with T2D, fasting glucose, and adiponectin in individuals of East Asian ancestry, with high-density lipoprotein, and with waist-to-hip ratio adjusted for body mass index in Europeans. These data support the hypothesis that additional genetic factors contributing to T2D risk, including insulin sensitivity loci, can be identified through interactions with insulin secretion loci. © 2018 WILEY PERIODICALS, INC.

Microbial diversity--insights from population genetics.

PubMed

Mes, Ted H M

2008-01-01

Although many environmental microbial populations are large and genetically diverse, both the level of diversity and the extent to which it is ecologically relevant remain enigmatic. Because the effective (or long-term) population size, N(e), is one of the parameters that determines population genetic diversity, tests and simulations that assume selectively neutral mutations may help to identify the processes that have shaped microbial diversity. Using ecologically important genes, tests of selective neutrality suggest that adaptive as well as non-adaptive types of selection act and that departure from neutrality may be widespread or restricted to small groups of genotypes. Population genetic simulations using population sizes between 10(3) and 10(7) suggest extremely high levels of microbial diversity in environments that sustain large populations. However, census and effective population sizes may differ considerably, and because we know nothing of the evolutionary history of environmental microbial populations, we also have no idea what N(e) of environmental populations is. On the one hand, this reflects our ignorance of the microbial world. On the other hand, the tests and simulations illustrate interactions between microbial diversity and microbial population genetics that should inform our thinking in microbial ecology. Because of the different views on microbial diversity across these disciplines, such interactions are crucial if we are to understand the role of genes in microbial communities.

Genetic counseling and presymptomatic testing programs for Machado-Joseph Disease: lessons from Brazil and Portugal

PubMed Central

Schuler-Faccini, Lavínia; Osorio, Claudio Maria; Romariz, Flavia; Paneque, Milena; Sequeiros, Jorge; Jardim, Laura Bannach

2014-01-01

Machado-Joseph disease (MJD) is an autosomal dominant, late-onset neurological disorder and the most common form of spinocerebellar ataxia (SCA) worldwide. Diagnostic genetic testing is available to detect the disease-causing mutation by direct sizing of the CAG repeat tract in the ataxin 3 gene. Presymptomatic testing (PST) can be used to identify persons at risk of developing the disease. Genetic counseling provides patients with information about the disease, genetic risks, PST, and the decision-making process. In this study, we present the protocol used in PST for MJD and the relevant observations from two centers: Brazil (Porto Alegre) and Portugal (Porto). We provide a case report that illustrates the significant ethical and psychological issues related to PST in late-onset neurological disorders. In both centers, counseling and PST are performed by a multidisciplinary team, and genetic testing is conducted at the same institutions. From 1999 to 2012, 343 individuals sought PST in Porto Alegre; 263 (77%) of these individuals were from families with MJD. In Porto, 1,530 individuals sought PST between 1996 and 2013, but only 66 (4%) individuals were from families with MJD. In Brazil, approximately 50% of the people seeking PST eventually took the test and received their results, whereas 77% took the test in Portugal. In this case report, we highlight several issues that might be raised by the consultand and how the team can extract significant information. Literature about PST testing for MJD and other SCAs is scarce, and we hope this report will encourage similar studies and enable the implementation of PST protocols in other populations, mainly in Latin America. PMID:24764760

Convergence between biological, behavioural and genetic determinants of obesity.

PubMed

Ghosh, Sujoy; Bouchard, Claude

2017-12-01

Multiple biological, behavioural and genetic determinants or correlates of obesity have been identified to date. Genome-wide association studies (GWAS) have contributed to the identification of more than 100 obesity-associated genetic variants, but their roles in causal processes leading to obesity remain largely unknown. Most variants are likely to have tissue-specific regulatory roles through joint contributions to biological pathways and networks, through changes in gene expression that influence quantitative traits, or through the regulation of the epigenome. The recent availability of large-scale functional genomics resources provides an opportunity to re-examine obesity GWAS data to begin elucidating the function of genetic variants. Interrogation of knockout mouse phenotype resources provides a further avenue to test for evidence of convergence between genetic variation and biological or behavioural determinants of obesity.

A universal genetic testing initiative for patients with high-grade, non-mucinous epithelial ovarian cancer and the implications for cancer treatment.

PubMed

Bednar, Erica M; Oakley, Holly D; Sun, Charlotte C; Burke, Catherine C; Munsell, Mark F; Westin, Shannon N; Lu, Karen H

2017-08-01

Genetic counseling (GC) and germline genetic testing (GT) for BRCA1 and BRCA2 are considered standard of care for patients with high-grade, non-mucinous epithelial ovarian, fallopian tube, and primary peritoneal cancers (HGOC). We describe a universal genetic testing initiative to increase the rates of recommendation and acceptance of GC and GT to >80% for patients with HGOC at our institution. Data from a consecutive cohort of patients seen in our gynecologic oncology clinics between 9/1/2012 and 8/31/2015 for evaluation of HGOC were retrospectively analyzed. Data were abstracted from the tumor registry, medical records, and research databases. Descriptive statistics were used to evaluate patient characteristics and GC, GT, and PARP inhibitor use. Various clinic interventions were developed, influenced by the Plan-Do-Study-Act cycle method, which included physician-coordinated GT, integrated GC, and assisted GC referrals. A cohort of 1636 patients presented to the gynecologic oncology clinics for evaluation of HGOC during our study period, and 1423 (87.0%) were recommended to have GC and GT. Of these, 1214 (85.3%) completed GT and 217 (17.9%) were found to have a BRCA1 or BRCA2 mutation. Among BRCA-positive patients, 167 had recurrent or progressive disease, and 56 of those received PARP inhibitor therapy. The rates of GC and GT recommendation and completion among patients with HGOC at our institution exceeded 80% following the implementation of a universal genetic testing initiative. Universal genetic testing of patients with HGOC is one strategy to identify those who may benefit from PARP inhibitor therapy. Copyright © 2017. Published by Elsevier Inc.

