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Sample records for genetic diagnosis pgd

  1. [Preimplantation genetic diagnosis (PGD) of hereditary cancer syndromes].

    PubMed

    Raszyková, L; Hořínová, V; Texl, P

    2012-01-01

    Advances in molecular biology techniques made possible genotype analysis from one or several cells. This can be used in preimplantation genetic diagnosis (PGD) not only of chromosomal aneuploidy but also of single gene diseases as well as hereditary cancer syndromes. PGD can be a benefit for those cases when the risk of transfer of pathological alteration from parent to offspring is unwelcome. We submit three cases of PGD with the results.

  2. Views of Preimplantation Genetic Diagnosis (PGD) among Psychiatrists and Neurologists

    PubMed Central

    Abbate, Kristopher J.; Klitzman, Robert; Chung, Wendy K.; Ottman, Ruth; Leu, Cheng-Shiun; Appelbaum, Paul S.

    2014-01-01

    Objective As prenatal genetic testing (GT) and Preimplantation Genetic Diagnosis (PGD) use increase, providers in many specialties may play roles in patient discussions and referrals. Hence, we examined key aspects of neurologists’ and psychiatrists’ views and approaches. Study Design We surveyed attitudes and practices among 163 neurologists and 372 psychiatrists. Results 24.9% of neurologists and 31.9% of psychiatrists had discussed prenatal GT with patients, but 95.3% didn’t feel comfortable discussing PGD; only 2.9% discussed it; and only 1.8% had patients ask about PGD. Most would refer for PGD for Huntington’s disease (HD) and Tay-Sachs, fewer for Cystic Fibrosis (CF), and fewer still for autism, Alzheimer’s (AD), or gender selection for family balancing; in each of these cases, psychiatrists > neurologists. Providers who’d refer for PGD for HD, CF, or gender selection differed from others in proportions of patients with insurance, were more likely to have undergone a GT themselves, and be concerned about discrimination. Conclusions These data, the first to examine how neurologists and psychiatrists view PGD, suggest they don’t feel comfortable discussing PGD, but have strong views about its use. Potential PGD use is associated with concerns about discrimination, and less experience with GT. These data highlight needs for enhancing education about these technologies among various providers. PMID:25098029

  3. Knowledge and Educational Needs about Pre-Implantation Genetic Diagnosis (PGD) among Oncology Nurses

    PubMed Central

    Quinn, Gwendolyn P.; Knapp, Caprice; Sehovic, Ivana; Ung, Danielle; Bowman, Meghan; Gonzalez, Luis; Vadaparampil, Susan T.

    2014-01-01

    Preimplantation genetic diagnosis (PGD), a form of assisted reproductive technology, is a new technology with limited awareness among health care professionals and hereditary cancer families. Nurses play a key role in the care of patients and are often in an ideal position to discuss and refer patients on sensitive quality of life issues, such as PGD. Two hundred and one nurses at Moffitt Cancer Center (MCC) responded to an online survey assessing knowledge and educational needs regarding PGD and families with hereditary cancer. The majority of respondents were female (n = 188), white (n = 175), had an RN/BSN degree (n = 83), and provided outpatient care at the cancer center (n = 102). More than half of respondents (78%) were unfamiliar with PGD prior to the survey and respondents who had heard of PGD had limited knowledge. More than half of the participants reported PGD was an acceptable option for families with hereditary cancer syndromes and thought individuals with a strong family or personal history should be provided with information about PGD. This study indicates that oncology nurses may benefit from and desire education about PGD. With advances in reproductive technology and options, further PGD education is needed among healthcare professionals. An examination of current oncology nursing curriculum and competencies regarding genetic education may identify need for future revisions and updates. PMID:26237394

  4. On the relation between moral, legal and evaluative justifications of pre-implantation genetic diagnosis (PGD).

    PubMed

    Lohmann, Georg

    2003-01-01

    In Germany the question whether to uphold or repeal the judicial prohibition on Pre-implantation Genetic Diagnosis (PGD) is being debated from quite different standpoints. This paper differentiates the major arguments according to their reasons as a) moral, b) evaluative (i.e. cultural/religious), and c) legal. The arguments for and against PGD can be divided by content into three groups: arguments relating to the status of the embryo, focusing on individual actions in the implementation of PGD, and relating to the foreseeable or probable consequences of PGD. In Germany, from a legal perspective, the status of the embryo does not permit the intervention of PGD; from a purely moral perspective, a prohibition on PGD does not appear defensible. It remains an open question, however, whether the moral argument permitting PGD should be restricted for evaluative (cultural) reasons. The paper discusses the species-ethical reasons, for which Jurgen Habermas sees worrisome consequences in the wake of PGD to the extent that we comprehend it as the forerunner of a 'positive eugenics'. It would so disrupt the natural preconditions of our universal morality. The question of whether to prohibit or allow PGD is not merely a question of simple moral and/or legal arguments, but demands a choice between evaluative, moral and (still to be specified) species-ethical arguments, and the question remains open.

  5. ESHRE Preimplantation Genetic Diagnosis (PGD) Consortium: preliminary assessment of data from January 1997 to September 1998. ESHRE PGD Consortium Steering Committee.

    PubMed

    Geraedts, J; Handyside, A; Harper, J; Liebaers, I; Sermon, K; Staessen, C; Thornhill, A; Vanderfaeillie, A; Viville, S

    1999-12-01

    The first clinical application of preimplantation genetic diagnosis (PGD) was reported almost a decade ago. Since then, the range of genetic defects that can be detected at single cell level has increased dramatically. At the 13th Annual Meeting of ESHRE in Edinburgh in 1997, a PGD Consortium was formed to undertake the first systematic and long-term study of the efficacy and clinical outcome of PGD. We report here the first data collection covering the period of January 1997 to September 1998. Referral data on 323 couples have been collected for a variety of monogenic and chromosomal disorders, providing information about which patients, at risk for which genetic diseases, are interested in PGD. Data were collected on 392 PGD cycles, resulting in 302 embryo transfers and 66 clinical pregnancies. Because of the importance of follow-up of the children born after PGD, participating centres were asked to contribute data on the pregnancies achieved and the children born after PGD since the start of their PGD programme. Data on 82 pregnancies and 110 fetal sacs were collected, and information was available on 79 children. Finally, biopsy, fluorescence in-situ hybridization and polymerase chain reaction protocols were collected, clearly showing that no consensus exists on technical aspects such as which culture medium to use, and emphasizing the role the PGD Consortium could play in setting up guidelines for good laboratory practice. In conclusion, it is clear that the effort of gathering data on PGD cycles is worthwhile and will be continued in the future, preferably using electronic data collection. PMID:10601110

  6. Preimplantation Genetic Diagnosis (PGD) on In-Vitro Fertilization (IVF) Websites: Presentations of Risks, Benefits and Other Information

    PubMed Central

    Klitzman, Robert; Zolovska, Beata; Folberth, William; Sauer, Mark V.; Chung, Wendy; Appelbaum, Paul

    2010-01-01

    Objective To examine information on Preimplantation Genetic Diagnosis (PGD) presented on In-Vitro Fertilization (IVF) clinic websites. Design We systematically sampled every third IVF clinic on the 2004 CDC provider list. Setting The Internet. Patients None. Interventions None. Main Outcome Measures Benefits, risks and other types of information mentioned regarding PGD. Results Of 135 sites examined, 88.1% had websites, and 70% mentioned PGD, of which 27% were university/hospital-based and 63% were private clinics. Sites mentioning PGD listed uses/benefits of PGD far more than the risks involved. Of these sites, 76% described testing for single gene diseases, but fewer mentioned risks of missing target diagnoses (35%), or risks for loss of embryo (18%); and 14% described PGD as new or controversial. Private clinics were more likely than other programs to: be on either the East or West Coasts; list certain PGD risks (e.g., diagnostic error); note that PGD was new or controversial; reference source of PGD information; provide accuracy rates of genetic testing of embryos; and offer gender selection for social reasons. Conclusions Most IVF clinics advertise PGD on-line, but the scope and quality of information about it varies widely, emphasizing benefits while minimizing risks. Clinics and patients may benefit from more thorough and consistent presentation of PGD, drawing on available evidence to best provide a realistic portrayal of PGD. PMID:18829009

  7. Accuracy of preimplantation genetic diagnosis (PGD) of single gene and chromosomal disorders

    SciTech Connect

    Verlinsky, Y.; Strom, C.; Rechitsky, S.

    1994-09-01

    We have developed a polar body inferred approach for preconception diagnosis of single gene and chromosomal disorders. Preconception PCR or FISH analysis was performed in a total of 310 first polar bodies for the following genetic conditions: cystic fibrosis, hemophilia A, alpha-1-antitrypsin deficiency, Tay Sachs disease, retinitis pigmentosa and common chromosomal trisomies. An important advantage of this approach is the avoidance of sperm (DNA) contamination, which is the major problem of PGD. We are currently applying FISH analysis of biopsied blastomeres, in combination with PCR or separately, and have demonstrated a significant improvement of the accuracy of PGD of X-linked disorders at this stage. Our data have also demonstrated feasibility of the application of FISH technique for PGD of chromosomal disorders. It was possible to detect chromosomal non-disjunctions and chromatid malsegregations in the first meiotic division, as well as to evaluate chromosomal mutations originating from the second meiotic nondisjunction.

  8. Preimplantation genetic diagnosis (PGD) in Europe: diversity of legislation a challenge to the community and its citizens.

    PubMed

    Soini, S

    2007-06-01

    Preimplantation genetic diagnosis (PGD) aims to safeguard the reproductive confidence of couples who have an increased risk of having a child with a serious hereditary disease. Non-directive genetic counselling is an essential part of PGD. Lately, performance of PGD for some new and non-medical indications, such as selecting for a tissue-matching embryo for a saviour sibling, or sex-selection for family-balancing, has raised ethical concerns. Who decides when to perform PGD, and for which conditions? The European member states have very diverse regulation on PGD. Some countries totally ban PGD, while the others keep close track of the new applications. The people in need of PGD seek it in the other member states. These cross-border treatments cause psychological stress and pose many so far unresolved legal questions. The individuals need more information about all the aspects of PGD. This article analyses contemporary indications for PGD in Europe and relevant ethical discussion, and second, shows the diversity in regulation and reflects the consequences thereof.

  9. Preimplantation genetic diagnosis (PGD) according to medical ethics and medical law

    PubMed Central

    Lutz, Emine Elif Vatanoğlu

    2012-01-01

    Assisted reproductive techniques not only nourish great and sometimes illusive hopes of couples who yearn for babies, but also spark new debates by reversing opinions, beliefs and values. Applications made to infertility clinics are increasing due to the influences such as broadcasts made by the media concerning assisted reproductive techniques and other infertility treatments, increase in the knowledge that people have about these problems, late marriages and postponement of childbearing age owing to sociological changes. Pre-implantation genetic diagnosis (PGD) is a technique applied to couples who are known to carry genetic diseases or who have children with genetic diseases. This technique is conducted by doctors in Turkey for its important contribution to decreasing the risk of genetic diseases and in order to raise healthy generations. In this paper, the general ethical debates and the legal situation in Turkey will be discussed. PMID:24627675

  10. Religious Scholars' Attitudes and Views on Ethical Issues Pertaining to Pre-Implantation Genetic Diagnosis (PGD) in Malaysia.

    PubMed

    Olesen, A; Nor, S N; Amin, L

    2016-09-01

    Pre-Implantation Genetic Diagnosis (PGD) represents the first fusion of genomics and assisted reproduction and the first reproductive technology that allows prospective parents to screen and select the genetic characteristics of their potential offspring. However, for some, the idea that we can intervene in the mechanisms of human existence at such a fundamental level can be, at a minimum, worrying and, at most, repugnant. Religious doctrines particularly are likely to collide with the rapidly advancing capability for science to make such interventions. This paper focuses on opinions and arguments of selected religious scholars regarding ethical issues pertaining to PGD. In-depth interviews were conducted with religious scholars from three different religious organizations in the Klang Valley, Malaysia. Findings showed that Christian scholars are very sceptical of the long-term use of PGD because of its possible effect on the value of humanity and the parent-children relationship. This differs from Islamic scholars, who view PGD as God-given knowledge in medical science to further help humans understand medical genetics. For Buddhist scholars, PGD is considered to be new medical technology that can be used to save lives, avoid suffering, and bring happiness to those who need it. Our results suggest that it is important to include the opinions and views of religious scholars when it comes to new medical technologies such as PGD, as their opinions will have a significant impact on people from various faiths, particularly in a multi-religious country like Malaysia where society places high value on marital relationships and on the traditional concepts of family.

  11. Religious Scholars' Attitudes and Views on Ethical Issues Pertaining to Pre-Implantation Genetic Diagnosis (PGD) in Malaysia.

    PubMed

    Olesen, A; Nor, S N; Amin, L

    2016-09-01

    Pre-Implantation Genetic Diagnosis (PGD) represents the first fusion of genomics and assisted reproduction and the first reproductive technology that allows prospective parents to screen and select the genetic characteristics of their potential offspring. However, for some, the idea that we can intervene in the mechanisms of human existence at such a fundamental level can be, at a minimum, worrying and, at most, repugnant. Religious doctrines particularly are likely to collide with the rapidly advancing capability for science to make such interventions. This paper focuses on opinions and arguments of selected religious scholars regarding ethical issues pertaining to PGD. In-depth interviews were conducted with religious scholars from three different religious organizations in the Klang Valley, Malaysia. Findings showed that Christian scholars are very sceptical of the long-term use of PGD because of its possible effect on the value of humanity and the parent-children relationship. This differs from Islamic scholars, who view PGD as God-given knowledge in medical science to further help humans understand medical genetics. For Buddhist scholars, PGD is considered to be new medical technology that can be used to save lives, avoid suffering, and bring happiness to those who need it. Our results suggest that it is important to include the opinions and views of religious scholars when it comes to new medical technologies such as PGD, as their opinions will have a significant impact on people from various faiths, particularly in a multi-religious country like Malaysia where society places high value on marital relationships and on the traditional concepts of family. PMID:27365102

  12. Media debates and 'ethical publicity' on social sex selection through preimplantation genetic diagnosis (PGD) technology in Australia.

    PubMed

    Whittaker, Andrea

    2015-01-01

    This paper offers a critical discourse analysis of media debate over social sex selection in the Australian media from 2008 to 2014. This period coincides with a review of the National Health and Medical Research Council's Ethical Guidelines on the Use of Assisted Reproductive Technology in Clinical Practice and Research (2007), which underlie the regulation of assisted reproductive clinics and practice in Australia. I examine the discussion of the ethics of pre-implatation genetic diagnosis (PGD) within the media as 'ethical publicity' to the lay public. Sex selection through PGD is both exemplary of and interconnected with a range of debates in Australia about the legitimacy of certain reproductive choices and the extent to which procreative liberties should be restricted. Major themes emerging from media reports on PGD sex selection in Australia are described. These include: the spectre of science out of control; ramifications for the contestation over the public funding of abortion in Australia; private choices versus public authorities regulating reproduction; and the ethics of travelling overseas for the technology. It is concluded that within Australia, the issue of PGD sex selection is framed in terms of questions of individual freedom against the principle of sex discrimination - a principle enshrined in legislation - and a commitment to publically-funded medical care.

  13. Derivation of HVR1, HVR2 and HVR3 human embryonic stem cell lines from IVF embryos after preimplantation genetic diagnosis (PGD) for monogenic disorder.

    PubMed

    Hmadcha, Abdelkrim; Aguilera, Yolanda; Lozano-Arana, Maria Dolores; Mellado, Nuria; Sánchez, Javier; Moya, Cristina; Sánchez-Palazón, Luis; Palacios, Jose; Antiñolo, Guillermo; Soria, Bernat

    2016-05-01

    From 106 human blastocyts donate for research after in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD) for monogenetic disorder, 3 human embryonic stem cells (hESCs) HVR1, HVR2 and HVR3 were successfully derived. HVR1 was assumed to be genetically normal, HVR2 carrying Becker muscular dystrophy and HVR3 Hemophilia B. Despite the translocation t(9;15)(q34.3;q14) detected in HVR2, all the 3 cell lines were characterised in vitro and in vivo as normal hESCs lines and were registered in the Spanish Stem Cell Bank. PMID:27346196

  14. ESHRE PGD consortium best practice guidelines for organization of a PGD centre for PGD/preimplantation genetic screening.

    PubMed

    Harton, G; Braude, P; Lashwood, A; Schmutzler, A; Traeger-Synodinos, J; Wilton, L; Harper, J C

    2011-01-01

    In 2005, the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium published a set of Guidelines for Best Practice PGD to give information, support and guidance to potential, existing and fledgling PGD programmes. Subsequent years have seen the introduction of new technologies as well as the evolution of current techniques. Additionally, in light of recent advice from ESHRE on how practice guidelines should be written/formulated, the Consortium believed it was timely to update the PGD guidelines. Rather than one document that covers all of PGD, the new guidelines are separated into four documents, including one relating to organization of the PGD centre and three relating to the methods used: DNA amplification, fluorescence in situ hybridization and biopsy/embryology. Here, we have updated the sections on organization of the PGD centre. One area that has continued to expand is Transport PGD, in which patients are treated at one IVF centre, whereas their gametes/embryos are tested elsewhere, at an independent PGD centre. Transport PGD/preimplantation genetic screening (PGS) has a unique set of challenges with respect to the nature of the sample and the rapid turn-around time required. PGS is currently controversial. Opinions of laboratory specialists and clinicians interested in PGD and PGS have been taken into account here. Current evidence suggests that PGS at cleavage stages is ineffective, but whether PGS at the blastocyst stage or on polar bodies might show improved delivery rates is still unclear. Thus, in this revision, PGS has been included. This document should assist everyone interested in PGD/PGS in developing the best laboratory and clinical practice possible.

  15. PGD for cystic fibrosis patients and couples at risk of an additional genetic disorder combined with 24-chromosome aneuploidy testing.

    PubMed

    Rechitsky, Svetlana; Verlinsky, Oleg; Kuliev, Anver

    2013-05-01

    Preimplantation genetic diagnosis (PGD) for inherited disorders is presently applied for more than 300 different conditions. The most frequent PGD indication is cystic fibrosis (CF), the largest series of which is reviewed here, totalling 404 PGD cycles. This involved testing for 52 different CFTR mutations with almost half of the cases (195/404 cycles) performed for ΔF508 mutation, one-quarter (103/404 cycles) for six other frequent mutations and only a few for the remaining 45 CFTR mutations. There were 44 PGD cycles performed for 25 CF-affected homozygous or double-heterozygous CF patients (18 male and seven female partners), which involved testing simultaneously for three mutations, resulting in birth of 13 healthy CF-free children and no misdiagnosis. PGD was also performed for six couples at a combined risk of producing offspring with CF and another genetic disorder. Concomitant testing for CFTR and other mutations resulted in birth of six healthy children, free of both CF and another genetic disorder in all but one cycle. A total of 96 PGD cycles for CF were performed with simultaneous aneuploidy testing, including microarray-based 24-chromosome analysis, as a comprehensive PGD for two or more conditions in the same biopsy material.

  16. Cultural Concerns when Counseling Orthodox Jewish Couples for Genetic Screening and PGD.

    PubMed

    Grazi, Richard V; Wolowelsky, Joel B

    2015-12-01

    There is a spectrum of attitudes within the Orthodox Jewish community towards genetic testing and PGD. Increased understanding of the belief systems of the Orthodox Jewish population will enhance the genetic counselors' ability to better serve this unique group of patients. By improving cultural competence, genetic counselors can help patients choose the testing options that they deem appropriate, while simultaneously respecting the patient's belief system. PMID:26174938

  17. Cultural Concerns when Counseling Orthodox Jewish Couples for Genetic Screening and PGD.

    PubMed

    Grazi, Richard V; Wolowelsky, Joel B

    2015-12-01

    There is a spectrum of attitudes within the Orthodox Jewish community towards genetic testing and PGD. Increased understanding of the belief systems of the Orthodox Jewish population will enhance the genetic counselors' ability to better serve this unique group of patients. By improving cultural competence, genetic counselors can help patients choose the testing options that they deem appropriate, while simultaneously respecting the patient's belief system.

  18. [Pre-implantation genetic diagnosis: indications, techniques, and results].

    PubMed

    Veiga, A; Boada, M; Barri, P N

    1998-01-01

    The combination of the technique of In Vitro Fertilization (IVF) and molecular genetics has led to the development of Preimplantation Genetic Diagnosis (PGD). Oocyte and embryo biopsy, Fluorescent in situ Hybridization (FISH) and Polymerase Chain Reaction (PCR) allow diagnostic procedures in couples with high risk and also certain IVF couples. We present a review of PGD indications, techniques and results. PMID:9810133

  19. Preimplantation genetic diagnosis and screening.

    PubMed

    Kearns, W G; Pen, R; Graham, J; Han, T; Carter, J; Moyer, M; Richter, K S; Tucker, M; Hoegerman, S F; Widra, E

    2005-11-01

    Preimplantation genetic diagnosis (PGD) identifies genetic abnormalities in preimplantation embryos prior to embryo transfer. PGD is an exciting technology that may improve the likelihood of a successful pregnancy and birth for five distinct patient groups: (1) those with infertility related to recurrent miscarriages or unsuccessful in vitro fertilization (IVF) cycles, (2) those with unexplained infertility, (3) advanced maternal age, (4) severe male factor infertility, and (5) couples at risk for transmitting a hereditary disease to their offspring. PGD is always performed following an IVF cycle where multiple oocytes are retrieved and fertilized. Sophisticated techniques such as multiprobe, multicolor fluorescence in situ hybridization are used to test single cells for structural or numerical chromosome abnormalities, whereas the polymerase chain reaction, linkage analysis, and DNA sequencing are used to analyze single cells for disease-specific DNA mutations. PGD allows one to transfer only those embryos identified as being free of genetic abnormalities, thus potentially increasing the implantation rate and decreasing the miscarriage rate. These technologies identify embryos free of specific genetic abnormalities and may increase the likelihood of achieving the patient's goal: the birth of a healthy infant.

  20. Preimplantation genetic diagnosis: technological advances to improve accuracy and range of applications.

    PubMed

    Kuliev, Anver; Verlinsky, Yury

    2008-04-01

    Preimplantation genetic diagnosis (PGD) is an option for couples who are at risk that enables them to have unaffected progeny without facing the risk of pregnancy termination after prenatal diagnosis as currently practiced. It is also one of the practical tools used in assisted reproduction technology to improve the chance of conception for infertility cases with poor prognosis. Because PGD is performed using a single biopsied cell, technological advances are important to improving PGD accuracy. This has contributed to the avoidance of misdiagnosis in PGD for single gene disorders, and extensive experience in PGD for chromosomal disorders suggests strategies for more reliable evaluation of the chromosomal status of the preimplantation embryo. This paper describes the present status of PGD for genetic and chromosomal disorders, its accuracy and range, and how PGD is an integral part of IVF and genetic practices.

  1. Preimplantation genetic diagnosis: public policy and public attitudes.

    PubMed

    Hudson, Kathy L

    2006-06-01

    This paper summarizes the regulatory framework surrounding preimplantation genetic diagnosis (PGD) in the United States. In addition, the author reports results of surveys that reveal conflicting popular opinions about the moral acceptability of manipulating embryos during PGD. For example, some people who feel that an embryo has as much moral status as a born baby nonetheless feel that using PGD to screen embryos for certain diseases is morally acceptable. The national debate about technologies like PGD is stunted because it is currently cast in the same terms as the debate over abortion rights. If national leaders begin discussions about regulation of PGD and similar technologies, it could help depolarize the debate to more accurately consider the nuanced views of the public.