Ethical, social, and cultural issues related to clinical genetic testing and counseling in low- and middle-income countries: protocol for a systematic review.

PubMed

Zhong, Adrina; Darren, Benedict; Dimaras, Helen

2017-07-11

There has been little focus in the literature on how to build genetic testing and counseling services in low- and middle-income countries in a responsible, ethical, and culturally appropriate manner. It is unclear to what extent this area is being explored and what form further research should take. The proposed knowledge synthesis aims to fill this gap in knowledge and mine the existing data to determine the breadth of work in this area and identify ethical, social, and cultural issues that have emerged. An integrated knowledge translation approach will be undertaken by engaging knowledge users throughout the review to ensure relevance to their practice. Electronic databases encompassing various disciplines, such as healthcare, social sciences, and public health, will be searched. Studies that address clinical genetic testing and/or counseling and ethical, social, and/or cultural issues of these genetic services, and are performed in low- and middle-income countries as defined by World Bank will be considered for inclusion. Two independent reviewers will be involved in a two-stage literature screening process, data extraction, and quality appraisal. Studies included in the review will be analyzed by thematic analysis. A narrative synthesis guided by the social ecological model will be used to summarize findings. This systematic review will provide a foundation of evidence regarding ethical, social, and cultural issues related to clinical genetic testing and counseling in low- and middle-income countries. Using the social ecological model as a conceptual framework will facilitate the understanding of broader influences of the sociocultural context on an individual's experience with clinical genetic testing and counseling, thereby informing interdisciplinary sectors in future recommendations for practice and policy. PROSPERO CRD42016042894.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waters, M.D.; Stack, H.F.; Garrett, N.E.

A graphic approach, terms a Genetic Activity Profile (GAP), was developed to display a matrix of data on the genetic and related effects of selected chemical agents. The profiles provide a visual overview of the quantitative (doses) and qualitative (test results) data for each chemical. Either the lowest effective dose or highest ineffective dose is recorded for each agent and bioassay. Up to 200 different test systems are represented across the GAP. Bioassay systems are organized according to the phylogeny of the test organisms and the end points of genetic activity. The methodology for producing and evaluating genetic activity profilemore » was developed in collaboration with the International Agency for Research on Cancer (IARC). Data on individual chemicals were compiles by IARC and by the US Environmental Protection Agency (EPA). Data are available on 343 compounds selected from volumes 1-53 of the IARC Monographs and on 115 compounds identified as Superfund Priority Substances. Software to display the GAPs on an IBM-compatible personal computer is available from the authors. Structurally similar compounds frequently display qualitatively and quantitatively similar profiles of genetic activity. Through examination of the patterns of GAPs of pairs and groups of chemicals, it is possible to make more informed decisions regarding the selection of test batteries to be used in evaluation of chemical analogs. GAPs provided useful data for development of weight-of-evidence hazard ranking schemes. Also, some knowledge of the potential genetic activity of complex environmental mixtures may be gained from an assessment of the genetic activity profiles of component chemicals. The fundamental techniques and computer programs devised for the GAP database may be used to develop similar databases in other disciplines. 36 refs., 2 figs.« less

Recommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity.

PubMed

Aminkeng, Folefac; Ross, Colin J D; Rassekh, Shahrad R; Hwang, Soomi; Rieder, Michael J; Bhavsar, Amit P; Smith, Anne; Sanatani, Shubhayan; Gelmon, Karen A; Bernstein, Daniel; Hayden, Michael R; Amstutz, Ursula; Carleton, Bruce C

2016-09-01

Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B - moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow-up, as well as therapeutic options within the current standard of clinical practice. Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT. © 2016 The British Pharmacological Society.

Recommendations for genetic testing to reduce the incidence of anthracycline‐induced cardiotoxicity

PubMed Central

Aminkeng, Folefac; Ross, Colin J. D.; Rassekh, Shahrad R.; Hwang, Soomi; Rieder, Michael J.; Bhavsar, Amit P.; Smith, Anne; Sanatani, Shubhayan; Gelmon, Karen A.; Bernstein, Daniel; Hayden, Michael R.; Amstutz, Ursula

2016-01-01

Aims Anthracycline‐induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline‐based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence‐based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. Methods We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. Results RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B – moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow‐up, as well as therapeutic options within the current standard of clinical practice. Conclusions Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT. PMID:27197003

Impact of Genetic Testing and Family Health History Based Risk Counseling on Behavior Change and Cognitive Precursors for Type 2 Diabetes.