  2. Comparison of attitudes regarding preimplantation genetic diagnosis among patients with hereditary cancer syndromes.

    PubMed

    Rich, Thereasa A; Liu, Mei; Etzel, Carol J; Bannon, Sarah A; Mork, Maureen E; Ready, Kaylene; Saraiya, Devki S; Grubbs, Elizabeth G; Perrier, Nancy D; Lu, Karen H; Arun, Banu K; Woodard, Terri L; Schover, Leslie R; Litton, Jennifer K

    2014-06-01

    Preimplantation genetic diagnosis (PGD) allows couples to avoid having a child with an inherited condition, potentially reducing cancer burden in families with a hereditary cancer predisposition. This study investigated and compared awareness and acceptance of PGD among patients with different hereditary cancer syndromes. Questionnaires were mailed to 984 adults with hereditary breast and ovarian cancer, Lynch syndrome, familial adenomatous polyposis, or multiple endocrine neoplasia type 1 or 2. Associations between clinical, demographic, and psychosocial factors and awareness and acceptance of PGD were examined. Of 370 respondents (38 % return rate), 28 % felt their syndrome impacted family planning, 24 % were aware of PGD, 72 % felt that PGD should be offered, 43 % would consider using PGD, and 29 % were uncertain. Family experience and syndrome-specific characteristics, such as disease severity, quality of life and availability of medical interventions as well as gender, family planning stage, and religiosity impact perceptions of the acceptability of PGD, though a high level of uncertainty exists. Hereditary cancer patients lack awareness of PGD despite feeling that PGD should be offered, highlighting the need for education on this topic. While we found attitudes about the acceptability of PGD to be generally similar to those reported in the literature and of genetics and ethics experts, we observed similarities and differences between syndromes that provide insight into why some hereditary cancer patients may find PGD more acceptable than others.

  3. Comparison of Attitudes Regarding Preimplantation Genetic Diagnosis Among Patients with Hereditary Cancer Syndromes

    PubMed Central

    Rich, Thereasa A.; Liu, Mei; Etzel, Carol J.; Bannon, Sarah A.; Mork, Maureen E.; Ready, Kaylene; Saraiya, Devki S.; Grubbs, Elizabeth G.; Perrier, Nancy D.; Lu, Karen H.; Arun, Banu K.; Woodard, Terri L.; Schover, Leslie R.; Litton, Jennifer K.

    2014-01-01

    Introduction Preimplantation Genetic Diagnosis (PGD) allows couples to avoid having a child with an inherited condition, potentially reducing cancer burden in families with a hereditary cancer predisposition. This study investigated awareness and acceptance of PGD among patients with hereditary cancer syndromes. Methods Questionnaires were mailed to 984 adults with hereditary breast and ovarian cancer, Lynch syndrome, familial adenomatous polyposis, or multiple endocrine neoplasia type 1 or 2. Associations between clinical, demographic, and psychosocial factors and awareness and acceptance of PGD were examined. Results Of 370 respondents (38% return rate), 28% felt their syndrome impacted family planning, 24% were aware of PGD, 72% felt that PGD should be offered, 43% would consider using PGD, and 29% were uncertain. Family experience and syndrome-specific characteristics, such as disease severity, quality of life and availability of medical interventions as well as gender, family planning stage, and religiosity impact perceptions of the acceptability of PGD, though a high level of uncertainty exists. Conclusion Hereditary cancer patients' opinions about the acceptability of PGD are similar to those of genetics and ethical experts. Patients should be told about PGD given that most had not heard of PGD, but feel that PGD should be offered. PMID:24072553

  4. Preimplantation genetic diagnosis: state of the art.

    PubMed

    Basille, Claire; Frydman, René; El Aly, Abdelwahab; Hesters, Laetitia; Fanchin, Renato; Tachdjian, Gérard; Steffann, Julie; LeLorc'h, Marc; Achour-Frydman, Nelly

    2009-07-01

    Preimplantation genetic diagnosis (PGD) is used to analyze embryos genetically before their transfer into the uterus. It was developed first in England in 1990, as part of progress in reproductive medicine, genetic and molecular biology. PGD offers couples at risk the chance to have an unaffected child, without facing termination of pregnancy. Embryos are obtained by in vitro fertilization with intracytoplasmic sperm injection (ICSI), and are biopsied mostly on day 3; blastocyst biopsy is mentioned as a possible alternative. The genetic analysis is performed on one or two blastomeres, by fluorescent in situ hybridization (FISH) for cytogenetic diagnosis, or polymerase chain reaction (PCR) for molecular diagnosis. Genetic analysis of the first or second polar body can be used to study maternal genetic contribution. Only unaffected embryos are transferred into the uterus. To improve the accuracy of the diagnosis, new technologies are emerging, with comparative genomic hybridization (CGH) and microarrays. In Europe, depending on national regulations, PGD is either prohibited, or allowed, or practiced in the absence of recommendations. The indications are chromosomal abnormalities, X-linked diseases or single gene disorders. The number of disorders being tested increases. In Europe, data collection from the year 2004 reports that globally 69.6% of cycles lead to embryo transfer and implantation rate is 17%. European results from the year 2004 show a clinical pregnancy rate of 18% per oocyte retrieval and 25% per embryo transfer, leading to 528 babies born. The cohort studies concerning the paediatric follow-up of PGD babies show developmental outcomes similar to children conceived after IVF-ICSI. Recent advances include human leucocyte antigen (HLA) typing for PGD embryos, when an elder sibling is affected with a genetic disorder and needs stem cell transplantation. The HLA-matched offspring resulting can give cord blood at birth. Preimplantation genetic screening (PGS

  5. Preimplantation genetic diagnosis--an overview.

    PubMed

    Ogilvie, Caroline Mackie; Braude, Peter R; Scriven, Paul N

    2005-03-01

    Since the early 1990s, preimplantation genetic diagnosis (PGD) has been expanding in scope and applications. Selection of female embryos to avoid X-linked disease was carried out first by polymerase chain reaction, then by fluorescence in situ hybridization (FISH), and an ever-increasing number of tests for monogenic diseases have been developed. Couples with chromosome rearrangements such as Robertsonian and reciprocal translocations form a large referral group for most PGD centers and present a special challenge, due to the large number of genetically unbalanced embryos generated by meiotic segregation. Early protocols used blastomeres biopsied from cleavage-stage embryos; testing of first and second polar bodies is now a routine alternative, and blastocyst biopsy can also be used. More recently, the technology has been harnessed to provide PGD-AS, or aneuploidy screening. FISH probes specific for chromosomes commonly found to be aneuploid in early pregnancy loss are used to test blastomeres for aneuploidy, with the aim of replacing euploid embryos and increasing pregnancy rates in groups of women who have poor IVF success rates. More recent application of PGD to areas such as HLA typing and social sex selection have stoked public controversy and concern, while provoking interesting ethical debates and keeping PGD firmly in the public eye. PMID:15749997

  6. Preimplantation genetic diagnosis and rational choice under risk or uncertainty.

    PubMed

    Zuradzki, Tomasz

    2014-11-01

    In this paper I present an argument in favour of a parental duty to use preimplantation genetic diagnosis (PGD). I argue that if embryos created in vitro were able to decide for themselves in a rational manner, they would sometimes choose PGD as a method of selection. Couples, therefore, should respect their hypothetical choices on a principle similar to that of patient autonomy. My thesis shows that no matter which moral doctrine couples subscribe to, they ought to conduct the PGD procedure in the situations when it is impossible to implant all of the created embryos and if there is a significant risk for giving birth to a child with a serious condition.

  7. Preimplantation genetic diagnosis (embryo screening) for enlarged vestibular aqueduct due to SLC26A4 mutation.

    PubMed

    Wu, Chen-Chi; Lin, Shin-Yu; Su, Yi-Nin; Fang, Mei-Ya; Chen, Shee-Uan; Hsu, Chuan-Jen

    2010-01-01

    Preimplantation genetic diagnosis (PGD) is used to analyze embryos genetically before their transfer into the uterus. For families with genetic diseases, PGD offers a chance to have an unaffected child, without facing termination of pregnancy. Although PGD has been performed for many monogenic disorders, such as cystic fibrosis and beta-thalassemia, the application of PGD to hereditary hearing impairment has not been explored. In the present study, we reported the development and application of PGD protocols to address enlarged vestibular aqueduct (EVA), which is a common type of hereditary hearing impairment associated with mutations in the SLC26A4 gene. The family requesting PGD had a history of EVA, segregating the SLC26A4 c.919-2A-->G mutation. In short, the PGD process was composed of two steps: the development of a single-cell testing protocol and clinical PGD cycles (i.e., selection and implantation of unaffected embryos using the single-cell testing protocol). First, protocols for genetic testing in a single cell were established for the c.919-2A-->G mutation using GenomiPhi technology and primer extension mini-sequencing. These protocols were validated on single lymphocytes collected from both parents and their affected child. Two clinical PGD cycles were then performed for the parents, with the second cycle successfully leading to a singleton pregnancy. The baby was homozygous for the wild-type SLC26A4 allele and revealed a normal audiological phenotype after birth. To our knowledge, this is the first report in the literature describing successful PGD in families with genetic hearing impairment. In our opinion, the application of PGD in the field of hereditary hearing impairment involves fewer ethical controversies than other novel applications of PGD and traditional indications for PGD for other monogenic diseases. Therefore, the approach demonstrated in the present study can also be used in a large number of families with other types of hereditary

  8. Whole genome amplification in preimplantation genetic diagnosis.

    PubMed

    Zheng, Ying-ming; Wang, Ning; Li, Lei; Jin, Fan

    2011-01-01

    Preimplantation genetic diagnosis (PGD) refers to a procedure for genetically analyzing embryos prior to implantation, improving the chance of conception for patients at high risk of transmitting specific inherited disorders. This method has been widely used for a large number of genetic disorders since the first successful application in the early 1990s. Polymerase chain reaction (PCR) and fluorescent in situ hybridization (FISH) are the two main methods in PGD, but there are some inevitable shortcomings limiting the scope of genetic diagnosis. Fortunately, different whole genome amplification (WGA) techniques have been developed to overcome these problems. Sufficient DNA can be amplified and multiple tasks which need abundant DNA can be performed. Moreover, WGA products can be analyzed as a template for multi-loci and multi-gene during the subsequent DNA analysis. In this review, we will focus on the currently available WGA techniques and their applications, as well as the new technical trends from WGA products.

  9. Non-Invasive Prenatal Diagnosis in the Management of Preimplantation Genetic Diagnosis Pregnancies

    PubMed Central

    Bustamante-Aragones †, Ana; Perlado-Marina †, Sara; Trujillo-Tiebas, Maria José; Gallego-Merlo, Jesús; Lorda-Sanchez, Isabel; Rodríguez-Ramirez, Luz; Linares, Concepcion; Hernandez, Corazón; Rodriguez de Alba, Marta

    2014-01-01

    Prenatal diagnosis (PD) is recommended in pregnancies after a Preimplantation Genetic Diagnosis (PGD). However, conventional PD entails a risk of fetal loss which makes PGD patients reluctant to undergo obstetric invasive procedures. The presence of circulating fetal DNA in maternal blood allows performing a non-invasive prenatal diagnosis (NIPD) without risk for the pregnancy outcome. This work shows the introduction of NIPD for confirmation of PGD results in eight pregnancies. In those pregnancies referred to PGD for an X-linked disorder (six out of eight), fetal sex determination in maternal blood was performed to confirm fetal sex. One pregnancy referred to PGD for Marfan syndrome and one referred for Huntington disease (HD) were also analyzed. In seven out of eight cases, PGD results were confirmed by NIPD in maternal blood. No results were obtained in the HD pregnancy. NIPD in PGD pregnancies can be a reliable alternative for couples that after a long process feel reluctant to undergo PD due to the risk of pregnancy loss. PMID:26237485

  10. Recent advances in preimplantation genetic diagnosis and screening.

    PubMed

    Lu, Lina; Lv, Bo; Huang, Kevin; Xue, Zhigang; Zhu, Xianmin; Fan, Guoping

    2016-09-01

    Preimplantation genetic diagnosis/screening (PGD/PGS) aims to help couples lower the risks of transmitting genetic defects to their offspring, implantation failure, and/or miscarriage during in vitro fertilization (IVF) cycles. However, it is still being debated with regard to the practicality and diagnostic accuracy of PGD/PGS due to the concern of invasive biopsy and the potential mosaicism of embryos. Recently, several non-invasive and high-throughput assays have been developed to help overcome the challenges encountered in the conventional invasive biopsy and low-throughput analysis in PGD/PGS. In this mini-review, we will summarize the recent progresses of these new methods for PGD/PGS and discuss their potential applications in IVF clinics. PMID:27272212

  11. Provision and quality assurance of preimplantation genetic diagnosis in Europe.

    PubMed

    Corveleyn, Anniek; Morris, Michael A; Dequeker, Elisabeth; Sermon, Karen; Davies, James Lawford; Antiñolo, Guillermo; Schmutzler, Andreas; Vanecek, Jiri; Nagels, Nick; Zika, Eleni; Palau, Francesc; Ibarreta, Dolores

    2008-03-01

    Preimplantation genetic diagnosis (PGD) is now well established and provided in many European countries. However, regulations, professional standards and accreditation requirements can differ notably. Furthermore, no comprehensive independent data exist either about practice and provision in Europe or about the quality assurance practices and procedures designed to optimize the quality of the results. Consequently, a study was launched to obtain knowledge, currently lacking, of the provision and quality assurance of PGD services and cross-border activities in Europe. An online questionnaire was developed and sent to PGD providers, and expert opinions were obtained through interviews with professionals in specific countries. Information was gathered from 53 centres offering PGD in 17 European countries. There is a diverse array of tests available, with a trend for custom-made services. Although half of the centres have a designated quality manager, just 33% have achieved or are preparing for accreditation or certification. About 66% of the centres responded that they did not participate in external quality assessment, a problem exacerbated by the lack of existing PGD-specific schemes. Approximately 19% of the centres do not keep data on accuracy and 9% do not even follow up until birth. PGD is an expanding activity with an increasing international flow that accounts for approximately one-third of the activity reported. The survey highlights a significant need for improvement in quality assurance in PGD centres. On the positive side, important improvements in the quality management of these services are expected with the European Tissue Directive entering into force.

  12. Attitude towards pre-implantation genetic diagnosis for hereditary cancer.

    PubMed

    Lammens, Chantal; Bleiker, Eveline; Aaronson, Neil; Vriends, Annette; Ausems, Margreet; Jansweijer, Maaike; Wagner, Anja; Sijmons, Rolf; van den Ouweland, Ans; van der Luijt, Rob; Spruijt, Liesbeth; Gómez García, Encarna; Ruijs, Mariëlle; Verhoef, Senno

    2009-01-01

    The use of pre-implantation genetic diagnosis (PGD) for hereditary cancer is subject to on-going debate, particularly among professionals. This study evaluates the attitude towards PGD and attitude-associated characteristics of those concerned: family members with a hereditary cancer predisposition. Forty-eight Von Hippel-Lindau and 18 Li-Fraumeni Syndrome families were identified via the 9 family cancer clinics in the Netherlands. In total, 216 high risk family members and partners were approached, of whom 179 (83%) completed a self-report questionnaire. Of the high risk family members, 35% expressed a positive attitude towards PGD. Those with a current desire to have children were significantly more likely to have a positive attitude: 48% would consider the use of PGD. No other sociodemographic, medical or psychosocial variables were associated significantly with a positive attitude. The most frequently reported advantage of PGD is the avoidance of a possible pregnancy termination. Uncertainty about late effects was the most frequently reported disadvantage. These results indicate that approximately half of those contemplating a future pregnancy would consider the use of PGD. The actual uptake, however, is expected to be lower. There is no indication that psychosocial factors affect interest in PGD.

  13. New multiplex PCR-based protocol allowing indirect diagnosis of FSHD on single cells: can PGD be offered despite high risk of recombination?

    PubMed Central

    Barat-Houari, Mouna; Nguyen, Karine; Bernard, Rafaëlle; Fernandez, Céline; Vovan, Catherine; Bareil, Corinne; Van Kien, Philippe Khau; Thorel, Delphine; Tuffery-Giraud, Sylvie; Vasseur, Francis; Attarian, Shahram; Pouget, Jean; Girardet, Anne; Lévy, Nicolas; Claustres, Mireille

    2010-01-01

    Molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) involves the heterozygous contraction of the number of tandemly repeated D4Z4 units at chromosome 4q35.2. FSHD is associated with a range of 1–10 D4Z4 units instead of 11–150 in normal controls. Several factors complicate FSHD molecular diagnosis, especially the cis-segregation of D4Z4 contraction with a 4qA allele, whereas D4Z4 shortening is silent both on alleles 4qB and 10q. Discrimination of pathogenic 4q-D4Z4 alleles from highly homologous 10q-D4Z4 arrays requires the use of the conventional Southern blot, which is not suitable at the single-cell level. Preimplantation genetic diagnosis (PGD) is a frequent request from FSHD families with several affected relatives. We aimed to develop a rapid and sensitive PCR-based multiplex approach on single cells to perform an indirect familial segregation study of pathogenic alleles. Among several available polymorphic markers at 4q35.2, the four most proximal (D4S2390, D4S1652, D4S2930 and D4S1523, <1.23 Mb) showing the highest heterozygote frequencies (67–91%) were selected. Five recombination events in the D4S2390-D4S1523 interval were observed among 144 meioses. In the D4S2390-D4Z4 interval, no recombination event occurred among 28 FSHD meioses. Instead, a particular haplotype segregated with both clinical and molecular status, allowing the characterization of an at-risk allele in each tested FSHD family (maximal LOD score 2.98 for θ=0.0). This indirect protocol can easily complement conventional techniques in prenatal diagnosis. Although our multiplex PCR-based approach technically fulfils guidelines for single-cell analysis, the relatively high recombination risk hampers its application to PGD. PMID:19935833

  14. Current status of preimplantation genetic diagnosis in Japan

    PubMed Central

    Sato, Kenji; Sueoka, Kou; Iino, Kotaro; Senba, Hiroshi; Suzuki, Mariko; Mizuguchi, Yuki; Izumi, Yoko; Sato, Suguru; Nakabayashi, Akira; Tanaka, Mamoru

    2015-01-01

    This is a retrospective study aimingto clarify the current status of preimplantation genetic diagnosis (PGD) in Japan. Our data were collected from 12 facilities between September 2004 and September 2012, and entered into a database. A majority of PGD in Japan was performed for balanced structural chromosomal abnormalities in couples with recurrent miscarriage. PGD for monogenic diseases was performed only in two facilities. The average maternal age was 38 years for monogenic diseases and 40 years for chromosomal abnormalities. Overall there have been671 cycles to oocyte retrieval reported. Of these cycles, 85% (572 cycles)were for chromosomal abnormalities, and 15% (99 cycles) for monogenic diseases. Diagnosis rates in the current study were 70.8% for monogenic diseases and 94.0% for chromosomal abnormalities. Rates of embryo transfer of PGD were 62.7% for monogenic diseases and 25.5% for chromosomal abnormalities. Clinical pregnancy rates per embryo transfer were 12.0% for monogenic diseases and 35.6% for chromosomal abnormalities. Our study is the first PGD report from all facilities which had the approval of the ethics committee of the Japanese Society of Obstetrics and Gynecology. We have built a basis for gathering continuous PGD data in Japan. PMID:26124570

  15. Preimplantation genetic diagnosis: design or too much design

    PubMed Central

    Verpoest, W.

    2009-01-01

    Preimplantation genetic diagnosis (PGD) is a technique that was first applied in humans in 1990 (Handyside et al., 1990; Verlinsky et al., 1990). Thirty years on an estimated 15000 children have been conceived and born using PGD, a number dwarfed by the huge number of children already conceived via conventional in vitro fertilisation. In contrast to numerous reports on reproductive outcome in conventional IVF, data on reproductive outcome of PGD are scarse. There is ongoing debate about the diagnostic accuracy and clinical relevance of Preimplantation genetic screening for aneuploidy (PGS) (Shahine et al., 2006; Twisk et al., 2006), however well conducted prospective randomized studies are few. In this PhD summary, the author describes the reproductive results of a large PGD program and applies life table analysis with multiple regression analysis and comparative analysis where appropriate. Potential risks of PGD including misdiagnosis, perinatal mortality and monozygotic twinning rate are assessed. The aim is to provide both patients and physicians with adequate information on all reproductive aspects of PGD as a diagnostic and therapeutic tool. PMID:25489466

  16. Gender eugenics? The ethics of PGD for intersex conditions.

    PubMed

    Sparrow, Robert

    2013-01-01

    This article discusses the ethics of the use of preimplantation genetic diagnosis (PGD) to prevent the birth of children with intersex conditions/disorders of sex development (DSDs), such as congenital adrenal hyperplasia (CAH) and androgen insensitivity syndrome (AIS). While pediatric surgeries performed on children with ambiguous genitalia have been the topic of intense bioethical controversy, there has been almost no discussion to date of the ethics of the use of PGD to reduce the prevalence of these conditions. I suggest that PGD for those conditions that involve serious medical risks for those born with them is morally permissible and that PGD for other "cosmetic" variations in sexual anatomy is more defensible than might first appear. However, importantly, the arguments that establish the latter claim have radical and disturbing implications for our attitude toward diversity more generally. PMID:24024804

  17. Gender eugenics? The ethics of PGD for intersex conditions.

    PubMed

    Sparrow, Robert

    2013-01-01

    This article discusses the ethics of the use of preimplantation genetic diagnosis (PGD) to prevent the birth of children with intersex conditions/disorders of sex development (DSDs), such as congenital adrenal hyperplasia (CAH) and androgen insensitivity syndrome (AIS). While pediatric surgeries performed on children with ambiguous genitalia have been the topic of intense bioethical controversy, there has been almost no discussion to date of the ethics of the use of PGD to reduce the prevalence of these conditions. I suggest that PGD for those conditions that involve serious medical risks for those born with them is morally permissible and that PGD for other "cosmetic" variations in sexual anatomy is more defensible than might first appear. However, importantly, the arguments that establish the latter claim have radical and disturbing implications for our attitude toward diversity more generally.

  18. Anticipating issues related to increasing preimplantation genetic diagnosis use: a research agenda.

    PubMed

    Klitzman, Robert; Appelbaum, Paul S; Chung, Wendy; Sauer, Mark

    2008-01-01

    Increasing use of preimplantation genetic diagnosis (PGD) poses numerous clinical, social, psychological, ethical, legal and policy dilemmas, many of which have received little attention. Patients and providers are now considering and using PGD for a widening array of genetic disorders, and patients may increasingly seek 'designer babies.' In the USA, although governmental oversight policies have been discussed, few specific guidelines exist. Hence, increasingly, patients and providers will face challenging ethical and policy questions of when and for whom to use PGD, and how it should be financed. These issues should be better clarified and addressed through collection of data concerning the current use of PGD in the USA, including factors involved in decision making about PGD use, as well as the education of the various communities that are, and should be, involved in its implementation. Improved understanding of these issues will ultimately enhance the development and implementation of future clinical guidelines and policies.

  19. Anticipating issues related to increasing preimplantation genetic diagnosis use: a research agenda.

    PubMed

    Klitzman, Robert; Appelbaum, Paul S; Chung, Wendy; Sauer, Mark

    2008-01-01

    Increasing use of preimplantation genetic diagnosis (PGD) poses numerous clinical, social, psychological, ethical, legal and policy dilemmas, many of which have received little attention. Patients and providers are now considering and using PGD for a widening array of genetic disorders, and patients may increasingly seek 'designer babies.' In the USA, although governmental oversight policies have been discussed, few specific guidelines exist. Hence, increasingly, patients and providers will face challenging ethical and policy questions of when and for whom to use PGD, and how it should be financed. These issues should be better clarified and addressed through collection of data concerning the current use of PGD in the USA, including factors involved in decision making about PGD use, as well as the education of the various communities that are, and should be, involved in its implementation. Improved understanding of these issues will ultimately enhance the development and implementation of future clinical guidelines and policies. PMID:18644221

  20. Practices and ethical concerns regarding preimplantation diagnosis. Who regulates preimplantation genetic diagnosis in Brazil?