PubMed

Wu, R Ryanne; Myers, Rachel A; Hauser, Elizabeth R; Vorderstrasse, Allison; Cho, Alex; Ginsburg, Geoffrey S; Orlando, Lori A

2017-02-01

Family health history (FHH) in the context of risk assessment has been shown to positively impact risk perception and behavior change. The added value of genetic risk testing is less certain. The aim of this study was to determine the impact of Type 2 Diabetes (T2D) FHH and genetic risk counseling on behavior and its cognitive precursors. Subjects were non-diabetic patients randomized to counseling that included FHH +/- T2D genetic testing. Measurements included weight, BMI, fasting glucose at baseline and 12 months and behavioral and cognitive precursor (T2D risk perception and control over disease development) surveys at baseline, 3, and 12 months. 391 subjects enrolled of which 312 completed the study. Behavioral and clinical outcomes did not differ across FHH or genetic risk but cognitive precursors did. Higher FHH risk was associated with a stronger perceived T2D risk (p Kendall  < 0.001) and with a perception of "serious" risk (p Kendall  < 0.001). Genetic risk did not influence risk perception, but was correlated with an increase in perception of "serious" risk for moderate (p Kendall  = 0.04) and average FHH risk subjects (p Kendall  = 0.01), though not for the high FHH risk group. Perceived control over T2D risk was high and not affected by FHH or genetic risk. FHH appears to have a strong impact on cognitive precursors of behavior change, suggesting it could be leveraged to enhance risk counseling, particularly when lifestyle change is desirable. Genetic risk was able to alter perceptions about the seriousness of T2D risk in those with moderate and average FHH risk, suggesting that FHH could be used to selectively identify individuals who may benefit from genetic risk testing.

Genomic Analyses of Patients With Unexplained Early-Onset Scoliosis.

PubMed

Gao, Xiaochong; Gotway, Garrett; Rathjen, Karl; Johnston, Charles; Sparagana, Steven; Wise, Carol A

2014-09-01

To test for rare genetic mutations, a cohort of patients with unexplained early-onset scoliosis (EOS) was screened using high-density microarray genotyping. A cohort of patients with adolescent idiopathic scoliosis (AIS) was similarly screened and the results were compared. Patients with scoliosis in infancy or early childhood (EOS) are at high risk for progressive deformity and associated problems including respiratory compromise. Early-onset scoliosis is frequently associated with genetic disorders but many patients present with nonspecific clinical features and without an associated diagnosis. The authors hypothesized that EOS in these patients may be caused by rare genetic mutations detectable by next-generation genomic methods. The researchers identified 24 patients with unexplained EOS from pediatric orthopedic clinics. They genotyped them, along with 39 connecting family members, using the Illumina OmniExpress-12, version 1.0 beadchip. Resulting genotypes were analyzed for chromosomal changes, specifically copy number variation and absence of heterozygosity. They screened 482 adolescent idiopathic scoliosis (AIS) patients and 744 healthy controls, who were similarly genotyped with the same beadchip, for chromosomal changes identified in the EOS cohort. Copy number variation and absence of heterozygosity analyses revealed a genetic diagnosis of chromosome 15q24 microdeletion syndrome in 1 patient and maternal uniparental disomy of chromosome 14 in a second one. Prior genetic testing and clinical evaluations had been negative in both cases. A large novel chromosome 10 deletion was likely causal in a third EOS patient. These mutations identified in the EOS patients were absent in AIS patients and controls, and thus were not associated with AIS or found in asymptomatic individuals. These data underscore the usefulness of updated genetic evaluations including high-density microarray-based genotyping and other next-generation methods in patients with unexplained EOS, even when prior genetic studies were negative. These data also suggest the intriguing possibility that other mutations detectable by whole genome sequencing, as well as epigenetic effects, await discovery in the EOS population. Copyright © 2014 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.

Exome Sequencing in the Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia

PubMed Central

Fogel, Brent L.; Lee, Hane; Deignan, Joshua L.; Strom, Samuel P.; Kantarci, Sibel; Wang, Xizhe; Quintero-Rivera, Fabiola; Vilain, Eric; Grody, Wayne W.; Perlman, Susan; Geschwind, Daniel H.; Nelson, Stanley F.

2015-01-01

IMPORTANCE Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established. OBJECTIVE To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia. DESIGN, SETTING, AND PARTICIPANTS We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia. MAIN OUTCOMES AND MEASURES Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation. RESULTS We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias. CONCLUSIONS AND RELEVANCE This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia. PMID:25133958

Adaptive divergence despite strong genetic drift: genomic analysis of the evolutionary mechanisms causing genetic differentiation in the island fox (Urocyon littoralis).

PubMed

Funk, W Chris; Lovich, Robert E; Hohenlohe, Paul A; Hofman, Courtney A; Morrison, Scott A; Sillett, T Scott; Ghalambor, Cameron K; Maldonado, Jesus E; Rick, Torben C; Day, Mitch D; Polato, Nicholas R; Fitzpatrick, Sarah W; Coonan, Timothy J; Crooks, Kevin R; Dillon, Adam; Garcelon, David K; King, Julie L; Boser, Christina L; Gould, Nicholas; Andelt, William F

2016-05-01

The evolutionary mechanisms generating the tremendous biodiversity of islands have long fascinated evolutionary biologists. Genetic drift and divergent selection are predicted to be strong on islands and both could drive population divergence and speciation. Alternatively, strong genetic drift may preclude adaptation. We conducted a genomic analysis to test the roles of genetic drift and divergent selection in causing genetic differentiation among populations of the island fox (Urocyon littoralis). This species consists of six subspecies, each of which occupies a different California Channel Island. Analysis of 5293 SNP loci generated using Restriction-site Associated DNA (RAD) sequencing found support for genetic drift as the dominant evolutionary mechanism driving population divergence among island fox populations. In particular, populations had exceptionally low genetic variation, small Ne (range = 2.1-89.7; median = 19.4), and significant genetic signatures of bottlenecks. Moreover, islands with the lowest genetic variation (and, by inference, the strongest historical genetic drift) were most genetically differentiated from mainland grey foxes, and vice versa, indicating genetic drift drives genome-wide divergence. Nonetheless, outlier tests identified 3.6-6.6% of loci as high FST outliers, suggesting that despite strong genetic drift, divergent selection contributes to population divergence. Patterns of similarity among populations based on high FST outliers mirrored patterns based on morphology, providing additional evidence that outliers reflect adaptive divergence. Extremely low genetic variation and small Ne in some island fox populations, particularly on San Nicolas Island, suggest that they may be vulnerable to fixation of deleterious alleles, decreased fitness and reduced adaptive potential. © 2016 John Wiley & Sons Ltd.

Examination of association to autism of common genetic variationin genes related to dopamine.

PubMed

Anderson, B M; Schnetz-Boutaud, N; Bartlett, J; Wright, H H; Abramson, R K; Cuccaro, M L; Gilbert, J R; Pericak-Vance, M A; Haines, J L

2008-12-01

Autism is a severe neurodevelopmental disorder characterized by a triad of complications. Autistic individuals display significant disturbances in language and reciprocal social interactions, combined with repetitive and stereotypic behaviors. Prevalence studies suggest that autism is more common than originally believed, with recent estimates citing a rate of one in 150. Although multiple genetic linkage and association studies have yielded multiple suggestive genes or chromosomal regions, a specific risk locus has yet to be identified and widely confirmed. Because many etiologies have been suggested for this complex syndrome, we hypothesize that one of the difficulties in identifying autism genes is that multiple genetic variants may be required to significantly increase the risk of developing autism. Thus, we took the alternative approach of examining 14 prominent dopamine pathway candidate genes for detailed study by genotyping 28 single nucleotide polymorphisms. Although we did observe a nominally significant association for rs2239535 (P=0.008) on chromosome 20, single-locus analysis did not reveal any results as significant after correction for multiple comparisons. No significant interaction was identified when Multifactor Dimensionality Reduction was employed to test specifically for multilocus effects. Although genome-wide linkage scans in autism have provided support for linkage to various loci along the dopamine pathway, our study does not provide strong evidence of linkage or association to any specific gene or combination of genes within the pathway. These results demonstrate that common genetic variation within the tested genes located within this pathway at most play a minor to moderate role in overall autism pathogenesis.

Multivariate Analysis of Genotype-Phenotype Association.

PubMed

Mitteroecker, Philipp; Cheverud, James M; Pavlicev, Mihaela

2016-04-01

With the advent of modern imaging and measurement technology, complex phenotypes are increasingly represented by large numbers of measurements, which may not bear biological meaning one by one. For such multivariate phenotypes, studying the pairwise associations between all measurements and all alleles is highly inefficient and prevents insight into the genetic pattern underlying the observed phenotypes. We present a new method for identifying patterns of allelic variation (genetic latent variables) that are maximally associated-in terms of effect size-with patterns of phenotypic variation (phenotypic latent variables). This multivariate genotype-phenotype mapping (MGP) separates phenotypic features under strong genetic control from less genetically determined features and thus permits an analysis of the multivariate structure of genotype-phenotype association, including its dimensionality and the clustering of genetic and phenotypic variables within this association. Different variants of MGP maximize different measures of genotype-phenotype association: genetic effect, genetic variance, or heritability. In an application to a mouse sample, scored for 353 SNPs and 11 phenotypic traits, the first dimension of genetic and phenotypic latent variables accounted for >70% of genetic variation present in all 11 measurements; 43% of variation in this phenotypic pattern was explained by the corresponding genetic latent variable. The first three dimensions together sufficed to account for almost 90% of genetic variation in the measurements and for all the interpretable genotype-phenotype association. Each dimension can be tested as a whole against the hypothesis of no association, thereby reducing the number of statistical tests from 7766 to 3-the maximal number of meaningful independent tests. Important alleles can be selected based on their effect size (additive or nonadditive effect on the phenotypic latent variable). This low dimensionality of the genotype-phenotype map has important consequences for gene identification and may shed light on the evolvability of organisms. Copyright © 2016 by the Genetics Society of America.

Behavioral Phenotyping Assays for Genetic Mouse Models of Neurodevelopmental, Neurodegenerative, and Psychiatric Disorders.

PubMed

Sukoff Rizzo, Stacey J; Crawley, Jacqueline N

2017-02-08

Animal models offer heuristic research tools to understand the causes of human diseases and to identify potential treatments. With rapidly evolving genetic engineering technologies, mutations identified in a human disorder can be generated in the mouse genome. Phenotypic outcomes of the mutation are then explicated to confirm hypotheses about causes and to discover effective therapeutics. Most neurodevelopmental, neurodegenerative, and psychiatric disorders are diagnosed primarily by their prominent behavioral symptoms. Mouse behavioral assays analogous to the human symptoms have been developed to analyze the consequences of mutations and to evaluate proposed therapeutics preclinically. Here we describe the range of mouse behavioral tests available in the established behavioral neuroscience literature, along with examples of their translational applications. Concepts presented have been successfully used in other species, including flies, worms, fish, rats, pigs, and nonhuman primates. Identical strategies can be employed to test hypotheses about environmental causes and gene × environment interactions.