    PubMed Central

    Damian, B.B.; Bonetti, T.C.S.; Horovitz, D.D.G.

    2014-01-01

    Preimplantation genetic diagnosis (PGD) was originally developed to diagnose embryo-related genetic abnormalities for couples who present a high risk of a specific inherited disorder. Because this technology involves embryo selection, the medical, bioethical, and legal implications of the technique have been debated, particularly when it is used to select features that are not related to serious diseases. Although several initiatives have attempted to achieve regulatory harmonization, the diversity of healthcare services available and the presence of cultural differences have hampered attempts to achieve this goal. Thus, in different countries, the provision of PGD and regulatory frameworks reflect the perceptions of scientific groups, legislators, and society regarding this technology. In Brazil, several texts have been analyzed by the National Congress to regulate the use of assisted reproduction technologies. Legislative debates, however, are not conclusive, and limited information has been published on how PGD is specifically regulated. The country requires the development of new regulatory standards to ensure adequate access to this technology and to guarantee its safe practice. This study examined official documents published on PGD regulation in Brazil and demonstrated how little direct oversight of PGD currently exists. It provides relevant information to encourage reflection on a particular regulation model in a Brazilian context, and should serve as part of the basis to enable further reform of the clinical practice of PGD in the country. PMID:25493379

  1. Practices and ethical concerns regarding preimplantation diagnosis. Who regulates preimplantation genetic diagnosis in Brazil?

    PubMed

    Damian, B B; Bonetti, T C S; Horovitz, D D G

    2015-01-01

    Preimplantation genetic diagnosis (PGD) was originally developed to diagnose embryo-related genetic abnormalities for couples who present a high risk of a specific inherited disorder. Because this technology involves embryo selection, the medical, bioethical, and legal implications of the technique have been debated, particularly when it is used to select features that are not related to serious diseases. Although several initiatives have attempted to achieve regulatory harmonization, the diversity of healthcare services available and the presence of cultural differences have hampered attempts to achieve this goal. Thus, in different countries, the provision of PGD and regulatory frameworks reflect the perceptions of scientific groups, legislators, and society regarding this technology. In Brazil, several texts have been analyzed by the National Congress to regulate the use of assisted reproduction technologies. Legislative debates, however, are not conclusive, and limited information has been published on how PGD is specifically regulated. The country requires the development of new regulatory standards to ensure adequate access to this technology and to guarantee its safe practice. This study examined official documents published on PGD regulation in Brazil and demonstrated how little direct oversight of PGD currently exists. It provides relevant information to encourage reflection on a particular regulation model in a Brazilian context, and should serve as part of the basis to enable further reform of the clinical practice of PGD in the country.

  2. Practices and ethical concerns regarding preimplantation diagnosis. Who regulates preimplantation genetic diagnosis in Brazil?

    PubMed

    Damian, B B; Bonetti, T C S; Horovitz, D D G

    2014-10-31

    Preimplantation genetic diagnosis (PGD) was originally developed to diagnose embryo-related genetic abnormalities for couples who present a high risk of a specific inherited disorder. Because this technology involves embryo selection, the medical, bioethical, and legal implications of the technique have been debated, particularly when it is used to select features that are not related to serious diseases. Although several initiatives have attempted to achieve regulatory harmonization, the diversity of healthcare services available and the presence of cultural differences have hampered attempts to achieve this goal. Thus, in different countries, the provision of PGD and regulatory frameworks reflect the perceptions of scientific groups, legislators, and society regarding this technology. In Brazil, several texts have been analyzed by the National Congress to regulate the use of assisted reproduction technologies. Legislative debates, however, are not conclusive, and limited information has been published on how PGD is specifically regulated. The country requires the development of new regulatory standards to ensure adequate access to this technology and to guarantee its safe practice. This study examined official documents published on PGD regulation in Brazil and demonstrated how little direct oversight of PGD currently exists. It provides relevant information to encourage reflection on a particular regulation model in a Brazilian context, and should serve as part of the basis to enable further reform of the clinical practice of PGD in the country.

  3. Outcomes of in vitro fertilization with preimplantation genetic diagnosis: an analysis of the United States Assisted Reproductive Technology Surveillance Data, 2011–2012

    PubMed Central

    Chang, Jeani; Boulet, Sheree L.; Jeng, Gary; Flowers, Lisa; Kissin, Dmitry M.

    2016-01-01

    Objective To assess the characteristics of IVF cycles for which preimplantation genetic diagnosis (PGD) was used and to evaluate indications for PGD and treatment outcomes associated with this procedure as compared with cycles without PGD with the data from the U.S. National ART Surveillance System. Design Retrospective cohort study. Setting None. Patient(s) Fresh autologous cycles that involved transfer of at least one embryo at blastocyst when available. Intervention(s) None. Main Outcome Measure(s) PGD indications and age-specific reproductive outcomes. Result(s) There were a total of 97,069 non-PGD cycles and 9,833 PGD cycles: 55.6% were performed for aneuploidy screening (PGD Aneuploidy), 29.1% for other reasons (PGD Other), and 15.3% for genetic testing (PGD Genetic). In comparison to non-PGD cycles, PGD Aneuploidy cycles showed a decreased odds of miscarriage among women 35–37 years (adjusted odds ratio [aOR] 0.62; 95% CI, 0.45–0.87) and women >37 years (aOR 0.55; 95% CI, 0.43–0.70); and an increased odds of clinical pregnancy (aOR 1.18; 95% CI, 1.05–1.34), live-birth delivery (aOR 1.43; 95% CI, 1.26–1.62), and multiple-birth delivery (aOR 1.98; 95% CI, 1.52–2.57) among women >37 years. Conclusion(s) Aneuploidy screening was the most common indication for PGD. Use of PGD was not observed to be associated with an increased odds of clinical pregnancy or live birth for women <35 years. PGD for aneuploidy was associated with a decreased odds of miscarriage for women >35 years, but an increased odds of a live-birth and a multiple live-birth delivery among women >37 years. PMID:26551441

  4. Peutz-Jeghers syndrome and family planning: the attitude towards prenatal diagnosis and pre-implantation genetic diagnosis.

    PubMed

    van Lier, Margot G F; Korsse, Susanne E; Mathus-Vliegen, Elisabeth M H; Kuipers, Ernst J; van den Ouweland, Ans M W; Vanheusden, Kathleen; van Leerdam, Monique E; Wagner, Anja

    2012-02-01

    Peutz-Jeghers syndrome (PJS) is a hereditary disorder caused by LKB1 gene mutations, and is associated with considerable morbidity and decreased life expectancy. This study was conducted to assess the attitude of PJS patients towards family planning, prenatal diagnosis (PND) and pregnancy termination, and pre-implantation genetic diagnosis (PGD). In a cross-sectional study, 61 adult PJS patients were asked to complete a questionnaire concerning genetic testing, family planning, PND and PGD. The questionnaire was completed by 52 patients (85% response rate, 44% males) with a median age of 44 (range 18-74) years. A total of 37 (71%) respondents had undergone genetic testing. In all, 24 respondents (46%, 75% males) had children. A total of 15 (29%) respondents reported that their diagnosis of PJS had influenced their decisions regarding family planning, including 10 patients (19%, 9/10 females) who did not want to have children because of their disease. Termination of pregnancy after PND in case of a foetus with PJS was considered 'acceptable' for 15% of the respondents, whereas 52% considered PGD acceptable. In conclusion, the diagnosis of PJS influences the decisions regarding family planning in one third of PJS patients, especially in women. Most patients have a negative attitude towards pregnancy termination after PND, while PGD in case of PJS is judged more acceptable. These results emphasise the importance of discussing aspects regarding family planning with PJS patients, including PND and PGD.

  5. Reiterative changes in the Italian regulation on IVF: the effect on PGD patients' reproductive decisions.

    PubMed

    Gianaroli, Luca; Crivello, Anna Maria; Stanghellini, Ilaria; Ferraretti, Anna Pia; Tabanelli, Carla; Magli, Maria Cristina

    2014-01-01

    National legislations represent one of the main factors influencing access to assisted reproduction treatment. The Italian situation in the last decade is an example of how the treatment of patients for preimplantation genetic diagnosis (PGD) was more dependent on regulators than on medical choices. This report analysed how the changes in Italian regulation affected the number of PGD referrals to this study centre, as well as their decision to opt for cross-border reproductive care (CBRC). The analysis showed that during the period in which PGD was actually not performed because of the restriction imposed by the Italian law on IVF (from 24 February 2004 to 7 May 2009) there was a significant decrease in the number of referrals asking for PGD (2.5% of total referrals) compared with the previous years (3.3%; P < 0.025) and following years when PGD was legalized (5.1%; P < 0.001). The number of couples opting for CBRC had an opposite trend, reaching a maximum when PGD was banned from Italian centres (55 couples), whereas after the readmission of PGD, only eight couples went abroad for treatment. Concomitantly, since May 2009, the proportion of couples performing a PGD cycle in this centre has constantly increased. PMID:24268726

  6. Preimplantation genetic diagnosis for Charcot-Marie-Tooth disease

    PubMed Central

    Lee, Hyoung-Song; Kim, Min Jee; Ko, Duck Sung; Jeon, Eun Jin; Kim, Jin Young

    2013-01-01

    Objective Preimplantation genetic diagnosis (PGD) is an assisted reproductive technique for couples carrying genetic risks. Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy, with a prevalence rate of 1/2,500. In this study, we report on our experience with PGD cycles performed for CMT types 1A and 2F. Methods Before clinical PGD, we assessed the amplification rate and allele drop-out (ADO) rate of multiplex fluorescent polymerase chain reaction (PCR) followed by fragment analysis or sequencing using single lymphocytes. We performed six cycles of PGD for CMT1A and one cycle for CMT2F. Results Two duplex and two triplex protocols were developed according to the available markers for each CMT1A couple. Depending on the PCR protocols, the amplification rates and ADO rates ranged from 90.0% to 98.3% and 0.0% to 11.1%, respectively. For CMT2F, the amplification rates and ADO rates were 93.3% and 4.8%, respectively. In case of CMT1A, 60 out of 63 embryos (95.2%) were diagnosed and 13 out of 21 unaffected embryos were transferred in five cycles. Two pregnancies were achieved and three babies were delivered without any complications. In the case of CMT2F, a total of eight embryos were analyzed and diagnosed. Seven embryos were diagnosed as unaffected and four embryos were transferred, resulting in a twin pregnancy. Two healthy babies were delivered. Conclusion This is the first report of successful pregnancy and delivery after specific PGD for CMT disease in Korea. Our PGD procedure could provide healthy babies to couples with a high risk of transmitting genetic diseases. PMID:24505562

  7. Hereditary breast and ovarian cancer and reproduction: an observational study on the suitability of preimplantation genetic diagnosis for both asymptomatic carriers and breast cancer survivors.

    PubMed

    Derks-Smeets, Inge A P; de Die-Smulders, Christine E M; Mackens, Shari; van Golde, Ron; Paulussen, Aimee D; Dreesen, Jos; Tournaye, Herman; Verdyck, Pieter; Tjan-Heijnen, Vivianne C G; Meijer-Hoogeveen, Madelon; De Greve, Jacques; Geraedts, Joep; De Rycke, Martine; Bonduelle, Maryse; Verpoest, Willem M

    2014-06-01

    Preimplantation genetic diagnosis (PGD) is a reproductive option for BRCA1/2 mutation carriers wishing to avoid transmission of the predisposition for hereditary breast and ovarian cancer (HBOC) to their offspring. Embryos obtained by in vitro fertilisation (IVF/ICSI) are tested for the presence of the mutation. Only BRCA-negative embryos are transferred into the uterus. The suitability and outcome of PGD for HBOC are evaluated in an observational cohort study on treatments carried out in two of Western-Europe's largest PGD centres from 2006 until 2012. Male carriers, asymptomatic female carriers and breast cancer survivors were eligible. If available, PGD on embryos cryopreserved before chemotherapy was possible. Generic PGD-PCR tests were developed based on haplotyping, if necessary combined with mutation detection. 70 Couples underwent PGD for BRCA1/2. 42/71 carriers (59.2 %) were female, six (14.3 %) of whom have had breast cancer prior to PGD. In total, 145 PGD cycles were performed. 720 embryos were tested, identifying 294 (40.8 %) as BRCA-negative. Of fresh IVF/PGD cycles, 23.9 % resulted in a clinical pregnancy. Three cycles involved PGD on embryos cryopreserved before chemotherapy; two of these women delivered a healthy child. Overall, 38 children were liveborn. Two BRCA1 carriers were diagnosed with breast cancer shortly after PGD treatment, despite negative screening prior to PGD. PGD for HBOC proved to be suitable, yielding good pregnancy rates for asymptomatic carriers as well as breast cancer survivors. Because of two cases of breast cancer shortly after treatment, maternal safety of IVF(PGD) in female carriers needs further evaluation.

  8. The politics of human embryo research and the motivation to achieve PGD

    PubMed Central

    Theodosiou, Anastasia A.; Johnson, Martin H.

    2011-01-01

    This article reports a historical study of factors influencing the achievement of clinical preimplantation genetic diagnosis (PGD) in 1990, 22 years after its first demonstration in animals. During the 1970s, research on PGD continued in large farm animals, but serious interest in human PGD was not evident until 1986. First, interest in PGD during the 1970s waned with the advent of prenatal testing, which for gynaecologists was clinically more familiar, technically simpler and ethically less challenging than IVF. Indeed, IVF was viewed with widespread suspicion until the first IVF births in 1978. Second, interest in clinical PGD was stimulated by the UK Parliamentary reaction against human embryo research that greeted the Warnock Report in 1984. This hostility led scientists to initiate a pro-research campaign, further galvanized in 1985 by MP Enoch Powell’s bid to ban such research. However, while Powell abhorred embryo research, he approved of PGD, a stance that divided the anti-research lobby. Accordingly, the campaigners for research emphasized that it was needed to achieve PGD. Powell demanded evidence of such projects and PGD research increased from 1986. It is concluded that UK political debates on embryo research played a critical role in stimulating the achievement of clinical PGD. Human pregnancies following preimplantation genetic diagnosis (PGD) for embryo sex were announced in 1990, 22 years after the technique was pioneered in animals. PGD in humans required not only technological advances, such as IVF and sensitive diagnostic tests, but also the motivation to develop and apply them. Our historical analysis shows that, although research on PGD continued in large farm animals during the 1970s, and techniques of the required sensitivity were developed on mouse embryo models, interest in clinical PGD was not evident until 1986. Two factors stimulated this sudden change in motivation. First, interest in PGD was depressed during the 1970s by the advent

  9. [BETWEEN USAGE AND POLEMIC, AN ARGUMENT IN FAVOUR OF CLARIFYING THE TERMINOLOGY FOR PREIMPLANTATION GENETIC DIAGNOSIS].

    PubMed

    Côté, Stéphanie; Ravitsky, Vardit; Hamet, Pavel; Bouffard, Chantal

    2015-12-01

    Over 30 years ago, preimplantation genetic diagnosis (PGD) was developed to help couples at risk of transmitting a serious genetic disease to their offspring. Today, the range of medical and non-medical uses of PGD has expanded considerably and some raise much controversy. This is the case, for example, with In-Vitro Fertilization to select embryos as 'saviour siblings' or to screen for susceptibility and predisposition to late onset diseases or conditions of variable penetrance. The situation is even more problematic in the case of sex selection or selection of traits that are culturally valued or discredited (such as deafness, behavioral traits, or height). The debate surrounding PGD has been employing terms to describe these particular uses that have contributed to a focus on the negative effects, thus preventing a distinction between the abuses and the benefits of this reproductive technology. In this context, this paper proposes a terminological clarification that would allow distinguishing medical and non-medical use and, therefore, the issues relevant to each. A more accurate and less generic nomenclature could prevent a conflation of different levels of ethical, clinical and social issues under the single term 'PGD'. For the vast majority of medical uses, we propose to keep: 'preimplantation genetic diagnosis (PGD)', which emphasizes that it is a genetic diagnosis. For non-medical uses, we suggest: 'preimplantation genetic trait selection (PGTS)'. PMID:27120827

  10. Knowledge, attitudes, and clinical experience of physicians regarding preimplantation genetic diagnosis for hereditary cancer predisposition syndromes.

    PubMed

    Brandt, Amanda C; Tschirgi, Matthew L; Ready, Kaylene J; Sun, Charlotte; Darilek, Sandra; Hecht, Jacqueline; Arun, Banu K; Lu, Karen H

    2010-09-01

    Approximately 5-10% of cancers are caused by an inherited predisposition. Individuals affected by hereditary cancer are often concerned about transmitting a predisposition to cancer to their children. Preimplantation genetic diagnosis (PGD) is a technology that allows embryos without a deleterious mutation associated with a hereditary cancer syndrome to be identified and implanted. The aim of this study is to assess the knowledge, attitudes, and clinical experience of physicians regarding PGD for hereditary cancer predisposition syndromes. Hereditary Breast and Ovarian Cancer (HBOC) and Familial Adenomatous Polyposis (FAP) are two hereditary cancer syndromes highlighted in this present study. A survey assessing physicians' attitudes, knowledge, and clinical practice was completed by a total of 373 gynecologic oncologists (GYN ONCs) and obstetrics and gynecologists (OB/GYNs). Physicians had a limited knowledge of PGD for hereditary cancer; however, physicians reported PGD was an appropriate option for patients with either HBOC or FAP. Although GYN ONCs were more likely to care for patients with hereditary cancer (P < 0.001), they were less likely than OB/GYNs to refer their patients to a PGD specialist (P = 0.004). While 80% of GYN ONCs and 91% of OB/GYNs would refer patients to a PGD specialist, clinical experience indicates that only 29% actually referred their patients. Since 68% of physicians had incorrect or limited knowledge of PGD for hereditary cancer, there is a need for additional education.

  11. Preimplantation genetic diagnosis: current status and new developments.

    PubMed

    Lissens, W; Sermon, K

    1997-08-01

    Preimplantation genetic diagnosis (PGD) is a very early form of prenatal diagnosis aimed at eliminating embryos carrying serious genetic diseases before implantation. To this end, two major technologies are in use: the polymerase chain reaction (PCR) for monogenic diseases and fluorescent in-situ hybridization (FISH) for chromosomal aberrations. In this review, a number of problems arising from the use of these technologies, as well as their possible solutions and new developments, are discussed. Concerning PCR, the phenomenon of allelic drop-out, as well as methods to reduce this problem, such as fluorescent PCR, are described. The advantages and disadvantages of sperm separation by flow cytometry as an adjunct to sex determination for the avoidance of X-linked disease are discussed. The application of FISH for aneuploidy detection is commented upon and the advances in cell recycling, in which PCR and FISH are combined, are analysed. Finally, diseases for which PGD is currently possible are summarized.

  12. [Extending preimplantation genetic diagnosis to HLA typing: the French exception].

    PubMed

    Steffann, Julie; Frydman, Nelly; Burlet, Philippe; Gigarel, Nadine; Hesters, Laetitia; Kerbrat, Violaine; Lamazou, Frédéric; Munnich, Arnold; Frydman, René

    2011-01-01

    Umut-Talha, a "sibling savior", was born on 26 January 2011 at Beclère Hospital after embryo selection at the Paris preimplantation genetic diagnosis (PGD) center. His birth revived the controversy over "double PGD". This procedure, authorized in France since 2006, allows couples who already have a child with a serious, incurable genetic disease, to opt for PGD in order to select a healthy embryo that is HLA-matched to the affected sibling and who may thus serve as an ombilical cord blood donor. The procedure is particularly complex and the baby take-home rate is still very low. Double PGD is strictly regulated in France, and candidate couples must first receive individual authorization from the Biomedicine Agency. In our experience, these couples have a strong desire to have children, as reflected by the large number of prior spontaneous pregnancies (25% of couples). Likewise, most of these couples request embryo transfer even when there is no HLA-matched embryo, which accounts for more than half of embryo transfers. The controversy surrounding this practice has flared up again in recent weeks, over the concepts of "designer babies" and "double savior siblings" (the baby is selected to be free of the hereditary disease, and may also serve as a stem cell donor for the affected sibling).

  13. [Extending preimplantation genetic diagnosis to HLA typing: the French exception].

    PubMed

    Steffann, Julie; Frydman, Nelly; Burlet, Philippe; Gigarel, Nadine; Hesters, Laetitia; Kerbrat, Violaine; Lamazou, Frédéric; Munnich, Arnold; Frydman, René

    2011-01-01

    Umut-Talha, a "sibling savior", was born on 26 January 2011 at Beclère Hospital after embryo selection at the Paris preimplantation genetic diagnosis (PGD) center. His birth revived the controversy over "double PGD". This procedure, authorized in France since 2006, allows couples who already have a child with a serious, incurable genetic disease, to opt for PGD in order to select a healthy embryo that is HLA-matched to the affected sibling and who may thus serve as an ombilical cord blood donor. The procedure is particularly complex and the baby take-home rate is still very low. Double PGD is strictly regulated in France, and candidate couples must first receive individual authorization from the Biomedicine Agency. In our experience, these couples have a strong desire to have children, as reflected by the large number of prior spontaneous pregnancies (25% of couples). Likewise, most of these couples request embryo transfer even when there is no HLA-matched embryo, which accounts for more than half of embryo transfers. The controversy surrounding this practice has flared up again in recent weeks, over the concepts of "designer babies" and "double savior siblings" (the baby is selected to be free of the hereditary disease, and may also serve as a stem cell donor for the affected sibling). PMID:22375367

  14. Whole genome amplification from single cells in preimplantation genetic diagnosis and prenatal diagnosis.

    PubMed

    Peng, Wen; Takabayashi, Haruo; Ikawa, Kazumi

    2007-03-01

    The literature on whole genome amplification (WGA) techniques and their application to preimplantation genetic diagnosis (PGD) and prenatal diagnosis is reviewed. General polymerase chain reaction (PCR) fails to provide adequate information from limited cells in PGD and non-invasive prenatal diagnosis. Therefore several WGA techniques, such as primer extension preamplification (PEP) and degenerate oligonucleotide primed PCR (DOP-PCR), have been developed and successfully applied to clinical work during the past decade, especially in PGD and prenatal diagnosis. These techniques can provide ample amplification of genetic sequences from single cells for a series of subsequent PCR analyses such as restriction fragment length polymorphisms (RFLP) and comparative genomic hybridization (CGH), thus opening up a new area for prenatal diagnosis. However, several problems have been reported in the application of these techniques. The ideal WGA technique should have high yield, faithful representation of the original template, complete coverage of the genome, and simply performed procedure. In order to make good use of these techniques in future research and clinical work, it is undoubtedly necessary for an extensive understanding of the merits and pitfalls of these recently developed techniques.

  15. First successful application of preimplantation genetic diagnosis and haplotyping for congenital hyperinsulinism.

    PubMed

    Qubbaj, Wafa; Al-Swaid, Abdulrahman; Al-Hassan, Saad; Awartani, Khalid; Deek, Hesham; Coskun, Serdar

    2011-01-01

    Congenital hyperinsulinism is the most common cause of persistent hypoglycaemia in infancy. Early surgical intervention is usually required to prevent brain damage. The prevention of the transmission to the offspring is important in families carrying the mutated gene. Preimplantation genetic diagnosis (PGD) is an early genetic testing procedure for couples at risk of transmitting inherited diseases. A 36-year-old Saudi woman married to her first cousin with four affected children was referred for PGD. The hyperinsulinism disease was caused by a novel homozygous mutation in the KCNJ11 gene, an arginine 301 to proline (R301P) substitution.PGD was achieved by whole genome amplification followed by mutation detection combined with short tandem repeat identifier analysis in the first cycle and with haplotyping in the second cycle. The first and second cycles resulted in the births of healthy twin girls and a boy, respectively. As far as is known, this is the first application of PGD to hyperinsulinism. A feasible strategy including whole genome amplification followed by direct mutation detection combined with haplotyping is described.Utilizing haplotyping increases the efficiency of PGD diagnosis as well as confirming the genetic diagnosis. It reveals the parental origin of each inherited chromosome.