Woman's Pre-Conception Evaluation: Genetic and Fetal Risk Considerations for Counselling and Informed Choice.

PubMed

Wilson, R Douglas

2017-10-11

To inform reproductive and other health care providers about genetic and fetal risk information to consider during a woman/couples' pre-conception evaluation, including considerations for genetic risk assessment, genetic screening, or testing to allow for improved counselling and informed choice. This genetic information can be used for patient education, planning, and possible pre-conception and/or prenatal testing. This information may allow improved risk assessment for pre-conception counselling for individual patients and their families. PubMed or Medline and the Cochrane Database were searched in May 2017 using appropriate key words ("pre-conception," "genetic disease," "maternal," "family history," "genetic," "health risk," "genetic health surveillance," "prenatal screening," "prenatal diagnosis," "birth defects," and "teratogen"). Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, and national and international medical specialty societies. The benefits for the patient and her family include an increased understanding of relevant genetic risk pre-conception and in early pregnancy, and better pregnancy outcomes as a result of use of the information. The harm includes potential increased anxiety or psychological stress associated with the possibility of identifying genetic risks. The evidence obtained was peer-reviewed by the Genetics Committee of The Society of Obstetricians and Gynaecologists of Canada. Consideration for Care Statements For this review article, the Consideration for Care Statements use the GRADE strength and quality as it is comparable for the clinician and the patient/public user. [GRADE from the Canadian Task Force on Preventive Health Care (www.canadiantaskforce.ca). For clinicians, Strong = The recommendation would apply to most individuals. Formal discussion aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. For patients/public, Strong = We believe most people in this situation would want the recommended course of actions and only a small number would not. Quality of evidence (High, Moderate, Low) based on the confidence that the true effect lies close to that of the estimate of the effect.] Conclusion Pre-conception planning is presently underutilized by both patients and providers. Pre-conception genetic assessment is only a part of the counselling, education, and health management change that can improve perinatal and maternal morbidity and mortality. A published literature review on pre-conception genetic counselling identified mainly clinical cohort studies, surveys, and expert opinion with no RCTs. There is strong support for pre-conception counselling and moderate quality based on the understanding that most individuals would support and use pre-conception counselling when choice, timing, and ease of access is considered. Copyright © 2017 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.

Genetics and Insurance in Australia: Concerns around a Self-Regulated Industry.

PubMed

Newson, Ainsley J; Tiller, Jane; Keogh, Louise A; Otlowski, Margaret; Lacaze, Paul

2017-01-01

Regulating the use of genetic information in insurance is an issue of ongoing international debate. In Australia, providers of life and other mutually rated insurance products can request applicants to disclose all results from any genetic test. Insurers can then use this information to adjust premiums and make policy decisions. The Australian Financial Services Council (FSC; an industry body) developed and maintains the relevant industry standard, which was updated in late 2016. Aims/Objective: To review the 2016 FSC Standard in light of relevant research and determine the legitimacy of the Australian regulatory environment regarding use of genetic information by insurers. We identified five concerns arising from the 2016 FSC Standard: (1) use of results obtained from research; (2) the requirement for an applicant to disclose whether they are "considering" a genetic test; (3) failure to account for genome sequencing and other technology developments; (4) limited evidence regarding adverse selection; and (5) the inappropriateness of industry self-regulation. Industry self-regulation of the use of genetic information by life insurers, combined with a lack of government oversight, is inappropriate and threatens to impede the progress of genomic medicine in Australia. At this critical time, Australia requires closer government oversight of the use of genetic information in insurance. © 2017 S. Karger AG, Basel.

Ambiguous genitalia: what prenatal genetic testing is practical?

PubMed

Adam, Margaret P; Fechner, Patricia Y; Ramsdell, Linda A; Badaru, Angela; Grady, Richard E; Pagon, Roberta A; McCauley, Elizabeth; Cheng, Edith Y; Parisi, Melissa A; Shnorhavorian, Margarett

2012-06-01

Concern for ambiguous genitalia or chromosome-phenotype discordance detected in a prenatal setting has increased over the last two decades. Practitioners faced with this prenatal finding have a variety of genetic tests available to them; however, it is unclear to what extent prenatal testing for disorders of sex development (DSD) is useful or practical. We undertook a retrospective review of the medical records of 140 individuals evaluated through the DSD clinic at Seattle Children's Hospital with birthdates from 01/01/1994 through 08/16/2011 to determine the rate of prenatal detection of ambiguous genitalia in individuals with DSD, what prenatal diagnostic workup was undertaken, and the postnatal outcome, including whether a postnatal genetic diagnosis was confirmed. Of all 140 subjects, 34 (24%) were identified prenatally. The most common postnatal diagnoses were penoscrotal hypospadias with transposition of the scrotum with no known genetic cause (24/140; 17%) and 21-hydroxylase deficiency (20/140; 14%). Apart from these, no single diagnosis comprised more than a few cases. Prenatal diagnostic testing varied widely, from no tests to multiple molecular tests with amniotic fluid hormone concentrations. In the absence of other fetal anomalies or growth retardation on ultrasound, prenatal karyotype with fluorescence in situ hybridization for the SRY gene is the most useful test when ambiguous genitalia is suspected. Further prenatal testing for Smith-Lemli-Opitz syndrome in 46,XY individuals and congenital adrenal hyperplasia in 46,XX individuals may be considered. However, targeted molecular testing for rare DSD conditions in the absence of a family history of DSD has a low yield. Copyright © 2012 Wiley Periodicals, Inc.

Polygenic risk, rapid childhood growth, and the development of obesity: evidence from a 4-decade longitudinal study.

PubMed

Belsky, Daniel W; Moffitt, Terrie E; Houts, Renate; Bennett, Gary G; Biddle, Andrea K; Blumenthal, James A; Evans, James P; Harrington, Honalee; Sugden, Karen; Williams, Benjamin; Poulton, Richie; Caspi, Avshalom

2012-06-01

To test how genomic loci identified in genome-wide association studies influence the development of obesity. A 38-year prospective longitudinal study of a representative birth cohort. The Dunedin Multidisciplinary Health and Development Study, Dunedin, New Zealand. One thousand thirty-seven male and female study members. We assessed genetic risk with a multilocus genetic risk score. The genetic risk score was composed of single-nucleotide polymorphisms identified in genome-wide association studies of obesity-related phenotypes. We assessed family history from parent body mass index data collected when study members were 11 years of age. Body mass index growth curves, developmental phenotypes of obesity, and adult obesity outcomes were defined from anthropometric assessments at birth and at 12 subsequent in-person interviews through 38 years of age. Individuals with higher genetic risk scores were more likely to be chronically obese in adulthood. Genetic risk first manifested as rapid growth during early childhood. Genetic risk was unrelated to birth weight. After birth, children at higher genetic risk gained weight more rapidly and reached adiposity rebound earlier and at a higher body mass index. In turn, these developmental phenotypes predicted adult obesity, mediating about half the genetic effect on adult obesity risk. Genetic associations with growth and obesity risk were independent of family history, indicating that the genetic risk score could provide novel information to clinicians. Genetic variation linked with obesity risk operates, in part, through accelerating growth in the early childhood years after birth. Etiological research and prevention strategies should target early childhood to address the obesity epidemic.

High burden of genetic conditions diagnosed in a cardiac neurodevelopmental clinic.

PubMed

Goldenberg, Paula C; Adler, Betsy J; Parrott, Ashley; Anixt, Julia; Mason, Karen; Phillips, Jannel; Cooper, David S; Ware, Stephanie M; Marino, Bradley S

2017-04-01

There is a known high prevalence of genetic and clinical syndrome diagnoses in the paediatric cardiac population. These disorders often have multisystem effects, which may have an important impact on neurodevelopmental outcomes. Taken together, these facts suggest that patients and families may benefit from consultation by genetic specialists in a cardiac neurodevelopmental clinic. This study assessed the burden of genetic disorders and utility of genetics evaluation in a cardiac neurodevelopmental clinic. A retrospective chart review was conducted of patients evaluated in a cardiac neurodevelopmental clinic from 6 December, 2011 to 16 April, 2013. All patients were seen by a cardiovascular geneticist with genetic counselling support. A total of 214 patients were included in this study; 64 of these patients had a pre-existing genetic or syndromic diagnosis. Following genetics evaluation, an additional 19 were given a new clinical or laboratory-confirmed genetic diagnosis including environmental such as teratogenic exposures, malformation associations, chromosomal disorders, and single-gene disorders. Genetic testing was recommended for 112 patients; radiological imaging to screen for congenital anomalies for 17 patients; subspecialist medical referrals for 73 patients; and non-genetic clinical laboratory testing for 14 patients. Syndrome-specific guidelines were available and followed for 25 patients with known diagnosis. American Academy of Pediatrics Red Book asplenia guideline recommendations were given for five heterotaxy patients, and family-based cardiac screening was recommended for 23 families affected by left ventricular outflow tract obstruction. Genetics involvement in a cardiac neurodevelopmental clinic is helpful in identifying new unifying diagnoses and providing syndrome-specific care, which may impact the patient's overall health status and neurodevelopmental outcome.

Identifying signatures of positive selection in pigmentation genes in two South Asian populations.

PubMed

Jonnalagadda, Manjari; Bharti, Neeraj; Patil, Yatish; Ozarkar, Shantanu; K, Sunitha Manjari; Joshi, Rajendra; Norton, Heather

2017-09-10

Skin pigmentation is a polygenic trait showing wide phenotypic variations among global populations. While numerous pigmentation genes have been identified to be under positive selection among European and East populations, genes contributing to phenotypic variation in skin pigmentation within and among South Asian populations are still poorly understood. The present study uses data from the Phase 3 of the 1000 genomes project focusing on two South Asian populations-GIH (Gujarati Indian from Houston, Texas) and ITU (Indian Telugu from UK), so as to decode the genetic architecture involved in adaptation to ultraviolet radiation in South Asian populations. Statistical tests included were (1) tests to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima's D, Fay and Wu's H and Fu and Li's D* and F*), (2) tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb), and (3) tests based on genetic differentiation between populations (LSBL). Twenty-two pigmentation genes fall in the top 1% for at least one statistic in the GIH population, 5 of which (LYST, OCA2, SLC24A5, SLC45A2, and TYR) have been previously associated with normal variation in skin, hair, or eye color. In comparison, 17 genes fall in the top 1% for at least one statistic in the ITU population. Twelve loci which are identified as outliers in the ITU scan were also identified in the GIH population. These results suggest that selection may have affected these loci broadly across the region. © 2017 Wiley Periodicals, Inc.