  16. Multiple displacement amplification for preimplantation genetic diagnosis of fragile X syndrome.

    PubMed

    Lee, H-S; Kim, M J; Lim, C K; Cho, J W; Song, I O; Kang, I S

    2011-01-01

    Preimplantation genetic diagnosis (PGD) has become an assisted reproductive technique for couples that have genetic risks. Despite the many advantages provided by PGD, there are several problems, including amplification failure, allele drop-out and amplification inefficiency. We evaluated multiple displacement amplification (MDA) for PGD of the fragile X syndrome. Whole genome amplification was performed using MDA. MDA products were subjected to fluorescent PCR of fragile X mental retardation-1 (FMR1) CGG repeats, amelogenin and two polymorphic markers. In the pre-clinical tests, the amplification rates of the FMR1 CGG repeat, DXS1215 and FRAXAC1 were 84.2, 87.5 and 75.0%, respectively, while the allele dropout rates were 31.3, 57.1 and 50.0%, respectively. In two PGD treatment cycles, 20 embryos among 30 embryos were successfully diagnosed as 10 normal embryos, four mutated embryos and six heterozygous carriers. Three healthy embryos were transferred to the uterus; however, no clinical pregnancy was achieved. Our data indicate that MDA and fluorescent PCR with four loci can be successfully applied to PGD for fragile X syndrome. Advanced methods for amplification of minuscule amounts of DNA could improve the sensitivity and reliability of PGD for complicated single gene disorders. PMID:22095609

  17. Multiple displacement amplification for preimplantation genetic diagnosis of fragile X syndrome.

    PubMed

    Lee, H-S; Kim, M J; Lim, C K; Cho, J W; Song, I O; Kang, I S

    2011-11-17

    Preimplantation genetic diagnosis (PGD) has become an assisted reproductive technique for couples that have genetic risks. Despite the many advantages provided by PGD, there are several problems, including amplification failure, allele drop-out and amplification inefficiency. We evaluated multiple displacement amplification (MDA) for PGD of the fragile X syndrome. Whole genome amplification was performed using MDA. MDA products were subjected to fluorescent PCR of fragile X mental retardation-1 (FMR1) CGG repeats, amelogenin and two polymorphic markers. In the pre-clinical tests, the amplification rates of the FMR1 CGG repeat, DXS1215 and FRAXAC1 were 84.2, 87.5 and 75.0%, respectively, while the allele dropout rates were 31.3, 57.1 and 50.0%, respectively. In two PGD treatment cycles, 20 embryos among 30 embryos were successfully diagnosed as 10 normal embryos, four mutated embryos and six heterozygous carriers. Three healthy embryos were transferred to the uterus; however, no clinical pregnancy was achieved. Our data indicate that MDA and fluorescent PCR with four loci can be successfully applied to PGD for fragile X syndrome. Advanced methods for amplification of minuscule amounts of DNA could improve the sensitivity and reliability of PGD for complicated single gene disorders.

  18. Breast Cancer, BRCA Mutations, and Attitudes Regarding Pregnancy and Preimplantation Genetic Diagnosis

    PubMed Central

    Woodson, Ashley H.; Muse, Kimberly I.; Lin, Heather; Jackson, Michelle; Mattair, Danielle N.; Schover, Leslie; Woodard, Terri; McKenzie, Laurie; Theriault, Richard L.; Hortobágyi, Gabriel N.; Arun, Banu; Peterson, Susan K.; Profato, Jessica

    2014-01-01

    Background. Women with premenopausal breast cancer may face treatment-related infertility and have a higher likelihood of a BRCA mutation, which may affect their attitudes toward future childbearing. Methods. Premenopausal women were invited to participate in a questionnaire study administered before and after BRCA genetic testing. We used the Impact of Event Scale (IES) to evaluate the pre- and post-testing impact of cancer or carrying a BRCA mutation on attitudes toward future childbearing. The likelihood of pursuing prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD) was also assessed in this setting. Univariate analyses determined factors contributing to attitudes toward future childbearing and likelihood of PND or PGD. Results. One hundred forty-eight pretesting and 114 post-testing questionnaires were completed. Women with a personal history of breast cancer had less change in IES than those with no history of breast cancer (p = .003). The 18 BRCA-positive women had a greater change in IES than the BRCA-negative women (p = .005). After testing, 31% and 24% of women would use PND and PGD, respectively. BRCA results did not significantly affect attitudes toward PND/PGD. Conclusion. BRCA results and history of breast cancer affect the psychological impact on future childbearing. Intentions to undergo PND or PGD do not appear to change after disclosure of BRCA results. Additional counseling for patients who have undergone BRCA testing may be warranted to educate patients about available fertility preservation options. PMID:24951607

  19. [The Cagliari (Italy) Court authorizes the preimplantation genetic diagnosis].

    PubMed

    Jorqui Azofra, María

    2007-01-01

    Today, preimplantation genetic diagnosis (PGD) has been greatly accepted within the framework of positive law of many European countries. Nevertheless, in other countries, such as Italy, it is forbidden by law. The ruling of the Civil Court of Cagliari which has authorized its use to a Sardinian couple, has opened, in this way, a small crack to be able to asses possible modifications to the Italian regulation on this matter. This article analyses the ruling of the Civil Court of Cagliari (Italy) from an ethical and legal perspective. The criteria which is used to analyse the legitimacy or illegitimacy of the practice of PGD is analysed. That is, on reasons which could justify or not the transfer of embryos in vitro to the woman. With this objective in mind, the Italian and Spanish normative models which regulates this controversial subject are looked at. As a conclusion, a critical evaluation of the arguments presented is made.

  20. Conceptualizing Couples’ Decision Making in PGD: Emerging Cognitive, Emotional, and Moral Dimensions

    PubMed Central

    Hershberger, Patricia E.; Pierce, Penny F.

    2009-01-01

    Objective To illuminate and synthesize what is known about the underlying decision making processes surrounding couples’ preimplantation genetic diagnosis (PGD) use or disuse and to formulate an initial conceptual framework that can guide future research and practice. Methods This systematic review targeted empirical studies published in English from 1990 to 2008 that examined the decision making process of couples or individual partners that had used, were eligible for, or had contemplated PGD. Sixteen studies met the eligibility requirements. To provide a more comprehensive review, empirical studies that examined healthcare professionals’ perceptions of couples’ decision making surrounding PGD use and key publications from a variety of disciplines supplemented the analysis. Results The conceptual framework formulated from the review demonstrates that couples’ PGD decision making is composed of three iterative and dynamic dimensions: cognitive appraisals, emotional responses, and moral judgments. Conclusion Couples think critically about uncertain and probabilistic information, grapple with conflicting emotions and incorporate moral perspectives into their decision making about whether or not to use PGD. Practice Implications The quality of care and decisional support for couples who are contemplating PGD use can be improved by incorporating focused questions and discussion from each of the dimensions into counseling sessions. PMID:20060677

  1. Preimplantation genetic diagnosis for autosomal recessive polycystic kidney disease.

    PubMed

    Gigarel, N; Frydman, N; Burlet, P; Kerbrat, V; Tachdjian, G; Fanchin, R; Antignac, C; Frydman, R; Munnich, A; Steffann, J

    2008-01-01

    Autosomal recessive polycystic kidney disease (ARPKD) is one of the most common hereditary renal cystic diseases, and is caused by mutations in the PKHD1 gene. Due to the poor prognosis, there is a strong demand for prenatal diagnosis. Preimplantation genetic diagnosis (PGD) represents an alternative because it avoids the physical and emotional trauma of a pregnancy termination in the case of an affected fetus. A standardized single-cell diagnostic procedure was developed, based on haplotype analysis, enabling PGD to be offered to couples at risk of transmitting ARPKD. Six linked markers within (D6S1714 and D6S243), or in close proximity to (D6S272, D6S436, KIAA0057, D6S1662) the PKHD1 gene were tested by multiplex nested-polymerase chain reaction (PCR), using a Qiagen multiplex PCR kit. PCR analyses were carried out on 50 single lymphocytes. The amplification rate was excellent (100%), with an allele drop-out (ADO) rate ranging from 0 to 8%. Five PGD cycles were performed and 23 embryos were biopsied and analysed using this test. Transferable embryos were obtained in 4 cycles, resulting in two pregnancies and the birth of a healthy boy. This standardized diagnostic procedure allowed the detection of recombination, contamination, and ADO events, providing high assay accuracy with wide applicability.

  2. Preimplantation genetic diagnosis for early-onset torsion dystonia.

    PubMed

    Rechitsky, S; Verlinsky, O; Kuliev, A; Ozen, S; Laziuk, K; Beck, R; Gleicher, N; Verlinsky, Y

    2004-02-01

    Early-onset primary torsion dystonia (DYT1) is the most severe and common form of hereditary movement disorders, characterized by sustained twisting contractures that begin in childhood, which is caused in majority of cases by a 3-bp deletion of the DYT1 gene on chromosome 9q34 at the heterozygote state. As there is no effective treatment of this disease, preimplantation genetic diagnosis (PGD) may be a useful option for at-risk couples to establish an DYT1 mutation-free pregnancy. PGD was performed for two obligate carriers of the DYT1 3-bp deletion, using blastomere testing to preselect the mutation-free embryos, based on mutation analysis with simultaneous testing of the three closely linked markers, D9S62, D9S63 and ASS. Of 19 tested blastomeres in three cycles, 17 had conclusive information about the mutation and linked markers, of which eight were predicted to be free of 3-bp deletion. Six of these embryos were transferred back to patients, two in each cycle, yielding singleton DYT1 3-bp deletion-free clinical pregnancies in two. One of these pregnancies was terminated due to severe anencephaly and the other resulted in birth of a mutation-free child. This is the first PGD for primary torsion dystonia, providing an alternative for those at-risk couples who cannot accept prenatal diagnosis and termination of pregnancy as an option for avoiding early onset torsion dystonia.

  3. A clinical perspective on ethical arguments around prenatal diagnosis and preimplantation genetic diagnosis for later onset inherited cancer predispositions.

    PubMed

    Clancy, Tara

    2010-03-01

    Prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) for later onset and/or reduced penetrance inherited cancer predispositions, e.g. familial adenomatous polyposis, hereditary non-polyposis colorectal cancer/Lynch syndrome and hereditary breast and ovarian cancer, raise a number of ethical issues. Some of these are the same as for conditions which present early in childhood, are fully penetrant and for which no/limited treatment options are possible; others relate to whether reduced penetrance and/or the availability of treatment mean that these are not serious (enough) conditions to warrant tests prior to/during pregnancy or to justify termination of pregnancy. However, attempts to reach a consensus on what counts as a serious (enough) condition in the context of PND and PGD have been unsuccessful. Such a definition may anyway be unhelpful if it cannot also take into account, for example, the woman's/couple's awareness and experience of the condition and the impact of the condition on affected individuals and their families. Individuals affected by, or at high risk of, later onset and/or reduced penetrance inherited cancer predispositions are generally supportive of access to PND and PGD for their own conditions, even if they would not consider using it themselves. Professionals working in clinical cancer genetics need to be prepared to discuss PND and PGD with this group of patients. PMID:19644768

  4. A clinical perspective on ethical arguments around prenatal diagnosis and preimplantation genetic diagnosis for later onset inherited cancer predispositions.

    PubMed

    Clancy, Tara

    2010-03-01

    Prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) for later onset and/or reduced penetrance inherited cancer predispositions, e.g. familial adenomatous polyposis, hereditary non-polyposis colorectal cancer/Lynch syndrome and hereditary breast and ovarian cancer, raise a number of ethical issues. Some of these are the same as for conditions which present early in childhood, are fully penetrant and for which no/limited treatment options are possible; others relate to whether reduced penetrance and/or the availability of treatment mean that these are not serious (enough) conditions to warrant tests prior to/during pregnancy or to justify termination of pregnancy. However, attempts to reach a consensus on what counts as a serious (enough) condition in the context of PND and PGD have been unsuccessful. Such a definition may anyway be unhelpful if it cannot also take into account, for example, the woman's/couple's awareness and experience of the condition and the impact of the condition on affected individuals and their families. Individuals affected by, or at high risk of, later onset and/or reduced penetrance inherited cancer predispositions are generally supportive of access to PND and PGD for their own conditions, even if they would not consider using it themselves. Professionals working in clinical cancer genetics need to be prepared to discuss PND and PGD with this group of patients.

  5. Clinical applications of MARSALA for preimplantation genetic diagnosis of spinal muscular atrophy.

    PubMed

    Ren, Yixin; Zhi, Xu; Zhu, Xiaohui; Huang, Jin; Lian, Ying; Li, Rong; Jin, Hongyan; Zhang, Yan; Zhang, Wenxin; Nie, Yanli; Wei, Yuan; Liu, Zhaohui; Song, Donghong; Liu, Ping; Qiao, Jie; Yan, Liying

    2016-09-20

    Conventional PCR methods combined with linkage analysis based on short tandem repeats (STRs) or Karyomapping with single nucleotide polymorphism (SNP) arrays, have been applied to preimplantation genetic diagnosis (PGD) for spinal muscular atrophy (SMA), an autosome recessive disorder. However, it has limitations in SMA diagnosis by Karyomapping, and these methods are unable to distinguish wild-type embryos with carriers effectively. Mutated allele revealed by sequencing with aneuploidy and linkage analyses (MARSALA) is a new method allowing embryo selection by a one-step next-generation sequencing (NGS) procedure, which has been applied in PGD for both autosome dominant and X-linked diseases in our group previously. In this study, we carried out PGD based on MARSALA for two carrier families with SMA affected children. As a result, one of the couples has given birth to a healthy baby free of mutations in SMA-causing gene. It is the first time that MARSALA was applied to PGD for SMA, and we can distinguish the embryos with heterozygous deletion (carriers) from the wild-type (normal) ones accurately through this NGS-based method. In addition, direct mutation detection allows us to identify the affected embryos (homozygous deletion), which can be regarded as probands for linkage analysis, in case that the affected family member is absent. In the future, the NGS-based MARSALA method is expected to be used in PGD for all monogenetic disorders with known pathogenic gene mutation. PMID:27599922

  6. An update of preimplantation genetic diagnosis in gene diseases, chromosomal translocation, and aneuploidy screening.

    PubMed

    Chang, Li-Jung; Chen, Shee-Uan; Tsai, Yi-Yi; Hung, Chia-Cheng; Fang, Mei-Ya; Su, Yi-Ning; Yang, Yu-Shih

    2011-09-01

    Preimplantation genetic diagnosis (PGD) is gradually widely used in prevention of gene diseases and chromosomal abnormalities. Much improvement has been achieved in biopsy technique and molecular diagnosis. Blastocyst biopsy can increase diagnostic accuracy and reduce allele dropout. It is cost-effective and currently plays an important role. Whole genome amplification permits subsequent individual detection of multiple gene loci and screening all 23 pairs of chromosomes. For PGD of chromosomal translocation, fluorescence in-situ hybridization (FISH) is traditionally used, but with technical difficulty. Array comparative genomic hybridization (CGH) can detect translocation and 23 pairs of chromosomes that may replace FISH. Single nucleotide polymorphisms array with haplotyping can further distinguish between normal chromosomes and balanced translocation. PGD may shorten time to conceive and reduce miscarriage for patients with chromosomal translocation. PGD has a potential value for mitochondrial diseases. Preimplantation genetic haplotyping has been applied for unknown mutation sites of single gene disease. Preimplantation genetic screening (PGS) using limited FISH probes in the cleavage-stage embryo did not increase live birth rates for patients with advanced maternal age, unexplained recurrent abortions, and repeated implantation failure. Polar body and blastocyst biopsy may circumvent the problem of mosaicism. PGS using blastocyst biopsy and array CGH is encouraging and merit further studies. Cryopreservation of biopsied blastocysts instead of fresh transfer permits sufficient time for transportation and genetic analysis. Cryopreservation of embryos may avoid ovarian hyperstimulation syndrome and possible suboptimal endometrium. PMID:22384431

  7. [Preimplantation genetic diagnosis: update of the Parisian group].

    PubMed

    Frydman, René; Tachdjian, Gérard; Achour-Frydman, Nelly; Ray, Pierre; Romana, Serge; Hamamah, Samir; Marcadet-Fredet, Sabine; Kerbrat, Violaine; Fanchin, Renato; Kadoch, Jacques; Attie, Tania; Lelorc'h, M; Vekemans, Michel; Munnich, Arnold

    2002-01-01

    To report the birth of the first fourteen infants conceived after preimplantation genetic diagnosis (PGD) in our unit. Fifty-nine couples were enrolled between January 2000 and July 2001. They had a total of 71 oocyte pick-up cycles. The collected oocytes were inseminated by intracytoplasmic sperm injection. The resulting embryos were biopsied on the third day of development and the genetic analysis was performed on the same day. Most of the embryo transfers were carried out on the fourth day. The 71 oocyte pick-up cycles yielded 872 oocytes of which 731 were suitable for intracytoplasmic sperm injection. Among the 505 embryos obtained, 421 embryos were biopsied and genetic diagnosis was performed for 312 (74%) of these 127 embryos were transferred during the course of 58 transfer procedures. There were 18 biochemical and 12 ongoing (7 singles, 4 twins and 1 triple) pregnancies. Sixteen infants have been born and 2 are expected. PGD has gained a place among the choices offered to couples at risk of transmission of a serious and incurable genetic disease.

  8. High-risk consumers' perceptions of preimplantation genetic diagnosis for hereditary cancers: a systematic review and meta-analysis.

    PubMed

    Quinn, Gwendolyn P; Pal, Tuya; Murphy, Devin; Vadaparampil, Susan T; Kumar, Ambuj

    2012-02-01

    Individuals carrying deleterious germline mutations placing them at increased risk for hereditary cancer syndromes (high-risk consumers) often have a great deal of fear and concern over transmitting mutations to their offspring, particularly conditions which are autosomal dominant. Preimplantation genetic diagnosis (PGD) is a procedure that can detect certain germline cancer predisposing mutations present in embryos. The objective of this review was to assess high-risk consumers' knowledge and perceptions of PGD for hereditary cancers. A systematic literature review was conducted through PubMed, Wiley Interscience, PsychInfo, and Cochrane Library databases to identify all articles assessing consumer knowledge and attitudes of PGD for hereditary cancer syndromes. We assessed heterogeneity and the robustness of findings through additional analyses according to study location, hereditary cancer type, and sample size. Thirteen articles remained eligible after the application of specific criteria. Results show a general low level of knowledge about PGD for hereditary cancers, moderate rates of acceptability among high-risk groups, and high levels of need for information about PGD. Individuals in specific risk groups such as those with a personal or family history of hereditary breast and ovarian cancer (HBOC) syndrome or familial adenomatous polyposis (FAP) may benefit from educational information from healthcare professionals about the use of PGD.

  9. First successful double-factor PGD for Lynch syndrome: monogenic analysis and comprehensive aneuploidy screening.

    PubMed

    Daina, G; Ramos, L; Obradors, A; Rius, M; Martinez-Pasarell, O; Polo, A; Del Rey, J; Obradors, J; Benet, J; Navarro, J

    2013-07-01

    Preimplantation genetic diagnosis (PGD) has been applied worldwide for a great variety of single-gene disorders over the last 20 years. The aim of this work was to perform a double-factor preimplantation genetic diagnosis (DF-PGD) protocol in a family at risk for Lynch syndrome. The family underwent a DF-PGD approach in which two blastomeres from each cleavage-stage embryo were biopsied and used for monogenic and comprehensive cytogenetic analysis, respectively. Fourteen embryos were biopsied for the monogenic disease and after multiple displacement amplification (MDA), 12 embryos were diagnosed; 5 being non-affected and 7 affected by the disease. Thirteen were biopsied to perform the aneuploidy screening by short-comparative genomic hybridization (CGH). The improved DF-PGD approach permitted the selection of not only healthy but also euploid embryos for transfer. This has been the first time a double analysis of embryos has been performed in a family affected by Lynch syndrome, resulting in the birth of two healthy children. The protocol described in this work offers a reliable alternative for single-gene disorder assessment together with a comprehensive aneuploidy screening of the embryos that may increase the chances of pregnancy and birth of transferred embryos.

  10. Prevention of lysosomal storage diseases and derivation of mutant stem cell lines by preimplantation genetic diagnosis.

    PubMed

    Altarescu, Gheona; Beeri, Rachel; Eiges, Rachel; Epsztejn-Litman, Silvina; Eldar-Geva, Talia; Elstein, Deborah; Zimran, Ari; Margalioth, Ehud J; Levy-Lahad, Ephrat; Renbaum, Paul

    2012-01-01

    Preimplantation genetic diagnosis (PGD) allows birth of unaffected children for couples at risk for a genetic disorder. We present the strategy and outcome of PGD for four lysosomal storage disorders (LSD): Tay-Sachs disease (TSD), Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (HS), and subsequent development of stem cell lines. For each disease, we developed a family-specific fluorescent multiplex single-cell PCR protocol that included the familial mutation and informative markers surrounding the mutation. Embryo biopsy and PGD analysis were performed on either oocytes (polar bodies one and two) or on single blastomeres from a six-cell embryo. We treated twenty families carrying mutations in these lysosomal storage disorders, including 3 couples requiring simultaneous analysis for two disorders (TSD/GD, TSD/balanced Robertsonian translocation 45XYder(21;14), and HS/oculocutaneus albinism). These analyses led to an overall pregnancy rate/embryo transfer of 38% and the birth of 20 unaffected children from 17 families. We have found that PGD for lysosomal disorders is a safe and effective method to prevent birth of affected children. In addition, by using mutant embryos for the derivation of stem cell lines, we have successfully established GD and HS hESC lines for use as valuable models in LSD research. PMID:23320174

  11. Genetic diagnosis of human embryos.

    PubMed

    Bonnicksen, Andrea

    1992-01-01

    For all the worried talk about genetic engineering over the last two decades, it is surprising how quietly plans for the genetic diagnosis of human embryos have developed. The issues raised warrant careful examination: what needs are met through embryo diagnosis? Who bears responsibility for monitoring this technique? Under what overarching ethic should embryo diagnosis and, eventually, embryo therapy, be applied? What are the broader social implications raised by the genetic diagnosis of human embryos?

  12. Birth of healthy female twins after preimplantation genetic diagnosis of cystic fibrosis combined with gender determination.

    PubMed

    Ray, Pierre F; Frydman, Nelly; Attié, Tania; Hamamah, Samir; Kerbrat, Violaine; Tachdjian, Gérard; Romana, Serge; Vekemans, Michel; Frydman, René; Munnich, Arnold

    2002-07-01

    Two healthy sisters with a familial history of mental retardation were referred to our centre for preimplantation genetic diagnosis (PGD). Their two brothers showed severe mental retardation. The molecular basis for their disorder could not be identified, but one of the sisters and the mother presented a highly skewed pattern of X-inactivation reinforcing the likelihood of an X-linked mode of inheritance. Both sisters requested PGD to avoid the abortion of potentially affected male fetuses. PGD for sex by fluorescent in-situ hybridization was carried out for the first sister and resulted in the birth of a female child. The second sister and her partner, whose niece had cystic fibrosis (CF), were tested for CF mutations, and were both found to be deltaF508 heterozygous. We developed an efficient single cell PCR protocol for the simultaneous amplification of the CF (deltadeltaF508) locus as well as the X-linked amelogenin gene and its highly homologous pseudogene on the Y chromosome. Two PGD cycles were carried out to screen against male and deltaF508 homozygous deleted embryos. In each case several embryos could be selected for transfer and the second cycle resulted in a twin pregnancy followed by the birth of two healthy female infants.