Development and validation of a brief screening instrument for psychosocial risk associated with genetic testing: a pan-Canadian cohort study

PubMed Central

Esplen, Mary Jane; Cappelli, Mario; Wong, Jiahui; Bottorff, Joan L; Hunter, Jon; Carroll, June; Dorval, Michel; Wilson, Brenda; Allanson, Judith; Semotiuk, Kara; Aronson, Melyssa; Bordeleau, Louise; Charlemagne, Nicole; Meschino, Wendy

2013-01-01

Objectives To develop a brief, reliable and valid instrument to screen psychosocial risk among those who are undergoing genetic testing for Adult-Onset Hereditary Disease (AOHD). Design A prospective two-phase cohort study. Setting 5 genetic testing centres for AOHD, such as cancer, Huntington's disease or haemochromatosis, in ambulatory clinics of tertiary hospitals across Canada. Participants 141 individuals undergoing genetic testing were approached and consented to the instrument development phase of the study (Phase I). The Genetic Psychosocial Risk Instrument (GPRI) developed in Phase I was tested in Phase II for item refinement and validation. A separate cohort of 722 individuals consented to the study, 712 completed the baseline package and 463 completed all follow-up assessments. Most participants were female, at the mid-life stage. Individuals in advanced stages of the illness or with cognitive impairment or a language barrier were excluded. Interventions Phase I: GPRI items were generated from (1) a review of the literature, (2) input from genetic counsellors and (3) phase I participants. Phase II: further item refinement and validation were conducted with a second cohort of participants who completed the GPRI at baseline and were followed for psychological distress 1-month postgenetic testing results. Primary and secondary outcome measures GPRI, Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Brief Symptom Inventory (BSI) and Impact of Event Scale (IES). Results The final 20-item GPRI had a high reliability—Cronbach's α at 0.81. The construct validity was supported by high correlations between GPRI and BSI and IES. The predictive value was demonstrated by a receiver operating characteristic curve of 0.78 plotting GPRI against follow-up assessments using HAM-D and HAM-A. Conclusions With a cut-off score of 50, GPRI identified 84% of participants who displayed distress postgenetic testing results, supporting its potential usefulness in a clinical setting. PMID:23485718

OPATs: Omnibus P-value association tests.

PubMed

Chen, Chia-Wei; Yang, Hsin-Chou

2017-07-10

Combining statistical significances (P-values) from a set of single-locus association tests in genome-wide association studies is a proof-of-principle method for identifying disease-associated genomic segments, functional genes and biological pathways. We review P-value combinations for genome-wide association studies and introduce an integrated analysis tool, Omnibus P-value Association Tests (OPATs), which provides popular analysis methods of P-value combinations. The software OPATs programmed in R and R graphical user interface features a user-friendly interface. In addition to analysis modules for data quality control and single-locus association tests, OPATs provides three types of set-based association test: window-, gene- and biopathway-based association tests. P-value combinations with or without threshold and rank truncation are provided. The significance of a set-based association test is evaluated by using resampling procedures. Performance of the set-based association tests in OPATs has been evaluated by simulation studies and real data analyses. These set-based association tests help boost the statistical power, alleviate the multiple-testing problem, reduce the impact of genetic heterogeneity, increase the replication efficiency of association tests and facilitate the interpretation of association signals by streamlining the testing procedures and integrating the genetic effects of multiple variants in genomic regions of biological relevance. In summary, P-value combinations facilitate the identification of marker sets associated with disease susceptibility and uncover missing heritability in association studies, thereby establishing a foundation for the genetic dissection of complex diseases and traits. OPATs provides an easy-to-use and statistically powerful analysis tool for P-value combinations. OPATs, examples, and user guide can be downloaded from http://www.stat.sinica.edu.tw/hsinchou/genetics/association/OPATs.htm. © The Author 2017. Published by Oxford University Press.

The Role of Genetics in Advancing Precision Medicine for Alzheimer's Disease-A Narrative Review.

PubMed

Freudenberg-Hua, Yun; Li, Wentian; Davies, Peter

2018-01-01

Alzheimer's disease (AD) is the most common type of dementia, which has a substantial genetic component. AD affects predominantly older people. Accordingly, the prevalence of dementia has been rising as the population ages. To date, there are no effective interventions that can cure or halt the progression of AD. The only available treatments are the management of certain symptoms and consequences of dementia. The current state-of-the-art medical care for AD comprises three simple principles: prevent the preventable, achieve early diagnosis, and manage the manageable symptoms. This review provides a summary of the current state of knowledge of risk factors for AD, biological diagnostic testing, and prospects for treatment. Special emphasis is given to recent advances in genetics of AD and the way genomic data may support prevention, early intervention, and development of effective pharmacological treatments. Mutations in the APP, PSEN1 , and PSEN2 genes cause early onset Alzheimer's disease (EOAD) that follows a Mendelian inheritance pattern. For late onset Alzheimer's disease (LOAD), APOE4 was identified as a major risk allele more than two decades ago. Population-based genome-wide association studies of late onset AD have now additionally identified common variants at roughly 30 genetic loci. Furthermore, rare variants (allele frequency <1%) that influence the risk for LOAD have been identified in several genes. These genetic advances have broadened our insights into the biological underpinnings of AD. Moreover, the known genetic risk variants could be used to identify presymptomatic individuals at risk for AD and support diagnostic assessment of symptomatic subjects. Genetic knowledge may also facilitate precision medicine. The goal of precision medicine is to use biological knowledge and other health information to predict individual disease risk, understand disease etiology, identify disease subcategories, improve diagnosis, and provide personalized treatment strategies. We discuss the potential role of genetics in advancing precision medicine for AD along with its ethical challenges. We outline strategies to implement genomics into translational clinical research that will not only improve accuracy of dementia diagnosis, thus enabling more personalized treatment strategies, but may also speed up the discovery of novel drugs and interventions.