  13. Preimplantation genetic diagnosis for Pelizaeus-Merzbacher disease with testing for age-related aneuploidies.

    PubMed

    Verlinsky, Y; Rechitsky, S; Laziuk, K; Librach, C; Genovese, R; Kuliev, A

    2006-01-01

    Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive demyelinating disorder of the central nervous system, caused by mutations of the proteolipid protein 1 gene (PLP1 gene). As no specific therapy is available for PMD, preimplantation genetic diagnosis (PGD) may be a useful option for couples carrying this mutation. PGD was performed for a couple who had had one child with the L86P mutation in exon 3 of the PLP1 gene. Because of advanced maternal age, PGD for this single-gene disorder was performed together with testing for chromosomal abnormalities. Polar bodies and blastomeres were tested for the presence of maternal mutation and closely linked markers DXS8020 and PLP5' (CA)n. The same blastomeres were also tested for the copy number of chromosomes 13, 16, 18, 21, 22, X and Y, and five chromosomally abnormal embryos were identified. A total of three embryos predicted to be unaffected and free of chromosomal disorder were transferred back to the patient, resulting in a twin pregnancy and the birth of two healthy female infants confirmed to be free of PMD, representing the first PGD for PMD combined with aneuploidy testing.

  14. Preimplantation genetic diagnosis for inherited breast cancer: first clinical application and live birth in Spain.

    PubMed

    Ramón Y Cajal, Teresa; Polo, Ana; Martínez, Olga; Giménez, Carles; Arjona, César; Llort, Gemma; Bassas, Lluís; Viscasillas, Pere; Calaf, Joaquin

    2012-06-01

    Carriers of a mutation in BRCA1/2 genes confront a high lifetime risk of breast and ovarian cancer and fifty percent probability of passing the mutation to their offspring. Current options for risk management influence childbearing decisions. The indications for preimplantation genetic diagnosis (PGD) have now been expanded to include predisposition for single-gene, late-onset cancer but few cases have been reported to date despite the favorable opinion among professionals and carriers. A 28-year-old BRCA1 mutation carrier (5273G>A in exon 19) with a strong maternal history of breast cancer and 2 years of infertility decided to pursue PGD to have a healthy descendent after an accurate assessment of her reproductive options. The procedure was approved by the national regulation authority and a PGD cycle was initiated. Four out of 6 embryos harbored the mutation. The two unaffected embryos were implanted in the uterus. A singleton pregnancy was achieved and a male baby was delivered at term. Consented umbilical cord blood testing confirmed the accuracy of the technique. Individualized PGD for inherited breast predisposition is feasible in the context of a multidisciplinary team. PMID:22179695

  15. Customizing conception: a survey of preimplantation genetic diagnosis and the resulting social, ethical, and legal dilemmas.

    PubMed

    Roberts, Jason C

    2002-07-23

    One in six American couples experience difficulties conceiving a child. With fertility rates at an all time low, the business of treating infertility is booming. However, due to the United States prohibition on government funding for embryonic research, the $4 billion industry of assisted reproductive technologies (ART) has been incompletely monitored and largely removed from oversight. Additionally, due to the fervent abortion debate, in vitro fertilization (IVF) was introduced in the United States without a research phase and procedures have been forced to evolve in the private sector. Thus, the checks and balances on medical innovation that are generally imposed by the federal government for consumer protection are lacking. Decisions about when to go from the laboratory to the clinic are often left solely to the discretion of private physicians. Preimplantation genetic diagnosis (PGD) is just one of many such treatments offered by these clinics. This iBrief examines how, why, and to whom the reproductive procedure of PGD is offered. In addition, it evaluates the prospective effects to society that arise when PGD is used for sex selection and for nontherapeutic or enhancement purposes. Finally, it explores whether and how to regulate PGD in the United States by investigating approaches to policy making that have been adopted by the United Kingdom. PMID:15709286

  16. Clinical and Technical Overview of Preimplantation Genetic Diagnosis for Fragile X Syndrome: Experience at the University Hospital Virgen del Rocio in Spain.

    PubMed

    Fernández, Raquel M; Peciña, Ana; Lozano-Arana, Maria Dolores; Sánchez, Beatriz; García-Lozano, Juan Carlos; Borrego, Salud; Antiñolo, Guillermo

    2015-01-01

    Fragile X syndrome (FXS) accounts for about one-half of cases of X-linked intellectual disability and is the most common monogenic cause of mental impairment. Reproductive options for the FXS carriers include preimplantation genetic diagnosis (PGD). However, this strategy is considered by some centers as wasteful owing to the high prevalence of premature ovarian failure in FXS carriers and the difficulties in genetic diagnosis of the embryos. Here we present the results of our PGD Program applied to FXS, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 11 couples have participated in our PGD Program for FXS since 2010. Overall, 15 cycles were performed, providing a total of 43 embryos. The overall percentage of transfers per cycle was 46.67% and the live birth rate per cycle was 13.33%. As expected, these percentages are considerably lower than the ones obtained in PGD for other pathologies. Our program resulted in the birth of 3 unaffected babies of FXS for 2 of the 11 couples (18.2%) supporting that, despite the important drawbacks of PGD for FXS, efforts should be devoted in offering this reproductive option to the affected families.

  17. Preimplantation genetic diagnosis for gender selection in the United States

    SciTech Connect

    Colls, P.; Silver, L.; Olivera, G.; Weier, J.; Escudero, T.; Goodall, N.; Tomkin, G.; Munne, S.

    2009-08-20

    Preimplantation genetic diagnosis (PGD) of gender selection for non medical reasons has been considered an unethical procedure by several authors and agencies in the Western society on the basis of disrupting the sex ratio, being discriminatory againsts women and disposal of normal embryos of the non desired gender. In this study, the analysis of a large series of PGD procedures for gender selection from a wide geographical area in the United States, shows that in general there is no deviation in preference towards any specific gender except for a preference of males in some ethnic populations of Chinese, Indian and Middle Eastern origin that represent a small percentage of the US population. In cases where only normal embryos of the non-desired gender are available, 45.5% of the couples elect to cancel the transfer, while 54.5% of them are open to have transferred embryos of the non-desired gender, this fact being strongly linked to cultural and ethnical background of the parents. In addition this study adds some evidence to the proposition that in couples with previous children of a given gender there is no biological predisposition towards producing embryos of that same gender. Based on these facts, it seems that objections to gender selection formulated by ethics committees and scientific societies are not well-founded.

  18. AB011. Preimplantation genetic diagnosis—experience from Hong Kong

    PubMed Central

    Chung, Brian Hon-Yin

    2015-01-01

    Preimplantation genetic diagnosis (PGD) is a technology used to determine whether a genetic or chromosomal disorder is present in embryos during an in-vitro fertilization (IVF) cycle. PGD screens embryos prior to their transfer to the uterus. Initially, PGD was developed to detect early onset life threatening single gene disorders for couples who are aware of their hereditary risks through family history or based on carrier testing. Since then, the use of PGD has expanded to detect late onset disorders such as Huntington disease and hereditary cancer predisposition syndromes. PGD treatment has been available in Hong Kong since 2002. In Hong Kong, couples seeking PGD treatment are required to see two doctors, one of whom must have proper training in clinical genetics and/or genetic counselling. The purposes of genetic counselling include educating patients about the genetic condition and ensuring that patients are given informed choices on the available options. PGD can provide reassurance of having healthy children for couples at high risks passing the genetic change. Yet there are more ethical concerns when the requests become increasingly complex. Multidisciplinary PGD board meeting has a key role in cases with ethical concerns. We illustrate with case examples the practice of PGD-related genetic counselling in Hong Kong.

  19. Healthy Baby Born to a Robertsonian Translocation Carrier following Next-Generation Sequencing-Based Preimplantation Genetic Diagnosis: A Case Report

    PubMed Central

    Lukaszuk, Krzysztof; Pukszta, Sebastian; Ochman, Karolina; Cybulska, Celina; Liss, Joanna; Pastuszek, Ewa; Zabielska, Judyta; Woclawek-Potocka, Izabela

    2015-01-01

    Preimplantation genetic diagnosis (PGD) is well established method for treatment of genetic problems associated with infertility. Moreover, PGD with next-generation sequencing (NGS) provide new possibilities for diagnosis and new parameters for evaluation in, for example, aneuploidy screening. The aim of the study was to report the successful pregnancy outcome following PGD with NGS as the method for 24 chromosome aneuploidy screening in the case of Robertsonian translocation. Day 3 embryos screening for chromosomal aneuploidy was performed in two consecutive in vitro fertilization (IVF) cycles, first with fluorescent in situ hybridization (FISH), and then with NGS-based protocol. In each IVF attempt, three embryos were biopsied. Short duration of procedures enabled fresh embryo transfer without the need for vitrification. First IVF cycle with the embryo selected using PGD analysis with the FISH method ended with pregnancy loss in week 8. The second attempt with NGS-based aneuploidy screening led to exclusion of the following two embryos: one embryo with 22 monosomy and one with multiple aneuploidies. The transfer of the only euploid blastocyst resulted in the successful pregnancy outcome. The identification of the euploid embryo based on the NGS application was the first successful clinical application of NGS-based PGD in the case of the Robertsonian translocation carrier couple. PMID:26495179

  20. Case report: first successful application of preimplantation genetic diagnosis for hereditary angiooedema.

    PubMed

    Bautista-Llácer, Rosa; Alberola, Trinitat M; Vendrell, Xavier; Fernández, Esther; Pérez-Alonso, Manuel

    2010-11-01

    Hereditary angiooedema is an autosomal dominant disease caused by mutations in the SERPING1 gene. It is characterized by oedemas in different parts of the body, being particularly dangerous when swelling involves the upper airway. Preimplantation genetic diagnosis (PGD) was performed in a couple where the woman carries a deletion of 2.9Kb that includes exon 4 of the SERPING1 gene. Four polymorphic short tandem repeat markers were tested in order to establish the disease-bearing haplotype and three of them were fully informative. Amplification efficiency at the preclinical work up ranged from 71% to 100% for each locus and allele drop out rates were between 0% and 20% for the polymorphic markers. The couple underwent PGD using fluorescent multiplex heminested polymerase chain reaction. Six embryos were biopsied and five of them were diagnosed as healthy. Two embryos were transferred and a singleton pregnancy was achieved, resulting in the birth of a healthy boy.

  1. Successful PGD for late infantile neuronal ceroid lipofuscinosis achieved by combined chromosome and TPP1 gene analysis.

    PubMed

    Shen, Jiandong; Cram, David Stephen; Wu, Wei; Cai, Lingbo; Yang, Xiaoyu; Sun, Xueping; Cui, Yugui; Liu, Jiayin

    2013-08-01

    Late infantile neuronal ceroid lipofuscinosis (NCL-2) is a severe debilitating autosomal recessive disease caused by mutations in TPP1. There are no effective treatments, resulting in early childhood death. A couple with two affected children presented for reproductive genetic counselling and chose to undertake IVF and preimplantation genetic diagnosis (PGD) to avoid the possibility of another affected child. However, DNA testing revealed only one mutation in the proband inherited from mother. Linkage analysis identified five informative linked short tandem repeat markers to aid the genetic diagnosis. Following IVF, five cleavage-stage embryos were biopsied and blastomeres were first subjected to whole-genome amplification, then a series of down-stream molecular genetic analyses to diagnose TPP1 genotype and finally array comparative genomic hybridization (CGH) to assess the chromosomal ploidy of each embryo. Two unaffected euploid embryos were identified for transfer. One was transferred on day 5 resulting in an ongoing pregnancy. Confirmatory prenatal diagnosis by amniocentesis showed concordance of the embryo and fetal diagnosis. As far as is known, this is the first successful report of PGD for NCL-2 using double-factor PGD with simultaneous single-gene testing and array CGH to identify an unaffected and chromosomally normal embryo for transfer.

  2. Preimplantation genetic diagnosis of skin fragility-ectodermal dysplasia syndrome.

    PubMed

    Fassihi, H; Grace, J; Lashwood, A; Whittock, N V; Braude, P R; Pickering, S J; McGrath, J A

    2006-03-01

    Skin fragility-ectodermal dysplasia syndrome is an autosomal recessive disorder caused by loss-of-function mutations in the desmosomal protein, plakophilin 1. Clinically, there may be considerable morbidity from extensive skin erosions and painful fissures on the palms and soles. In the absence of any specific treatment, prenatal diagnosis is an option for couples at reproductive risk of recurrence. In 2000, we developed and applied a single cell nested polymerase chain reaction protocol to test one couple for compound heterozygous plakophilin 1 gene mutations by preimplantation genetic diagnosis (PGD). Although pregnancy was established, an unrelated trisomy 22 led to a spontaneous abortion. However, eight embryos of known genetic status were cryopreserved at that stage, and we planned to undertake subsequent frozen embryo replacement cycles that might lead to the birth of an unaffected child in this family. Embryo cryopreservation was carried out in June 2000 using standard protocols in a three-step freezing procedure. Four embryos were thawed in March 2003, one of which was viable and was used in a frozen embryo replacement cycle, but pregnancy did not occur. The remaining four embryos were thawed in February 2004, two of which were viable (both carriers of the paternal mutation) and these were used in a second frozen embryo replacement cycle, and a singleton pregnancy was established. The child's plakophilin 1 genotype was assessed by direct nucleotide sequencing across the site of both potential mutations. Following two frozen embryo replacement cycles, and almost 4 years after the initial embryo biopsy and mutation analysis, a pregnancy was achieved that progressed to term with the birth of a healthy baby girl. Nucleotide sequencing of cord blood DNA, taken immediately after delivery, showed that the child was a heterozygous carrier of the paternal mutation but not of the maternal mutation. This case demonstrates the value of embryo cryopreservation, which

  3. The European Court legitimates access of Italian couples to assisted reproductive techniques and to pre-implantation genetic diagnosis.

    PubMed

    Turillazzi, Emanuela; Frati, Paola; Busardò, Francesco Paolo; Gulino, Matteo; Fineschi, Vittorio

    2015-07-01

    On 28 August 2012, the European Court of Human Rights (ECHR) issued a judgment regarding the requirements for the legitimate access of couples to assisted reproductive techniques (ART) and to pre-implantation genetic diagnosis (PGD). This judgment concerns the case of an Italian couple who found out after their first child was born with cystic fibrosis that they were healthy carriers of the disease. When the woman became pregnant again in 2010 and underwent fetal screening, it was found that the unborn child also had cystic fibrosis, whereupon she had the pregnancy terminated on medical grounds. In order to have the embryo genetically screened prior to implantation under the procedure of PGD, the couple sought to use in vitro fertilisation to have another child. Since article 1 of the Italian law strictly limits access to ART to sterile/infertile couples or those in which the man has a sexually transmissible disease, the couple appealed to the European court, raising the question of the violation of articles 8 and 14 of the European Convention on Human Rights. The applicants lodged a complaint that they were not allowed legitimate access to ART and to PGD to select an embryo not affected by the disease. The European Court affirmed that the prohibition imposed by Italian law violated article 8 of the European Convention on Human Rights. Focusing on important regulatory and legal differences among EU Nations in providing ART treatments and PGD, we derived some important similarities and differences. PMID:24777348

  4. The European Court legitimates access of Italian couples to assisted reproductive techniques and to pre-implantation genetic diagnosis.

    PubMed

    Turillazzi, Emanuela; Frati, Paola; Busardò, Francesco Paolo; Gulino, Matteo; Fineschi, Vittorio

    2015-07-01

    On 28 August 2012, the European Court of Human Rights (ECHR) issued a judgment regarding the requirements for the legitimate access of couples to assisted reproductive techniques (ART) and to pre-implantation genetic diagnosis (PGD). This judgment concerns the case of an Italian couple who found out after their first child was born with cystic fibrosis that they were healthy carriers of the disease. When the woman became pregnant again in 2010 and underwent fetal screening, it was found that the unborn child also had cystic fibrosis, whereupon she had the pregnancy terminated on medical grounds. In order to have the embryo genetically screened prior to implantation under the procedure of PGD, the couple sought to use in vitro fertilisation to have another child. Since article 1 of the Italian law strictly limits access to ART to sterile/infertile couples or those in which the man has a sexually transmissible disease, the couple appealed to the European court, raising the question of the violation of articles 8 and 14 of the European Convention on Human Rights. The applicants lodged a complaint that they were not allowed legitimate access to ART and to PGD to select an embryo not affected by the disease. The European Court affirmed that the prohibition imposed by Italian law violated article 8 of the European Convention on Human Rights. Focusing on important regulatory and legal differences among EU Nations in providing ART treatments and PGD, we derived some important similarities and differences.

  5. The use of preimplantation genetic diagnosis in sex selection for family balancing in India.

    PubMed

    Malpani, A; Malpani, A; Modi, D

    2002-01-01

    This paper describes the use of preimplantation genetic diagnosis (PGD) in sexing embryos for family balancing in a private IVF clinic in India from April 1999 to April 2001. Embryos were biopsied and analysed on day 3, cultured in sequential media and then transferred on day 4 or day 5 after morphological selection of the best embryos. From a total of 42 cycles started, 14 clinical pregnancies and nine live births have been achieved so far, with five ongoing pregnancies. The benefits of delayed transfer 24-48 h after the embryo biopsy are that PGD centres could use the extra time available to confirm the diagnosis or introduce additional diagnostic tests for the same embryo. The selection of blastocysts for transfer should also permit the transfer of fewer embryos, thus reducing the risk of multiple gestations and increasing the pregnancy rate as a consequence of the expected higher implantation rate. This is the first report of the use of PGD in sex selection for family balancing in India, where couples place a premium on having baby boys, and the social and ethical aspects of the use of this technology in this setting are briefly discussed.

  6. Complex preimplantation genetic diagnosis for beta-thalassaemia, sideroblastic anaemia, and human leukocyte antigen (HLA)-typing.

    PubMed

    Kakourou, Georgia; Vrettou, Christina; Kattamis, Antonis; Destouni, Aspasia; Poulou, Myrto; Moutafi, Maria; Kokkali, Georgia; Pantos, Konstantinos; Davies, Stephen; Kitsiou-Tzeli, Sophia; Kanavakis, Emmanuel; Traeger-Synodinos, Joanne

    2016-01-01

    Preimplantation genetic diagnosis (PGD) to select histocompatible siblings to facilitate curative haematopoeitic stem-cell transplantation (HSCT) is now an acceptable option in the absence of an available human leukocyte antigen (HLA) compatible donor. We describe a case where the couple who requested HLA-PGD, were both carriers of two serious haematological diseases, beta-thalassaemia and sideroblastic anaemia. Their daughter, affected with sideroblastic anaemia, was programmed to have HSCT. A multiplex-fluorescent-touchdown-PCR protocol was optimized for the simultaneous amplification of: the two HBB-gene mutated regions (c.118C> T, c.25-26delAA), four short tandem repeats (STRs) in chr11p15.5 linked to the HBB gene, the SLC25A38 gene mutation (c.726C > T), two STRs in chr3p22.1 linked to the SLC25A38 gene, plus eleven informative STRs for HLA-haplotyping (chr6p22.1-21.3). This was followed by real-time nested PCR and high-resolution melting analysis (HRMA) for the detection of HBB and SLC25A38 gene mutations, as well as the analysis of all STRs on an automatic genetic analyzer (sequencer). The couple completed four clinical in vitro fertilization (IVF)/PGD cycles. At least one matched unaffected embryo was identified and transferred in each cycle. A twin pregnancy was established in the fourth PGD cycle and genotyping results at all loci were confirmed by prenatal diagnosis. Two healthy baby girls were delivered at week 38 of pregnancy. The need to exclude two familial disorders for HLA-PGD is rarely encountered. The methodological approach described here is fast, accurate, clinically-validated, and of relatively low cost. PMID:26636621

  7. Preimplantation Genetic Diagnosis: Prenatal Testing for Embryos Finally Achieving Its Potential

    PubMed Central

    Stern, Harvey J.

    2014-01-01

    Preimplantation genetic diagnosis was developed nearly a quarter-century ago as an alternative form of prenatal diagnosis that is carried out on embryos. Initially offered for diagnosis in couples at-risk for single gene genetic disorders, such as cystic fibrosis, spinal muscular atrophy and Huntington disease, preimplantation genetic diagnosis (PGD) has most frequently been employed in assisted reproduction for detection of chromosome aneuploidy from advancing maternal age or structural chromosome rearrangements. Major improvements have been seen in PGD analysis with movement away from older, less effective technologies, such as fluorescence in situ hybridization (FISH), to newer molecular tools, such as DNA microarrays and next generation sequencing. Improved results have also started to be seen with decreasing use of Day 3 blastomere biopsy in favor of polar body or Day 5 trophectoderm biopsy. Discussions regarding the scientific, ethical, legal and social issues surrounding the use of sequence data from embryo biopsy have begun and must continue to avoid concern regarding eugenic or inappropriate use of this technology. PMID:26237262

  8. Experience of Preimplantation Genetic Diagnosis with HLA Matching at the University Hospital Virgen del Rocío in Spain: Technical and Clinical Overview

    PubMed Central

    Fernández, Raquel María; Peciña, Ana; Lozano-Arana, Maria Dolores; Sánchez, Beatriz; Guardiola, Jordi; García-Lozano, Juan Carlos; Borrego, Salud; Antiñolo, Guillermo

    2014-01-01

    Preimplantation genetic diagnosis (PGD) of genetic diseases, combined with HLA matching (PGD-HLA), is an option for couples at risk of transmitting a genetic disease to select unaffected embryos of an HLA tissue type compatible with that of an existing affected child. Here we present the results of our PGD-HLA program at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. Seven couples have participated in our program because of different indications. Overall, 26 cycles were performed, providing a total of 202 embryos. A conclusive molecular diagnosis and HLA-typing could be assured in 96% of the embryos. The percentage of transfers per cycle was 26.9% and the birth rate per cycle was 7.7% per transfer. Our PGD-HLA program resulted in the birth of 2 healthy babies, HLA-identical to their affected siblings, with successful subsequent haematopoietic stem cell (HSC) transplantations. Both HSC-transplanted children are currently doing well 48 and 21 months following transplantation, respectively. All the procedures, including HSCs umbilical cord transplantation, were performed in our hospital. PMID:24868528

  9. Experience of preimplantation genetic diagnosis with HLA matching at the University Hospital Virgen del Rocío in Spain: technical and clinical overview.

    PubMed

    Fernández, Raquel María; Peciña, Ana; Lozano-Arana, Maria Dolores; Sánchez, Beatriz; Guardiola, Jordi; García-Lozano, Juan Carlos; Borrego, Salud; Antiñolo, Guillermo

    2014-01-01

    Preimplantation genetic diagnosis (PGD) of genetic diseases, combined with HLA matching (PGD-HLA), is an option for couples at risk of transmitting a genetic disease to select unaffected embryos of an HLA tissue type compatible with that of an existing affected child. Here we present the results of our PGD-HLA program at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. Seven couples have participated in our program because of different indications. Overall, 26 cycles were performed, providing a total of 202 embryos. A conclusive molecular diagnosis and HLA-typing could be assured in 96% of the embryos. The percentage of transfers per cycle was 26.9% and the birth rate per cycle was 7.7% per transfer. Our PGD-HLA program resulted in the birth of 2 healthy babies, HLA-identical to their affected siblings, with successful subsequent haematopoietic stem cell (HSC) transplantations. Both HSC-transplanted children are currently doing well 48 and 21 months following transplantation, respectively. All the procedures, including HSCs umbilical cord transplantation, were performed in our hospital.

  10. Failure mode and effects analysis of witnessing protocols for ensuring traceability during PGD/PGS cycles.

    PubMed

    Cimadomo, Danilo; Ubaldi, Filippo Maria; Capalbo, Antonio; Maggiulli, Roberta; Scarica, Catello; Romano, Stefania; Poggiana, Cristina; Zuccarello, Daniela; Giancani, Adriano; Vaiarelli, Alberto; Rienzi, Laura

    2016-09-01

    Preimplantation genetic diagnosis and aneuploidy testing (PGD/PGS) use is constantly growing in IVF, and embryo/biopsy traceability during the additional laboratory procedures needed is pivotal. An electronic witnessing system (EWS), which showed a significant value in decreasing mismatch occurrence and increasing detection possibilities during standard care IVF, still does not guarantee the same level of efficiency during PGD/PGS cycles. Specifically, EWS cannot follow single embryos throughout the procedure. This is however critical when an unambiguous diagnosis corresponds to each embryo. Failure Mode and Effects Analysis (FMEA) is a proactive method generally adopted to define tools ensuring safety along a procedure. Due to the implementation of a large quantitative PCR (qPCR)-based blastocyst stage PGD/PGS programme in our centre, and to evaluate the potential procedural risks, a FMEA was performed in September 2014. Forty-four failure modes were identified, among which six were given a moderate risk priority number (>15) (RPN; product of estimated occurrence, severity and detection). Specific corrective measures were then introduced and implemented, and a second evaluation performed six months later. The meticulous and careful application of such measures allowed the risks to be decreased along the whole protocol, by reducing their estimated occurrence and/or increasing detection possibilities.

  11. Failure mode and effects analysis of witnessing protocols for ensuring traceability during PGD/PGS cycles.

    PubMed

    Cimadomo, Danilo; Ubaldi, Filippo Maria; Capalbo, Antonio; Maggiulli, Roberta; Scarica, Catello; Romano, Stefania; Poggiana, Cristina; Zuccarello, Daniela; Giancani, Adriano; Vaiarelli, Alberto; Rienzi, Laura

    2016-09-01

    Preimplantation genetic diagnosis and aneuploidy testing (PGD/PGS) use is constantly growing in IVF, and embryo/biopsy traceability during the additional laboratory procedures needed is pivotal. An electronic witnessing system (EWS), which showed a significant value in decreasing mismatch occurrence and increasing detection possibilities during standard care IVF, still does not guarantee the same level of efficiency during PGD/PGS cycles. Specifically, EWS cannot follow single embryos throughout the procedure. This is however critical when an unambiguous diagnosis corresponds to each embryo. Failure Mode and Effects Analysis (FMEA) is a proactive method generally adopted to define tools ensuring safety along a procedure. Due to the implementation of a large quantitative PCR (qPCR)-based blastocyst stage PGD/PGS programme in our centre, and to evaluate the potential procedural risks, a FMEA was performed in September 2014. Forty-four failure modes were identified, among which six were given a moderate risk priority number (>15) (RPN; product of estimated occurrence, severity and detection). Specific corrective measures were then introduced and implemented, and a second evaluation performed six months later. The meticulous and careful application of such measures allowed the risks to be decreased along the whole protocol, by reducing their estimated occurrence and/or increasing detection possibilities. PMID:27372783

  12. Ethics of PGD: thoughts on the consequences of typing HLA in embryos.

    PubMed

    Edwards, R G

    2004-08-01

    As with so many fields of study associated with assisted human reproduction, many ethical issues are raised by the practice of preimplantation diagnosis of inherited disease (PGD). Some are part and parcel of assisted conception, e.g.the rights of human embryos in vitro and of embryologists to establish them, carry out research and discard them. Others unique to clinical PGD were discussed at an earlier meeting on PGD (Edwards et al., 2003). Recent developments in PGD are discussed briefly in this Commentary, especially the ethics of designer babies.

  13. Ethics of PGD: thoughts on the consequences of typing HLA in embryos.

    PubMed

    Edwards, R G

    2004-08-01

    As with so many fields of study associated with assisted human reproduction, many ethical issues are raised by the practice of preimplantation diagnosis of inherited disease (PGD). Some are part and parcel of assisted conception, e.g.the rights of human embryos in vitro and of embryologists to establish them, carry out research and discard them. Others unique to clinical PGD were discussed at an earlier meeting on PGD (Edwards et al., 2003). Recent developments in PGD are discussed briefly in this Commentary, especially the ethics of designer babies. PMID:15333255

  14. Experience of Preimplantation Genetic Diagnosis for Hemophilia at the University Hospital Virgen Del Rocío in Spain: Technical and Clinical Overview.

    PubMed

    Fernández, Raquel M; Peciña, Ana; Sánchez, Beatriz; Lozano-Arana, Maria Dolores; García-Lozano, Juan Carlos; Pérez-Garrido, Rosario; Núñez, Ramiro; Borrego, Salud; Antiñolo, Guillermo

    2015-01-01

    Hemophilia A and B are the most common hereditary hemorrhagic disorders, with an X-linked mode of inheritance. Reproductive options for the families affected with hemophilia, aiming at the prevention of the birth of children with severe coagulation disorders, include preimplantation genetic diagnosis (PGD). Here we present the results of our PGD Program applied to hemophilia, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 34 couples have been included in our program since 2005 (30 for hemophilia A and 4 for hemophilia B). Overall, 60 cycles were performed, providing a total of 508 embryos. The overall percentage of transfers per cycle was 81.7% and the live birth rate per cycle ranged from 10.3 to 24.1% depending on the methodological approach applied. Although PGD for hemophilia can be focused on gender selection of female embryos, our results demonstrate that methodological approaches that allow the diagnosis of the hemophilia status of every embryo have notorious advantages. Our PGD Program resulted in the birth of 12 healthy babies for 10 out of the 34 couples (29.4%), constituting a relevant achievement for the Spanish Public Health System within the field of haematological disorders.

  15. Experience of Preimplantation Genetic Diagnosis for Hemophilia at the University Hospital Virgen Del Rocío in Spain: Technical and Clinical Overview

    PubMed Central

    Fernández, Raquel M.; Peciña, Ana; Sánchez, Beatriz; Lozano-Arana, Maria Dolores; García-Lozano, Juan Carlos; Pérez-Garrido, Rosario; Núñez, Ramiro; Borrego, Salud; Antiñolo, Guillermo

    2015-01-01

    Hemophilia A and B are the most common hereditary hemorrhagic disorders, with an X-linked mode of inheritance. Reproductive options for the families affected with hemophilia, aiming at the prevention of the birth of children with severe coagulation disorders, include preimplantation genetic diagnosis (PGD). Here we present the results of our PGD Program applied to hemophilia, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 34 couples have been included in our program since 2005 (30 for hemophilia A and 4 for hemophilia B). Overall, 60 cycles were performed, providing a total of 508 embryos. The overall percentage of transfers per cycle was 81.7% and the live birth rate per cycle ranged from 10.3 to 24.1% depending on the methodological approach applied. Although PGD for hemophilia can be focused on gender selection of female embryos, our results demonstrate that methodological approaches that allow the diagnosis of the hemophilia status of every embryo have notorious advantages. Our PGD Program resulted in the birth of 12 healthy babies for 10 out of the 34 couples (29.4%), constituting a relevant achievement for the Spanish Public Health System within the field of haematological disorders. PMID:26258137

  16. Experience of Preimplantation Genetic Diagnosis for Hemophilia at the University Hospital Virgen Del Rocío in Spain: Technical and Clinical Overview.

    PubMed

    Fernández, Raquel M; Peciña, Ana; Sánchez, Beatriz; Lozano-Arana, Maria Dolores; García-Lozano, Juan Carlos; Pérez-Garrido, Rosario; Núñez, Ramiro; Borrego, Salud; Antiñolo, Guillermo

    2015-01-01

    Hemophilia A and B are the most common hereditary hemorrhagic disorders, with an X-linked mode of inheritance. Reproductive options for the families affected with hemophilia, aiming at the prevention of the birth of children with severe coagulation disorders, include preimplantation genetic diagnosis (PGD). Here we present the results of our PGD Program applied to hemophilia, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 34 couples have been included in our program since 2005 (30 for hemophilia A and 4 for hemophilia B). Overall, 60 cycles were performed, providing a total of 508 embryos. The overall percentage of transfers per cycle was 81.7% and the live birth rate per cycle ranged from 10.3 to 24.1% depending on the methodological approach applied. Although PGD for hemophilia can be focused on gender selection of female embryos, our results demonstrate that methodological approaches that allow the diagnosis of the hemophilia status of every embryo have notorious advantages. Our PGD Program resulted in the birth of 12 healthy babies for 10 out of the 34 couples (29.4%), constituting a relevant achievement for the Spanish Public Health System within the field of haematological disorders. PMID:26258137

  17. A comparison of different lysis buffers to assess allele dropout from single cells for preimplantation genetic diagnosis.

    PubMed

    Thornhill, A R; McGrath, J A; Eady, R A; Braude, P R; Handyside, A H

    2001-06-01

    Single cell polymerase chain reaction (PCR) for preimplantation genetic diagnosis (PGD) requires high efficiency and accuracy. Allele dropout (ADO), the random amplification failure of one of the two parental alleles, remains the most significant problem in PCR-based PGD testing since it can result in serious misdiagnosis for compound heterozygous or autosomal dominant conditions. A number of different strategies (including the use of lysis buffers to break down the cell and make the DNA accessible) have been employed to combat ADO with varying degrees of success, yet there is still no consensus among PGD centres over which lysis buffer should be used (ESHRE PGD Consortium, 1999). To address this issue, PCR amplification of three genes (CFTR, LAMA3 and PKP1) at different chromosomal loci was investigated. Single lymphocytes from individuals heterozygous for mutations within each of the three genes were collected and lysed in either alkaline lysis buffer (ALB) or proteinase K/SDS lysis buffer (PK). PCR amplification efficiencies were comparable between alkaline lysis and proteinase K lysis for PCR products spanning each of the three mutated loci (DeltaF508 in CFTR 90% vs 88%; R650X in LAMA3 82% vs 78%; and Y71X in PKP1 91% vs 87%). While there was no appreciable difference between ADO rates between the two lysis buffers for the LAMA3 PCR product (25% vs 26%), there were significant differences in ADO rates between ALB and PK for the CFTR PCR product (0% vs 23%) and the PKP1 PCR product (8% vs 56%). Based on these results, we are currently using ALB in preference to PK/SDS buffer for the lysis of cells in clinical PGD. PMID:11438956

  18. The results of pregnancies after gender selection by pre implantation genetic diagnosis and its relation with couple's age

    PubMed Central

    Panahi, Sorayya; Fahami, Fariba

    2015-01-01

    Background: Non-medical utilization of pre-implantation genetic diagnosis (PGD), like sex selection, is increasing, therefore it is necessary to follow-up the health and outcome of fertilization and newborn's birth followed PGD. The aim of this study was to evaluate the outcome of fertilization after sex selection by PGD and the relation between the age of parents and the outcome of fertilization. Materials and Methods: This was a retrospective descriptive correlative study conducted on 218 couples in Isfahan. Samples were selected through convenience sampling. The rate of chemical and clinical pregnancy and abortion, the frequency of success in achieving the desired sex, and the mean of gestational age and weight of newborns were gathered through reviewing medical files and phone interviews. Data was analyzed using independent t test and Pearson correlation test. Results: The rate of chemical and clinical pregnancy was 30.7% and 30.3% respectively, the rate of abortion was 26.9%, the frequency of success in achieving the desired sex was 100%, and the mean of gestational age and weight of newborns was 3260 (616) kg and 37.7 (2.07) weeks respectively. There was no significant relation between the age of parents and the rate of abortion, the rate of chemical and clinical pregnancy and newborn's gestational weight. But there was a significant relation between the age of men and gestational age of newborns (P = 0.04). Conclusions: PGD method was 100% successful in achieving the desired sex, but relatively high rate of abortion could indicate the effect of PGD on the embryo development process. PMID:26793251

  19. Preimplantation genetic diagnosis in an HIV-serodiscordant couple carrier for sickle cell disease: lessons from a case report.

    PubMed

    Gonzalez-Merino, E; Zengbe, V; Vannin, A S; Place, I; Bostan, A; Emiliani, S; Liesnard, C; Goffard, J C; Abramowicz, M; Englert, Y

    2009-03-01

    Since 1999, the Erasme Hospital Fertility Clinic has carried a special programme for patients with HIV seropositivity. The philosophy of the programme is to give access to these patients in a secure environment to the same technological facilities available to any other patients. Many of these patients being native from sub-Saharan countries, they are often sickle cell disease (SCD) carriers, a common autosomal recessive disorder in these regions, and a severe affection in homozygotes. We hereby report, for the first time, the birth of a healthy sickle haemoglobin (HbS) heterozygous baby after preimplantation genetic diagnosis (PGD) for SCD in an HIV-serodiscordant couple of HbS mutation carriers with longstanding infertility. The prospective mother was 35 years old and HIV positive with an undetectable viral load under highly active antiretroviral therapy. One carrier embryo was transferred and resulted in the birth of a healthy HbS carrier baby girl. Despite stimulation difficulties, sometimes described in HIV patients, PGD represents an interesting additional technology, especially in populations where the coexistence of both diseases is frequent. PGD could even be preferred to prenatal diagnosis for couples of HbS carriers if the woman is HIV positive, as invasive prenatal samplings carry a risk of materno-foetal viral transmission.

  20. Hereditary cancer predisposition syndromes and preimplantation genetic diagnosis: where are we now?

    PubMed

    Konstantopoulou, I; Pertesi, M; Fostira, F; Grivas, A; Yannoukakos, D

    2009-09-01

    Hereditary cancer predisposition syndromes have been model diseases in order to understand carcinogenesis in many different organs such as colon, breast, ovaries, stomach and others. Better understanding and follow up of these diseases have led to the increasing acceptance of cancer genetic testing and the improving survival of young patients with cancer. Once the mutation is identified in the gene, patients and their relatives have the option of preimplantation genetic diagnosis (PGD) in order to select embryos without familial cancer-predisposing mutations. This procedure has already been performed in several syndromes, including the common syndromes of genetic predisposition to colon and breast cancer. Despite the numerous ethical objections and legal arguments, PGD for adult-onset cancers is today a reality and couples with an inherited predisposing mutation deserve the same respect, support and right to choose if their child will be born having an extremely high risk for cancer development as in the case of other life-threatening diseases for which prenatal screening has become a standard.

  1. Preimplantation genetic diagnosis for Charcot-Marie-Tooth disease type 1A.

    PubMed

    De Vos, A; Sermon, K; De Rijcke, M; Goossens, V; Henderix, P; Van Ranst, N; Platteau, P; Lissens, W; Devroey, P; Van Steirteghem, A; Liebaers, I

    2003-07-01

    Charcot-Marie-Tooth (CMT) disease is the 'common' name for a range of hereditary peripheral neuropathies. CMT1 is the most common form and is transmitted in an autosomal dominant manner. CMT1A maps to chromosome 17p11.2 and is caused, in the majority of cases, by a 1.5 Mb DNA duplication, that includes the peripheral myelin protein 22 (PMP) gene. This paper reports on preimplantation genetic diagnosis (PGD) for CMT1A in five couples. The CMT1A duplication was detected by fluorescent PCR analysis using polymorphic (CA)n markers localized within the duplication. Single-cell PCR on blastomeres allowed genetic analysis of embryos obtained after ICSI. Only healthy unaffected embryos were transferred to the uterus. PCR experiments with single EBV-transformed lymphoblasts or with research blastomeres allowed the evaluation of amplification efficiencies, as well as contamination and allele drop-out (ADO) rates for each PCR protocol. Three simplex PCR protocols (using one primer pair) and two duplex PCR protocols (using two primer pairs) were developed for CMT1A. Additionally, a protocol using all three primer pairs in triplex was also established. Thirteen clinical ICSI-PGD cycles were performed for five couples (12 simplex PCR cycles and one duplex PCR cycle), resulting in seven embryo transfers. Three singleton pregnancies ensued in two couples and three healthy babies were delivered. This report describes different fluorescent PCR-based tests which allow efficient and accurate single-cell level detection of the CMT1A duplication. On the basis of the presence of the healthy allele of the affected parent-to-be (and/or absence of the affected one), healthy embryos can be selected for transfer. The assays are suitable for PGD for other couples who present with the same CMT1A duplication [depending on their informativity for the (CA)n markers available] as described here.

  2. Birth of a healthy female after preimplantation genetic diagnosis for Charcot-Marie-Tooth type X.

    PubMed

    Iacobelli, M; Greco, E; Rienzi, L; Ubaldi, F; Podini, D; Nuccitelli, A; Tesarik, J; Baldi, M; Fiorentino, F

    2003-11-01

    The X-linked dominant form of Charcot-Marie-Tooth syndrome (CMTX) is a clinically and genetically heterogeneous hereditary disorder of the peripheral nerves caused by mutations in the GJB1 gene that encodes a gap junction protein named connexin 32 (Cx32). Clinically, CMTX is characterized by peripheral motor and sensory deficit with muscle atrophy. A couple with a previous history of pregnancy termination after being diagnosed positive for CMTX by chorionic villus sampling, was referred for preimplantation genetic diagnosis (PGD). The female partner carried the causative H94Q, characterized by a C-->G substitution in codon 94 of exon 2 of the GJB1 gene. Embryos obtained after intracytoplasmic sperm injection (ICSI) were evaluated for the presence of the mother's mutation using polymerase chain reaction (PCR), followed by mutation analysis performed using the minisequencing method. Amelogenin sequences on the X and Y chromosomes were also co-amplified to provide a correlation between embryo gender and mutation presence. A single PGD cycle was performed, involving nine fertilized oocytes, five of which developed into good quality embryos useful for biopsy. Two unaffected embryos were transferred, resulting in a singleton pregnancy followed by the birth of a healthy female.

  3. Genetic counseling and prenatal diagnosis (image)

    MedlinePlus

    Genetic counseling (and prenatal diagnosis) provides parents with the knowledge to make intelligent, informed decisions regarding possible pregnancy and its outcome. If a pregnancy occurs the couple may want to evaluate the fetus by prenatal diagnosis.

  4. [Reverse genetics and prenatal diagnosis].

    PubMed

    Plauchu, H

    1988-05-01

    "Reverse" genetics is a research process consisting in finding the gene of a disease, then in "descending" toward the final product that it codes. This reasoning is the reverse of the one normally used which "ascends from the protein to the gene" and can be applied to the discovery of the pathogenic mechanism of a disease. There are numerous spin-offs of this new type of approach for prenatal diagnosis (PND). Thus, the discovery of polymorphic tracers surrounding the gene enables an indirect PND in informative families. Reliability is great if we have many probes at our disposal. Then, discovery of the gene itself permits a direct PND with the use of intragenic probes and synthetic oligonucleotides.

  5. Mutation-free baby born from a mitochondrial encephalopathy, lactic acidosis and stroke-like syndrome carrier after blastocyst trophectoderm preimplantation genetic diagnosis.

    PubMed

    Heindryckx, Björn; Neupane, Jitesh; Vandewoestyne, Mado; Christodoulou, Christodoulos; Jackers, Yens; Gerris, Jan; Van den Abbeel, Etienne; Van Coster, Rudy; Deforce, Dieter; De Sutter, Petra

    2014-09-01

    To investigate the applicability of preimplantation genetic diagnosis (PGD), we used trophectoderm (TE) biopsy to determine the mutation load in a 35-year-old female with mitochondrial encephalopathy, lactic acidosis and stroke-like syndrome (MELAS). Transfer of a mutation-free blastocyst gave birth to a healthy boy with undetectable mutation in any of the analyzed tissues. We found strong correlation among TE cells (r=0.90) within blastocysts and also between cytoplasmic fragments and TE (r=0.95). This is the first case of mutation-free baby born from a MELAS patient after TE biopsy and supports the applicability of blastocyst PGD for patients with mtDNA disorders to establish healthy offspring.

  6. Characterization of human PGD blastocysts with unbalanced chromosomal translocations and human embryonic stem cell line derivation?

    PubMed

    Frydman, N; Féraud, O; Bas, C; Amit, M; Frydman, R; Bennaceur-Griscelli, A; Tachdjian, G

    2009-01-01

    Novel embryonic stem cell lines derived from embryos carrying structural chromosomal abnormalities obtained after preimplantation genetic diagnosis (PGD) are of interest to study in terms of the influence of abnormalities on further development. A total of 22 unbalanced blastocysts obtained after PGD were analysed for structural chromosomal defects. Morphological description and chromosomal status of these blastocysts was established and they were used to derive human embryonic stem cell (ESC) lines. An outgrowth of cells was observed for six blastocysts (6/22; 27%). For two blastocysts, the exact morphology was unknown since they were at early stage, and for four blastocysts, the inner cell mass was clearly visible. Fifteen blastocysts carried an unbalanced chromosomal defect linked to a reciprocal translocation, resulting in a positive outgrowth of cells for five blastocysts. One human ESC line was obtained from a blastocyst carrying a partial chromosome-21 monosomy and a partial chromosome-1 trisomy. Six blastocysts carried an unbalanced chromosomal defect linked to a Robertsonian translocation, and one showed a positive outgrowth of cells. One blastocyst carried an unbalanced chromosomal defect linked to an insertion and no outgrowth was observed. The efficiency of deriving human ESC lines with constitutional chromosomal disorders was low and probably depends on the initial morphological aspect of the blastocysts and/or the type of the chromosomal disorders.

  7. Alport Syndrome Diagnosis

    MedlinePlus

    ... PGD can be performed on embryos created through in vitro fertilization. PGD refers to testing an embryo to determine whether it has the same genetic abnormality as the parent. Families interested in such an option should seek the counsel of ...

  8. Diagnosis: genetic testing cannot stand alone.

    PubMed

    Morales-Peralta, Estela

    2014-01-01

    Genetic testing uses advanced laboratory techniques to identify protein alterations, certain metabolites, chromosomes, or nucleic acids by which a genotype is determined or inferred. These tests provide insights into the molecular basis and physiopathology of genetic diseases, information which is critical for prevention, treatment and genetic counseling. Initiated in 1982, Cuba's National Program for Diagnosis, Management and Prevention of Birth Defects and Hereditary Diseases ensures availability of genetic tests to all Cubans who need them, free of charge, assisting physician-patient decisions. The tests may be used to confirm diagnoses, point to hereditary diseases and potential congenital problems during pregnancy or in pre-symptomatic stages, and diagnose carriers of recessive diseases.

  9. Reproductive outcomes following preimplantation genetic diagnosis using fluorescence in situ hybridization for 52 translocation carrier couples with a history of recurrent pregnancy loss.

    PubMed

    Kato, Keiichi; Aoyama, Naoki; Kawasaki, Nami; Hayashi, Hiroko; Xiaohui, Tang; Abe, Takashi; Kuroda, Tomoko

    2016-08-01

    Forty-six reciprocal and six Robertsonian translocation carrier couples who experienced recurrent pregnancy loss underwent fluorescence in situ hybridization-based preimplantation genetic diagnosis (PGD) for the presence of the two translocated chromosomes. Out of 52 couples, 17 (33%) were undergoing infertility treatment. In total, 239 PGD cycles as oocyte retrieval (OR) were applied. The transferrable rate of negatively diagnosed embryos at the cleavage stage was 26.3%; 71 embryos were transferred as single blastocysts. The clinical pregnancy rate per transfer was 60.6%. We obtained 41 healthy live births with 3 incidences of miscarriage (7.0%). The average cumulative live birth rate was 76.9% during 4.6 OR cycles using a mild ovarian stimulation strategy. The outcomes were classified into four groups based on carrier gender and maternal age (young (<38 years) or advanced). PGD was performed for 52 couples of which the average number of OR cycles was 4.1, 2.1, 6.7 and 4.5 in young female and male carriers and female and male carriers of advanced age; the live birth rate for a primiparity was 77.8, 72.7, 66.7 and 50.0% in those groups. These results suggest that the final live birth rate might be influenced by maternal age regardless of the gender of the carrier.