The Role of Genetics in Advancing Precision Medicine for Alzheimer’s Disease—A Narrative Review

PubMed Central

Freudenberg-Hua, Yun; Li, Wentian; Davies, Peter

2018-01-01

Alzheimer’s disease (AD) is the most common type of dementia, which has a substantial genetic component. AD affects predominantly older people. Accordingly, the prevalence of dementia has been rising as the population ages. To date, there are no effective interventions that can cure or halt the progression of AD. The only available treatments are the management of certain symptoms and consequences of dementia. The current state-of-the-art medical care for AD comprises three simple principles: prevent the preventable, achieve early diagnosis, and manage the manageable symptoms. This review provides a summary of the current state of knowledge of risk factors for AD, biological diagnostic testing, and prospects for treatment. Special emphasis is given to recent advances in genetics of AD and the way genomic data may support prevention, early intervention, and development of effective pharmacological treatments. Mutations in the APP, PSEN1, and PSEN2 genes cause early onset Alzheimer’s disease (EOAD) that follows a Mendelian inheritance pattern. For late onset Alzheimer’s disease (LOAD), APOE4 was identified as a major risk allele more than two decades ago. Population-based genome-wide association studies of late onset AD have now additionally identified common variants at roughly 30 genetic loci. Furthermore, rare variants (allele frequency <1%) that influence the risk for LOAD have been identified in several genes. These genetic advances have broadened our insights into the biological underpinnings of AD. Moreover, the known genetic risk variants could be used to identify presymptomatic individuals at risk for AD and support diagnostic assessment of symptomatic subjects. Genetic knowledge may also facilitate precision medicine. The goal of precision medicine is to use biological knowledge and other health information to predict individual disease risk, understand disease etiology, identify disease subcategories, improve diagnosis, and provide personalized treatment strategies. We discuss the potential role of genetics in advancing precision medicine for AD along with its ethical challenges. We outline strategies to implement genomics into translational clinical research that will not only improve accuracy of dementia diagnosis, thus enabling more personalized treatment strategies, but may also speed up the discovery of novel drugs and interventions. PMID:29740579

What Is Genetic Ancestry Testing?

MedlinePlus

... Testing What is genetic ancestry testing? What is genetic ancestry testing? Genetic ancestry testing, or genetic genealogy, ... mixed with other groups. For more information about genetic ancestry testing: The University of Utah provides video ...

Diagnostic genetic testing for patients with bilateral optic neuropathy and comparison of clinical features according to OPA1 mutation status.

PubMed

Gaier, Eric D; Boudreault, Katherine; Nakata, Isao; Janessian, Maria; Skidd, Philip; DelBono, Elizabeth; Allen, Keri F; Pasquale, Louis R; Place, Emily; Cestari, Dean M; Stacy, Rebecca C; Rizzo, Joseph F; Wiggs, Janey L

2017-01-01

Inherited optic neuropathy is genetically heterogeneous, and genetic testing has an important role in risk assessment and counseling. The purpose of this study is to determine the prevalence and spectrum of mutations in a group of patients referred for genetic testing to a tertiary center in the United States. In addition, we compared the clinical features of patients with and without mutations in OPA1 , the gene most commonly involved in dominantly inherited optic atrophy. Clinical data and genetic testing results were reviewed for 74 unrelated, consecutive patients referred with a history of insidious, relatively symmetric, bilateral visual loss secondary to an optic neuropathy. Patients were evaluated for disease-causing variants in OPA1 , OPA3 , WFS1 , and the entire mitochondrial genome with DNA sequencing and copy number variation (CNV) testing. Pathogenic DNA variants were found in 25 cases, with the majority (24 patients) located in OPA1 . Demographics, clinical history, and clinical features for the group of patients with mutations in OPA1 were compared to those without disease-causing variants. Compared to the patients without mutations, cases with mutations in OPA1 were more likely to have a family history of optic nerve disease (p = 0.027); however, 30.4% of patients without a family history of disease also had mutations in OPA1 . OPA1 mutation carriers had less severe mean deviation and pattern standard deviation on automated visual field testing than patients with optic atrophy without mutations in OPA1 (p<0.005). Other demographic and ocular features were not statistically significantly different between the two groups, including the fraction of patients with central scotomas (42.9% of OPA1 mutation positive and 66.0% of OPA1 mutation negative). Genetic testing identified disease-causing mutations in 34% of referred cases, with the majority of these in OPA1. Patients with mutations in OPA1 were more likely to have a family history of disease; however, 30.4% of patients without a family history were also found to have an OPA1 mutation. This observation, as well as similar frequencies of central scotomas in the groups with and without mutations in OPA1 , underscores the need for genetic testing to establish an OPA1 genetic diagnosis.