  10. Clinical Considerations of Preimplantation Genetic Diagnosis for Monogenic Diseases

    PubMed Central

    Hu, Xiaokun; Wang, Jing; Li, Yubin; Wang, Yizi; Ding, Chenhui; Zeng, Yanhong; Xu, Yanwen; Zhou, Canquan

    2015-01-01

    Purpose The aim of this study was to explore factors contribute to the success of PGD cycles for monogenic diseases. Methods During a 3-year period (January 2009 to December 2012), 184 consecutive ICSI-PGD cycles for monogenic diseases reaching the ovum pick-up and fresh embryo-transfer stage performed at the Reproductive Medicine Center of The First Affiliated Hospital Of Sun Yat-sen University were evaluated. Results ICSI was performed on 2206 metaphase II oocytes, and normal fertilization and cleavage rates were 83.4% (1840/2206) and 96.2% (1770/1840), respectively. In the present study, 60.5% (181/299) of day 3 good-quality embryos developed into good-quality embryos on day 4 after biopsy. Collectively, 42.9% clinical pregnancy rate (79/184) and 28.5% implantation rate (111/389) were presented. In the adjusted linear regression model, the only two significant factors affecting the number of genetically unaffected embryos were the number of biopsied embryos (coefficient: 0.390, 95%CI 0.317–0.463, P = 0.000) and basal FSH level (coefficient: 0.198, 95%CI 0.031–0.365, P = 0.021). In the adjusted binary logistic regression model, the only two significant factors affecting pregnancy outcome were the number of genetically available transferable embryos after PGD (adjusted OR 1.345, 95% CI 1.148–1.575, P = 0.000) and number of oocyte retrieved (adjusted OR 0.934, 95% CI 0.877–0.994, P = 0.031). Conclusion There should be at least four biopsied embryos to obtain at least one unaffected embryos in a PGD system for patients with single gene disorder and under the condition of basal FSH level smaller than 8.0mmol/L. Moreover, if only a low number (< 4) of biopsied embryos are available on day 3, the chance of unaffected embryos for transfer was small, with poor outcome. PMID:26421428

  11. [Preimplantation genetic diagnosis: technical and ethical considerations].

    PubMed

    Oliva Teles, Natália

    2011-01-01

    Following the advances in the techniques of medically assisted reproduction (ART), 1990 has seen the first born child after the development of pre-implantation genetic diagnosis. In this analysis embryos are tested for the presence of genetic anomalies at three to five days after fertilization and only unaffected embryos are transferred to the maternal uterus. The technique offers good prospects to couples at risk for conventional prenatal diagnosis. It is particularly useful where ART techniques are necessary, in which early embryo selection avoids later termination of pregnancy. In Portugal the application of laws concerning regulation of medically assisted reproduction in 2008 has clarified and formalised the medical and laboratory procedures and in some cases fundamentally changed them, particularly in the requirement to cryopreserve all high quality non-transferred embryos and in specifying conditions in which embryo experimentation may be permitted.

  12. Genetic Issues in the Diagnosis of Dystonias

    PubMed Central

    Petrucci, Simona; Valente, Enza Maria

    2013-01-01

    Dystonias are heterogeneous hyperkinetic movement disorders characterized by involuntary muscle contractions which result in twisting and repetitive movements and abnormal postures. Several causative genes have been identified, but their genetic bases still remain elusive. Primary Torsion Dystonias (PTDs), in which dystonia is the only clinical sign, can be inherited in a monogenic fashion, and many genes and loci have been identified for autosomal dominant (DYT1/TOR1A; DYT6/THAP1; DYT4/TUBB4a; DYT7; DYT13; DYT21; DYT23/CIZ1; DYT24/ANO3; DYT25/GNAL) and recessive (DYT2; DYT17) forms. However most sporadic cases, especially those with late-onset, are likely multifactorial, with genetic and environmental factors interplaying to reach a threshold of disease. At present, genetic counseling of dystonia patients remains a difficult task. Recently non-motor clinical findings in dystonias, new highlights in the pathophysiology of the disease, and the availability of high-throughput genome-wide techniques are proving useful tools to better understand the complexity of PTD genetics. We briefly review the genetic basis of the most common forms of hereditary PTDs, and discuss relevant issues related to molecular diagnosis and genetic counseling. PMID:23596437

  13. [Update on preimplantation genetic diagnosis and screening].

    PubMed

    Kőrösi, Tamás; Török, Olga; Vajta, Gábor

    2014-08-31

    Recent advancement in both human embryology and genomics has created a completely new situation for practical and widespread application of preimplantation genetic diagnosis and screening with a dramatic effect on assisted reproduction. The mapping of the first human genome and the advancement in sequencing technology and bioinformatics has led to the discovery of the exact genetic background of exponentially increasing number of diseases. In parallel, methods for culturing human embryos have also radically improved, enabling the late transfer, and the procedure of vitrification the safe cryopreservation. In consequence, refined genetic analyses have become available from blastocyst biopsy followed by the application of novel genomic methods. Furthermore, some studies suggest that by the selection of aneuploid embryos the pregnancy- and birth-rates can be increased. The amount and the depth of information obtainable from the embryos raise several technical and ethical questions that can be answered by further prospective randomized trials.

  14. Oligonucleotide microarrays in constitutional genetic diagnosis.

    PubMed

    Keren, Boris; Le Caignec, Cedric

    2011-06-01

    Oligonucleotide microarrays such as comparative genomic hybridization arrays and SNP microarrays enable the identification of genomic imbalances - also termed copy-number variants - with increasing resolution. This article will focus on the most significant applications of high-throughput oligonucleotide microarrays, both in genetic diagnosis and research. In genetic diagnosis, the method is becoming a standard tool for investigating patients with unexplained developmental delay/intellectual disability, autism spectrum disorders and/or with multiple congenital anomalies. Oligonucleotide microarray have also been recently applied to the detection of genomic imbalances in prenatal diagnosis either to characterize a chromosomal rearrangement that has previously been identified by standard prenatal karyotyping or to detect a cryptic genomic imbalance in a fetus with ultrasound abnormalities and a normal standard prenatal karyotype. In research, oligonucleotide microarrays have been used for a wide range of applications, such as the identification of new genes responsible for monogenic disorders and the association of a copy-number variant as a predisposing factor to a common disease. Despite its widespread use, the interpretation of results is not always straightforward. We will discuss several unexpected results and ethical issues raised by these new methods.

  15. DNA diagnosis of human genetic individuality.

    PubMed

    Pena, S D; Prado, V F; Epplen, J T

    1995-11-01

    DNA studies of the human genome have shown polymorphic variation at thousands of sites, defining an absolute genetic uniqueness for each individual. There are many circumstances in which it may be desirable to diagnose this molecular individuality, as for instance, in criminal investigations or paternity testing. Several techniques can be used for this DNA diagnosis and we can choose among them the one that best suits the specific problem at hand. In this review we describe the main methodologies in current use to investigate human DNA polymorphisms, discussing the best application of each option, as well as their advantages and disadvantages. PMID:8751139

  16. [Having a child and PND/PGD access in women with a BRCA1/2 mutation? Different approach whether ill or healthy].

    PubMed

    Pellegrini, Isabelle; Prodromou, Niki; Coupier, Isabelle; Huiart, Laetitia; Moretta, Jessica; Noguès, Catherine; Julian-Reynier, Claire

    2014-11-01

    Genetic tests in families with a mutation related to breast and ovarian cancers (BRCA1/2) are now offered to the persons before completion of their reproductive project. The aim of this qualitative study was to descriptively explore how the issues of reproduction are faced in women belonging to these families, and how the possible use of prenatal diagnostic (PND) and preimplantation genetic diagnosis (PGD) would be faced in a theoretical context. We conducted in-depth interviews, face to face, according to the so-called Grounded Theory approach. Twenty women with a BRCA genetic mutation participated in the study (age range: 31-57 years); 12 have had a breast and/or ovarian cancer. The knowledge of having the mutation did not modify the parental project; however prophylactic anexectomy was likely to alter it in some women. If the majority of women were in favor of PGD (n = 14), medical termination of pregnancy was a constraint towards the position in relation to PND. Besides ethical and moral arguments, the women's attitudes were constructed differently according to their own personal or familial experience of the disease. The women's perceptions of the cancer severity, risk and cure were organized according to this experience. PMID:25418592

  17. [Having a child and PND/PGD access in women with a BRCA1/2 mutation? Different approach whether ill or healthy].

    PubMed

    Pellegrini, Isabelle; Prodromou, Niki; Coupier, Isabelle; Huiart, Laetitia; Moretta, Jessica; Noguès, Catherine; Julian-Reynier, Claire

    2014-11-01

    Genetic tests in families with a mutation related to breast and ovarian cancers (BRCA1/2) are now offered to the persons before completion of their reproductive project. The aim of this qualitative study was to descriptively explore how the issues of reproduction are faced in women belonging to these families, and how the possible use of prenatal diagnostic (PND) and preimplantation genetic diagnosis (PGD) would be faced in a theoretical context. We conducted in-depth interviews, face to face, according to the so-called Grounded Theory approach. Twenty women with a BRCA genetic mutation participated in the study (age range: 31-57 years); 12 have had a breast and/or ovarian cancer. The knowledge of having the mutation did not modify the parental project; however prophylactic anexectomy was likely to alter it in some women. If the majority of women were in favor of PGD (n = 14), medical termination of pregnancy was a constraint towards the position in relation to PND. Besides ethical and moral arguments, the women's attitudes were constructed differently according to their own personal or familial experience of the disease. The women's perceptions of the cancer severity, risk and cure were organized according to this experience.

  18. The Impact of Biopsy on Human Embryo Developmental Potential during Preimplantation Genetic Diagnosis

    PubMed Central

    Cimadomo, Danilo; Capalbo, Antonio; Ubaldi, Filippo Maria; Scarica, Catello; Palagiano, Antonio; Canipari, Rita; Rienzi, Laura

    2016-01-01

    Preimplantation Genetic Diagnosis and Screening (PGD/PGS) for monogenic diseases and/or numerical/structural chromosomal abnormalities is a tool for embryo testing aimed at identifying nonaffected and/or euploid embryos in a cohort produced during an IVF cycle. A critical aspect of this technology is the potential detrimental effect that the biopsy itself can have upon the embryo. Different embryo biopsy strategies have been proposed. Cleavage stage blastomere biopsy still represents the most commonly used method in Europe nowadays, although this approach has been shown to have a negative impact on embryo viability and implantation potential. Polar body biopsy has been proposed as an alternative to embryo biopsy especially for aneuploidy testing. However, to date no sufficiently powered study has clarified the impact of this procedure on embryo reproductive competence. Blastocyst stage biopsy represents nowadays the safest approach not to impact embryo implantation potential. For this reason, as well as for the evidences of a higher consistency of the molecular analysis when performed on trophectoderm cells, blastocyst biopsy implementation is gradually increasing worldwide. The aim of this review is to present the evidences published to date on the impact of the biopsy at different stages of preimplantation development upon human embryos reproductive potential. PMID:26942198

  19. Genetics and cardiovascular disease: the impact of molecular diagnosis.

    PubMed

    Vengoechea, Jaime; McKelvey, Kent D

    2013-04-01

    Information technology is exponentially reducing the cost of genetic testing while multiple clinical applications emerge. Genetic diagnosis increasingly impacts prevention, diagnosis and treatment of disease. In cardiovascular medicine, the establishment of a specific genetic diagnosis may affect management of cardiomyopathy, arrhythmia, connective tissue and metabolic disease. Econometric studies have determined that genetic testing is cost-effective in hypertrophic cardiomyopathy and disease-specific interventions are now available for specific conditions. Identification of a specific genetic disorder now allows for more precise medicine in the affected individual and more accurate preventive care for asymptomatic family members.

  20. Spatial Rainfall Prediction Based on PGD-MRF Hybrid Model

    NASA Astrophysics Data System (ADS)

    Li, Y.; Chang, J.

    2015-12-01

    It is of great significance for decision making in water resources planning and management to predict climate variation, especially rainfall, accurately. The main goal of this study is to put forward a PGD-MRF hybrid model for monthly rainfall forecast, which is based on Poisson Gamma Distribution (PGD) and Markov Random Field(MRF) models, to make up for the deficiency of the atmospheric general circulation model (GCM) in low spatial resolution and difficultly simulating regional climate change. The Wei River Basin was taken as an case study to investigate the accuracy of PGD-MRF hybrid model. Based on the monthly rainfall data from 1960 to 2010 at eight meteorological stations, the PGD model was firstly set up to fit the statistical relationship between monthly precipitation and GCM output factors. Then the monthly rainfall data in historical period of 1960-2010 were simulated through the spatial correlation of monthly rainfall analyzed by MRF model. The statistical downscaling model (SDSM) was also employed to evaluate the performance of the PGD-MRF model. The comparison of results revealed that the PGD-MRF model had provided a superior alternative to SDSM for forecasting monthly rainfall at all these eight meteorological stations. To further illustrate the stability and representativeness of the PGD-MRF model, the monthly rainfall data from 2001 to 2010 at Huashan station were used to verify the model. The results showed that the PGD-MRF model had a good stability and great representativeness as well as a high prediction precision.

  1. Prenatal screening and prenatal diagnosis: contemporary practices in light of the past.

    PubMed

    Iltis, Ana S

    2016-06-01

    The 20th century eugenics movement in the USA and contemporary practices involving prenatal screening (PNS), prenatal diagnosis (PND), abortion and preimplantation genetic diagnosis (PGD) share important morally relevant similarities. I summarise some features of the 20th century eugenics movement; describe the contemporary standard of care in the USA regarding PNS, PND, abortion and PGD; and demonstrate that the 'old eugenics' the contemporary standard of care share the underlying view that social resources should be invested to prevent the birth of people with certain characteristics. This comparison makes evident the difficulty of crafting moral arguments that treat some uses of PNS, PND, abortion and PGD as licit and others as illicit. PMID:27161556

  2. Carrier-specific breakpoint-spanning DNA probes: an approach to preimplantation genetic diagnosis in interphase cells.

    PubMed

    Cassel, M J; Munné, S; Fung, J; Weier, H U

    1997-09-01

    Carriers of chromosomal inversions or other balanced rearrangements represent a significant fraction of patients in in-vitro fertilization (IVF) programmes due to recurrent reproductive problems. In most cases, chromosomal imbalance in fertilized oocytes is incompatible with embryo survival leading to increased rates of spontaneous abortions. Assuming that a fraction of the germ cells is karyotypically normal, these patients would greatly benefit from efficient procedures for generation and use of breakpoint-specific DNA hybridization probes in preconception and preimplantation genetic diagnosis (PGD). We describe the generation of such patient-specific probes to discriminate between normal and aberrant chromosomes in interphase cells. First, a large insert DNA library was screened for probes that bind adjacent to the chromosomal breakpoints or span them. Then, probe and hybridization parameters were optimized using white blood cells from the carrier to increase in hybridization signal intensity and contrast. Finally, the probes were tested on target cells (typically polar bodies or blastomeres) and a decision about the colour labelling scheme was made, before the probes can be used for preconception or preimplantation genetic analysis. Thus, it was demonstrated that cells with known structural abnormalities could be detected, based on hybridization of breakpoint spanning yeast artificial chromosome (YAC) DNA probes in interphase cells.

  3. Prenatal and pre-implantation genetic diagnosis.

    PubMed

    Vermeesch, Joris Robert; Voet, Thierry; Devriendt, Koenraad

    2016-09-15

    The past decade has seen the development of technologies that have revolutionized prenatal genetic testing; that is, genetic testing from conception until birth. Genome-wide single-cell arrays and high-throughput sequencing analyses are dramatically increasing our ability to detect embryonic and fetal genetic lesions, and have substantially improved embryo selection for in vitro fertilization (IVF). Moreover, both invasive and non-invasive mutation scanning of the genome are helping to identify the genetic causes of prenatal developmental disorders. These advances are changing clinical practice and pose novel challenges for genetic counselling and prenatal care. PMID:27629932

  4. Use of Contemporary Genetics in Cardiovascular Diagnosis

    PubMed Central

    George, Alfred L.

    2015-01-01

    An explosion of knowledge regarding the genetic and genomic basis for rare and common diseases has provided a framework for revolutionizing the practice of medicine. Achieving the reality of a genomic medicine era requires that basic discoveries are effectively translated into clinical practice through implementation of genetic and genomic testing. Clinical genetic tests have become routine for many inherited disorders and can be regarded as the standard-of-care in many circumstances including disorders affecting the cardiovascular system. New, high-throughput methods for determining the DNA sequence of all coding exons or complete genomes are being adopted for clinical use to expand the speed and breadth of genetic testing. Along with these extraordinary advances have emerged new challenges to practicing physicians for understanding when and how to use genetic testing along with how to appropriately interpret test results. This review will acquaint readers with general principles of genetic testing including newer technologies, test interpretation and pitfalls. The focus will be on testing genes responsible for monogenic disorders and on other emerging applications such as pharmacogenomic profiling. The discussion will be extended to the new paradigm of direct-to-consumer genetic testing and the value of assessing genomic risk for common diseases. PMID:25421045

  5. Translational Genetics for Diagnosis of Human Disorders of Sex Development

    PubMed Central

    Baxter, Ruth M.; Vilain, Eric

    2015-01-01

    Disorders of sex development (DSDs) are congenital conditions with discrepancies between the chromosomal, gonadal, and phenotypic sex of the individual. Such disorders have historically been difficult to diagnose and cause great stress to patients and their families. Genetic analysis of human samples has been instrumental in elucidating the molecules and pathways involved in the development of the bipotential gonad into a functioning testis or ovary. However, many DSD patients still do not receive a genetic diagnosis. New genetic and genomic technologies are expanding our knowledge of the underlying mechanism of DSDs and opening new avenues for clinical diagnosis. We review the genetic technologies that have elucidated the genes that are well established in sex determination in humans, discuss findings from more recent genomic technologies, and propose a new paradigm for clinical diagnosis of DSDs. PMID:23875799

  6. Genetic Approach to Diagnosis of Intellectual Disability.

    PubMed

    Puri, Ratna Dua; Tuteja, Moni; Verma, I C

    2016-10-01

    Intellectual disability is a non-specific phenotype present in a genetically heterogeneous group of disorders. It is characterized by deficits in intellectual and adaptive functioning, presenting before 18 y of age. Identifying the cause of ID is important to provide treatment where available, genetic counseling, recurrence risks and reproductive options for subsequent pregnancies. Advances in technology, especially next generation sequencing and microarrays, have greatly increased the diagnostic yield of evaluation in cases of ID. This paper describes the points in history taking and examination in the evaluation of a proband, and discusses the proper use of newer diagnostic technologies. PMID:27619815

  7. Lactose intolerance: diagnosis, genetic, and clinical factors.

    PubMed

    Mattar, Rejane; de Campos Mazo, Daniel Ferraz; Carrilho, Flair José

    2012-01-01

    Most people are born with the ability to digest lactose, the major carbohydrate in milk and the main source of nutrition until weaning. Approximately 75% of the world's population loses this ability at some point, while others can digest lactose into adulthood. This review discusses the lactase-persistence alleles that have arisen in different populations around the world, diagnosis of lactose intolerance, and its symptomatology and management. PMID:22826639

  8. Lactose intolerance: diagnosis, genetic, and clinical factors

    PubMed Central

    Mattar, Rejane; de Campos Mazo, Daniel Ferraz; Carrilho, Flair José

    2012-01-01

    Most people are born with the ability to digest lactose, the major carbohydrate in milk and the main source of nutrition until weaning. Approximately 75% of the world’s population loses this ability at some point, while others can digest lactose into adulthood. This review discusses the lactase-persistence alleles that have arisen in different populations around the world, diagnosis of lactose intolerance, and its symptomatology and management. PMID:22826639

  9. Structural chromosomal anomalies detected by prenatal genetic diagnosis: our experience.

    PubMed

    Farcaş, Simona; Crişan, C D; Andreescu, Nicoleta; Stoian, Monica; Motoc, A G M

    2013-01-01

    The prenatal diagnosis is currently widely spread and facilitates the acquiring of important genetic information about the fetus by a rate extremely accelerate and considered without precedent. In this paper, we like to present our experience concerning the genetic diagnosis and counseling offered for pregnancies in which a structural chromosomal aberration was found. The study group is formed by 528 prenatal samples of amniotic fluid and chorionic villi, received by our laboratory from 2006 through October 2012 for cytogenetic diagnosis. The appropriate genetic investigation was selected based on the indications for prenatal diagnosis. The cases with structural chromosomal anomalies and polymorphic variants were analyzed as regard to the maternal age, gestational age, referral indications and type of chromosomal anomaly found. A total number of 21 structural chromosomal anomalies and polymorphic variants were identified in the study group. Out of 21 structural chromosomal anomalies and polymorphic variants, six deletions and microdeletions, four situations with abnormal long "p" arm of acrocentric chromosomes, two duplications, two reciprocal translocations, two inversions, two additions, one Robertsonian translocation associating trisomy 13, one 9q heteromorphism and one complex chromosome rearrangement were noticed. To the best of our knowledge, this is the first Romanian study in which the diagnostic strategies and the management of the prenatal cases with structural rearrangements are presented. The data provided about the diagnosis strategy and the management of the prenatal cases with structural chromosomal anomalies represents a useful tool in genetic counseling of pregnancies diagnosed with rare structural chromosomal anomalies. PMID:23771085

  10. [Preimplantation Genetic Diagnosis by Blastocentesis: Problems and Perspectives].

    PubMed

    Zhigalina, D I; Skryabin, N A; Artyukhova, V G; Svetlakov, A V; Lebedev, I N

    2016-01-01

    The discovery of cell-free DNA in blastocoele fluid opens new perspectives for the development of preimplantation genetic diagnosis of human chromosomal and genetic diseases. In this review we analyzed the results of the first studies, which made it possible to evaluate the effectiveness of the application of a new source of biological material and showed a high degree of agreement between the results of molecular karyotyping with cell-free DNA and blastocyst cells. The results suggest the possibility of developing a noninvasive method of preimplantation genetic diagnosis, which may open a new round of progress in the field of assisted reproductive technologies and the genetics of early stages of human ontogenesis.

  11. [Diagnosis and treatment of genetic haemochromatosis].

    PubMed

    Milman, Nils Thorm

    2013-04-15

    Genetic haemochromatosis is a complex disorder/disease, which can be caused by a multiplicity of mutations in genes involved in iron metabolism being located on different chromosomes. In Caucasians, mutations in the HFE-gene account for the most common form of haemochromatosis (type 1). Non-HFE-haemochromatoses are less frequent and consist of juvenile haemochromatosis (type 2A and 2B) and TRF2-related haemochromatosis (type 3), which all respond to phlebotomies. The others comprise ferroportin disease (type 4A) atypical ferroportin disease (type 4B), acoeruloplasminaemia, atransferrinaemia and DMT1-associated haemochromatosis.

  12. Genetics and diagnosis of central diabetes insipidus.

    PubMed

    Bichet, Daniel G

    2012-04-01

    Most of the central diabetes insipidus cases seen in general practice are acquired but the rare cases of hereditary autosomal dominant or recessive neurohypophyseal diabetes insipidus have provided further cellular understanding of the mechanisms responsible for pre-hormone folding, maturation and release. Autosomal dominant central diabetes insipidus is secondary to the toxic accumulation of vasopressin mutants as fibrillar aggregates in the endoplasmic reticulum of hypothalamic magnocellular neurons producing vasopressin. As well, Trpv1(-/-) and Trpv4(-/-) mice have shed new light on the perception of tonicity through the stretch receptors TRPVs expressed both in central and peripheral neurons. The genomic information provided by sequencing the AVP gene is key to the routine care of these patients and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families. In addition, simple, inexpensive blood and urine measurements together with clinical characteristics and brain magnetic resonance imaging (MRI) could distinguish between central, nephrogenic and polydipsic cases. PMID:22520736

  13. Genetics and diagnosis of central diabetes insipidus.

    PubMed

    Bichet, Daniel G

    2012-04-01

    Most of the central diabetes insipidus cases seen in general practice are acquired but the rare cases of hereditary autosomal dominant or recessive neurohypophyseal diabetes insipidus have provided further cellular understanding of the mechanisms responsible for pre-hormone folding, maturation and release. Autosomal dominant central diabetes insipidus is secondary to the toxic accumulation of vasopressin mutants as fibrillar aggregates in the endoplasmic reticulum of hypothalamic magnocellular neurons producing vasopressin. As well, Trpv1(-/-) and Trpv4(-/-) mice have shed new light on the perception of tonicity through the stretch receptors TRPVs expressed both in central and peripheral neurons. The genomic information provided by sequencing the AVP gene is key to the routine care of these patients and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families. In addition, simple, inexpensive blood and urine measurements together with clinical characteristics and brain magnetic resonance imaging (MRI) could distinguish between central, nephrogenic and polydipsic cases.

  14. Critical Issues for Dentistry: PGD Program Directors Respond.

    ERIC Educational Resources Information Center

    Atchison, Kathryn A.; Cheffetz, Susan E.

    2002-01-01

    Surveyed directors of programs in postgraduate education in general dentistry (PGD) about critical issues facing their programs. Identified 12 themes: lack of postdoctoral applicants; student quality; professionalism and attitudes; number of postdoctoral positions; lack of funding; quality of facilities; special patient care; program curriculum;…

  15. Preimplantation genetic diagnosis for cystic fibrosis: a case report

    PubMed Central

    Biazotti, Maria Cristina Santoro; Pinto, Walter; de Albuquerque, Maria Cecília Romano Maciel; Fujihara, Litsuko Shimabukuro; Suganuma, Cláudia Haru; Reigota, Renata Bednar; Bertuzzo, Carmen Sílvia

    2015-01-01

    Cystic fibrosis is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. This disorder produces a variable phenotype including lung disease, pancreatic insufficiency, and meconium ileus plus bilateral agenesis of the vas deferens causing obstructive azoospermia and male infertility. Preimplantation genetic diagnosis is an alternative that allows identification of embryos affected by this or other genetic diseases. We report a case of couple with cystic fibrosis; the woman had the I148 T mutation and the man had the Delta F508 gene mutation. The couple underwent in vitro fertilization, associated with preimplantation genetic diagnosis, and with subsequent selection of healthy embryos for uterine transfer. The result was an uneventful pregnancy and delivery of a healthy male baby. PMID:25993078

  16. Hyperinsulinaemic Hypoglycaemia: Genetic Mechanisms, Diagnosis and Management

    PubMed Central

    Mohamed, Zainaba; Arya, Ved Bhushan; Hussain, Khalid

    2012-01-01

    Hyperinsulinaemic hypoglycaemia (HH) is characterized by unregulated insulin secretion from pancreatic β-cells. Untreated hypoglycaemia in infants can lead to seizures, developmental delay, and subsequent permanent brain injury. Early identification and meticulous managementof these patients is vital to prevent neurological insult. Mutations in eight different genes (ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1, HNF4A and UCP2) have been identified to date in patients with congenital forms of hyperinsulinism (CHI). The most severe forms of CHI are due to mutations in ABCC8 and KCJN11, which encode the two components of pancreatic β-cell ATP-sensitive potassium channel. Recent advancement in understanding the genetic aetiology, histological characterisation into focal and diffuse variety combined with improved imaging (such as fluorine 18 L-3, 4-dihydroxyphenylalanine positron emission tomography 18F-DOPA-PET scanning) and laparoscopic surgical techniques have greatly improved management. In adults, HH can be due to an insulinoma, pancreatogenous hypoglycaemic syndrome, post gastric-bypass surgery for morbid obesity as well as to mutations in insulin receptor gene. This review provides an overview of the molecular basis of CHI and outlines the clinical presentation, diagnostic criteria, and management of these patients. Conflict of interest:None declared. PMID:23032149

  17. Workshop on molecular methods for genetic diagnosis. Final technical report

    SciTech Connect

    Rinchik, E.M.

    1997-07-01

    The Sarah Lawrence College Human Genetics Program received Department of Energy funding to offer a continuing medical education workshop for genetic counselors in the New York metropolitan area. According to statistics from the National Society of Genetic Counselors, there are approximately 160 genetic counselors working in the tri-state area (New York, New Jersey, and Connecticut), and many of them had been working in the field for more than 10 years. Thus, there was a real need to offer these counselors an in-depth opportunity to learn the specifics of the major advances in molecular genetics, and, in particular, the new approaches to diagnostic testing for genetic disease. As a result of the DOE Award DE-FG02-95ER62048 ($20,583), in July 1995 we offered the {open_quotes}Workshop on Molecular Methods for Genetic Diagnosis{close_quotes} for 24 genetic counselors in the New York metropolitan area. The workshop included an initial review session on the basics of molecular biology, lectures and discussions on past and current topics in molecular genetics and diagnostic procedures, and, importantly, daily laboratory exercises. Each counselor gained not only background, but also firsthand experience, in the major techniques of biochemical and molecular methods for diagnosing genetic diseases as well as in mathematical and computational techniques involved in human genetics analyses. Our goal in offering this workshop was not to make genetic counselors experts in these laboratory diagnostic techniques, but to acquaint them, by hands-on experience, about some of the techniques currently in use. We also wanted to provide them a technical foundation upon which they can understand and appreciate new technical developments arising in the near future.

  18. Unusual presentation of familial Mediterranean fever: role of genetic diagnosis

    PubMed Central

    Nir-Paz, R.; Ben-Chetrit, E.; Pikarsky, E.; Hassin, D.; Hasin, Y.; Chajek-Shaul, T.

    2000-01-01

    OBJECTIVE—To describe the role of molecular analysis in the diagnosis of an unusual presentation of familial Mediterranean fever (FMF).
CASE REPORT—Two patients presenting with prolonged fever without signs and symptoms of serositis are described. FMF was diagnosed by genetic analysis, which disclosed that both patients were homozygous for the M694V mutation of the Mediterranean fever (MEFV) gene.
CONCLUSION—Molecular analysis of FMF should complement the investigation of patients with fever of unknown origin. This test enables a definite diagnosis of the disease and may promote the diagnosis and treatment of patients with an unusual or incomplete clinical picture of FMF.

 PMID:11005788

  19. The first family with Tay-Sachs disease in Cyprus: Genetic analysis reveals a nonsense (c.78G>A) and a silent (c.1305C>T) mutation and allows preimplantation genetic diagnosis.

    PubMed

    Georgiou, Theodoros; Christopoulos, George; Anastasiadou, Violetta; Hadjiloizou, Stavros; Cregeen, David; Jackson, Marie; Mavrikiou, Gavriella; Kleanthous, Marina; Drousiotou, Anthi

    2014-12-01

    Tay-Sachs disease (TSD) is a recessively inherited neurodegenerative disorder caused by mutations in the HEXA gene resulting in β-hexosaminidase A (HEX A) deficiency and neuronal accumulation of GM2 ganglioside. We describe the first patient with Tay-Sachs disease in the Cypriot population, a juvenile case which presented with developmental regression at the age of five. The diagnosis was confirmed by measurement of HEXA activity in plasma, peripheral leucocytes and fibroblasts. Sequencing the HEXA gene resulted in the identification of two previously described mutations: the nonsense mutation c.78G>A (p.Trp26X) and the silent mutation c.1305C>T (p.=). The silent mutation was reported once before in a juvenile TSD patient of West Indian origin with an unusually mild phenotype. The presence of this mutation in another juvenile TSD patient provides further evidence that it is a disease-causing mutation. Successful preimplantation genetic diagnosis (PGD) and prenatal follow-up were provided to the couple.

  20. The first family with Tay-Sachs disease in Cyprus: Genetic analysis reveals a nonsense (c.78G>A) and a silent (c.1305C>T) mutation and allows preimplantation genetic diagnosis.

    PubMed

    Georgiou, Theodoros; Christopoulos, George; Anastasiadou, Violetta; Hadjiloizou, Stavros; Cregeen, David; Jackson, Marie; Mavrikiou, Gavriella; Kleanthous, Marina; Drousiotou, Anthi

    2014-12-01

    Tay-Sachs disease (TSD) is a recessively inherited neurodegenerative disorder caused by mutations in the HEXA gene resulting in β-hexosaminidase A (HEX A) deficiency and neuronal accumulation of GM2 ganglioside. We describe the first patient with Tay-Sachs disease in the Cypriot population, a juvenile case which presented with developmental regression at the age of five. The diagnosis was confirmed by measurement of HEXA activity in plasma, peripheral leucocytes and fibroblasts. Sequencing the HEXA gene resulted in the identification of two previously described mutations: the nonsense mutation c.78G>A (p.Trp26X) and the silent mutation c.1305C>T (p.=). The silent mutation was reported once before in a juvenile TSD patient of West Indian origin with an unusually mild phenotype. The presence of this mutation in another juvenile TSD patient provides further evidence that it is a disease-causing mutation. Successful preimplantation genetic diagnosis (PGD) and prenatal follow-up were provided to the couple. PMID:25606403

  1. Genetic imprecision: Diagnosis of possible defects often cannot predict prognosis

    SciTech Connect

    Lewis, R.

    1991-05-01

    The author discusses the difficulties in using current genetic information for the detection of hereditary diseases. Although there have been many advances in cytogenetic and molecular testing, the diagnosis of defects does not necessarily predict prognosis. Detection of mutant alleles, mosaicism, familial chromosomal rearrangements and de novo chromosomal rearrangements lends uncertainties to genetic counselling. The problems have been compounded by a lack of follow-up to determine if a defect actually exists in a fetus aborted as a result of counselling; nor has there been long-term follow-up of fetuses carried to term that appear healthy at birth. Disappointments after the discovery of the cystic fibrosis gene were due to discovery of many mutations of the gene, making screening for the disease difficult. Some genetic counselors question the benefits of screening for this disease since with advances in treatment, life span has been lengthened and quality of life has been improved.

  2. PGD: a pangolin genome hub for the research community

    PubMed Central

    Tan, Tze King; Tan, Ka Yun; Hari, Ranjeev; Mohamed Yusoff, Aini; Wong, Guat Jah; Siow, Cheuk Chuen; Mutha, Naresh V.R.; Rayko, Mike; Komissarov, Aleksey; Dobrynin, Pavel; Krasheninnikova, Ksenia; Tamazian, Gaik; Paterson, Ian C.; Warren, Wesley C.; Johnson, Warren E.; O'Brien, Stephen J.; Choo, Siew Woh

    2016-01-01

    Pangolins (order Pholidota) are the only mammals covered by scales. We have recently sequenced and analyzed the genomes of two critically endangered Asian pangolin species, namely the Malayan pangolin (Manis javanica) and the Chinese pangolin (Manis pentadactyla). These complete genome sequences will serve as reference sequences for future research to address issues of species conservation and to advance knowledge in mammalian biology and evolution. To further facilitate the global research effort in pangolin biology, we developed the Pangolin Genome Database (PGD), as a future hub for hosting pangolin genomic and transcriptomic data and annotations, and with useful analysis tools for the research community. Currently, the PGD provides the reference pangolin genome and transcriptome data, gene sequences and functional information, expressed transcripts, pseudogenes, genomic variations, organ-specific expression data and other useful annotations. We anticipate that the PGD will be an invaluable platform for researchers who are interested in pangolin and mammalian research. We will continue updating this hub by including more data, annotation and analysis tools particularly from our research consortium. Database URL: http://pangolin-genome.um.edu.my

  3. PGD: a pangolin genome hub for the research community.

    PubMed

    Tan, Tze King; Tan, Ka Yun; Hari, Ranjeev; Mohamed Yusoff, Aini; Wong, Guat Jah; Siow, Cheuk Chuen; Mutha, Naresh V R; Rayko, Mike; Komissarov, Aleksey; Dobrynin, Pavel; Krasheninnikova, Ksenia; Tamazian, Gaik; Paterson, Ian C; Warren, Wesley C; Johnson, Warren E; O'Brien, Stephen J; Choo, Siew Woh

    2016-01-01

    Pangolins (order Pholidota) are the only mammals covered by scales. We have recently sequenced and analyzed the genomes of two critically endangered Asian pangolin species, namely the Malayan pangolin (Manis javanica) and the Chinese pangolin (Manis pentadactyla). These complete genome sequences will serve as reference sequences for future research to address issues of species conservation and to advance knowledge in mammalian biology and evolution. To further facilitate the global research effort in pangolin biology, we developed the Pangolin Genome Database (PGD), as a future hub for hosting pangolin genomic and transcriptomic data and annotations, and with useful analysis tools for the research community. Currently, the PGD provides the reference pangolin genome and transcriptome data, gene sequences and functional information, expressed transcripts, pseudogenes, genomic variations, organ-specific expression data and other useful annotations. We anticipate that the PGD will be an invaluable platform for researchers who are interested in pangolin and mammalian research. We will continue updating this hub by including more data, annotation and analysis tools particularly from our research consortium.Database URL: http://pangolin-genome.um.edu.my. PMID:27616775

  4. PGD: a pangolin genome hub for the research community

    PubMed Central

    Tan, Tze King; Tan, Ka Yun; Hari, Ranjeev; Mohamed Yusoff, Aini; Wong, Guat Jah; Siow, Cheuk Chuen; Mutha, Naresh V.R.; Rayko, Mike; Komissarov, Aleksey; Dobrynin, Pavel; Krasheninnikova, Ksenia; Tamazian, Gaik; Paterson, Ian C.; Warren, Wesley C.; Johnson, Warren E.; O'Brien, Stephen J.; Choo, Siew Woh

    2016-01-01

    Pangolins (order Pholidota) are the only mammals covered by scales. We have recently sequenced and analyzed the genomes of two critically endangered Asian pangolin species, namely the Malayan pangolin (Manis javanica) and the Chinese pangolin (Manis pentadactyla). These complete genome sequences will serve as reference sequences for future research to address issues of species conservation and to advance knowledge in mammalian biology and evolution. To further facilitate the global research effort in pangolin biology, we developed the Pangolin Genome Database (PGD), as a future hub for hosting pangolin genomic and transcriptomic data and annotations, and with useful analysis tools for the research community. Currently, the PGD provides the reference pangolin genome and transcriptome data, gene sequences and functional information, expressed transcripts, pseudogenes, genomic variations, organ-specific expression data and other useful annotations. We anticipate that the PGD will be an invaluable platform for researchers who are interested in pangolin and mammalian research. We will continue updating this hub by including more data, annotation and analysis tools particularly from our research consortium. Database URL: http://pangolin-genome.um.edu.my PMID:27616775

  5. PGD: a pangolin genome hub for the research community.

    PubMed

    Tan, Tze King; Tan, Ka Yun; Hari, Ranjeev; Mohamed Yusoff, Aini; Wong, Guat Jah; Siow, Cheuk Chuen; Mutha, Naresh V R; Rayko, Mike; Komissarov, Aleksey; Dobrynin, Pavel; Krasheninnikova, Ksenia; Tamazian, Gaik; Paterson, Ian C; Warren, Wesley C; Johnson, Warren E; O'Brien, Stephen J; Choo, Siew Woh

    2016-01-01

    Pangolins (order Pholidota) are the only mammals covered by scales. We have recently sequenced and analyzed the genomes of two critically endangered Asian pangolin species, namely the Malayan pangolin (Manis javanica) and the Chinese pangolin (Manis pentadactyla). These complete genome sequences will serve as reference sequences for future research to address issues of species conservation and to advance knowledge in mammalian biology and evolution. To further facilitate the global research effort in pangolin biology, we developed the Pangolin Genome Database (PGD), as a future hub for hosting pangolin genomic and transcriptomic data and annotations, and with useful analysis tools for the research community. Currently, the PGD provides the reference pangolin genome and transcriptome data, gene sequences and functional information, expressed transcripts, pseudogenes, genomic variations, organ-specific expression data and other useful annotations. We anticipate that the PGD will be an invaluable platform for researchers who are interested in pangolin and mammalian research. We will continue updating this hub by including more data, annotation and analysis tools particularly from our research consortium.Database URL: http://pangolin-genome.um.edu.my.

  6. High volume molecular genetic identification of single nucleotide polymorphisms using Genetic Bit Analysis Application to human genetic diagnosis

    SciTech Connect

    Boyce-Jacino, M.T.; Reynolds, J.; Nikiforov, T.

    1994-09-01

    The most common type of genetic disease-associated mutation is the single nucleotide polymorphism (SNP). Because most genetic diseases can be caused by multiple SNPs in the same gene, effective routine diagnosis of complex genetic diseases is dependent on a simple and reliable method of interrogating SNP sites. Molecular Tool`s solid phase assay capable of direct genotyping (single base sequencing) of SNP sites, Genetic Bit Analysis (GBA), involves hybridization-capture of a single-stranded PCR product to a sequence-specific, microtiter plate-bound oligonucleotide primer. The captured PCR product then acts as template for single-base extension of the capture primer across the polymorphic site, enabling direct determination of the base composition of the polymorphism through a simple colormetric assay. Genotyping in a high volume, semi-automated, processing system with a current capacity of 100 SNP interrogations per technician per day enables the screening of candidate mutations rapidly and cost-effectively, critically important to comprehensive genetic diagnosis. Using this gel-free technology, we have developed prototype diagnostic tests for CFTR and ApoE polymorphisms which enable direct sequencing of the polymorphic base at each site of interest. Routine clinical diagnosis of genetically complex diseases such as cystic fibrosis is dependent on this combination of robust biochemistry and simple format. Additionally, the ability to transfer the format and biochemistry to any disease gene of interest enables the broad application of this technology to clinical diagnostics, especially for genetically complex diseases.

  7. Multimodal genetic diagnosis of solid variant alveolar rhabdomyosarcoma.

    PubMed

    Cerveira, Nuno; Torres, Lurdes; Ribeiro, Franclim R; Henrique, Rui; Pinto, Armando; Bizarro, Susana; Ferreira, Ana M; Lopes, Carlos; Teixeira, Manuel R

    2005-12-01

    The most common types of rhabdomyosarcoma (RMS) are alveolar RMS (ARMS), which are characterized by the specific translocation t(2;13)(q35;q14) or its rarer variant, t(1;13)(p36;q14), producing the fusion genes PAX3-FKHR and PAX7-FKHR, respectively, and embryonal RMS (ERMS), which is characterized by multiple numeric chromosome changes. A solid variant of ARMS that is morphologically indistinguishable from ERMS has been described recently. We present two cases with an initial histopathologic diagnosis of ERMS in which the combined findings by cytogenetic, reverse-transcriptase polymerase chain reaction (RT-PCR), and comparative genomic hybridization (CGH) analyses demonstrate that both tumors were in fact the solid variant of ARMS. The cytogenetic analysis of patient 1 revealed a t(2;13)(q35;q14) and the RT-PCR study detected the corresponding PAX3-FKHR chimeric transcript. In patient 2, the cytogenetic finding of multiple trisomies was compatible with the initial histopathologic diagnosis of ERMS, but the finding of a PAX7-FKHR fusion transcript by RT-PCR pointed to the diagnosis of ARMS. Interestingly, the CGH findings of this case reconciled the molecular and cytogenetic data by detecting, in addition to the trisomies, amplification of chromosomal bands 1p36 and 13q14, where the PAX7 and FKHR genes are located, respectively. Our data indicate that this multimodal genetic analysis could be important for the differential diagnosis of these tumors. Furthermore, our findings and previous studies indicate that there are no apparent genetic differences between solid variant and typical ARMS. PMID:16337856

  8. Defects in Peroxisomal 6-Phosphogluconate Dehydrogenase Isoform PGD2 Prevent Gametophytic Interaction in Arabidopsis thaliana1[OPEN

    PubMed Central

    Hölscher, Christian; Meyer, Tanja; Fischer, Kerstin

    2016-01-01

    We studied the localization of 6-phosphogluconate dehydrogenase (PGD) isoforms of Arabidopsis (Arabidopsis thaliana). Similar polypeptide lengths of PGD1, PGD2, and PGD3 obscured which isoform may represent the cytosolic and/or plastidic enzyme plus whether PGD2 with a peroxisomal targeting motif also might target plastids. Reporter-fusion analyses in protoplasts revealed that, with a free N terminus, PGD1 and PGD3 accumulate in the cytosol and chloroplasts, whereas PGD2 remains in the cytosol. Mutagenesis of a conserved second ATG enhanced the plastidic localization of PGD1 and PGD3 but not PGD2. Amino-terminal deletions of PGD2 fusions with a free C terminus resulted in peroxisomal import after dimerization, and PGD2 could be immunodetected in purified peroxisomes. Repeated selfing of pgd2 transfer (T-)DNA alleles yielded no homozygous mutants, although siliques and seeds of heterozygous plants developed normally. Detailed analyses of the C-terminally truncated PGD2-1 protein showed that peroxisomal import and catalytic activity are abolished. Reciprocal backcrosses of pgd2-1 suggested that missing PGD activity in peroxisomes primarily affects the male gametophyte. Tetrad analyses in the quartet1-2 background revealed that pgd2-1 pollen is vital and in vitro germination normal, but pollen tube growth inside stylar tissues appeared less directed. Mutual gametophytic sterility was overcome by complementation with a genomic construct but not with a version lacking the first ATG. These analyses showed that peroxisomal PGD2 activity is required for guided growth of the male gametophytes and pollen tube-ovule interaction. Our report finally demonstrates an essential role of oxidative pentose-phosphate pathway reactions in peroxisomes, likely needed to sustain critical levels of nitric oxide and/or jasmonic acid, whose biosynthesis both depend on NADPH provision. PMID:26941195

  9. Molecular karyotyping: array CGH quality criteria for constitutional genetic diagnosis.

    PubMed

    Vermeesch, Joris R; Melotte, Cindy; Froyen, Guy; Van Vooren, Steven; Dutta, Binita; Maas, Nicole; Vermeulen, Stefan; Menten, Björn; Speleman, Frank; De Moor, Bart; Van Hummelen, Paul; Marynen, Peter; Fryns, Jean-Pierre; Devriendt, Koen

    2005-03-01

    Array CGH (comparative genomic hybridization) enables the identification of chromosomal copy number changes. The availability of clone sets covering the human genome opens the possibility for the widespread use of array CGH for both research and diagnostic purposes. In this manuscript we report on the parameters that were critical for successful implementation of the technology, assess quality criteria, and discuss the potential benefits and pitfalls of the technology for improved pre- and postnatal constitutional genetic diagnosis. We propose to name the genome-wide array CGH "molecular karyotyping," in analogy with conventional karyotyping that uses staining methods to visualize chromosomes.

  10. Genetic diagnosis of factor V Leiden using heteroduplex technology.

    PubMed

    Bowen, D J; Standen, G R; Granville, S; Bowley, S; Wood, N A; Bidwell, J

    1997-01-01

    A new genetic test has been developed for detection of the mutation known as factor V Leiden. The test employs heteroduplex technology and comprises a single PCR reaction followed immediately by PCR product analysis. It therefore represents the minimum practical route from blood/tissue sample to genetic result. A cohort of 100 patients with a history of thrombosis have been screened using both the new heteroduplex test and a previously described PCR-restriction endonuclease test. Results gave 100% correlation: normals 75 (75%), heterozygotes 24 (24%) and homozygotes 1 (1%). The heteroduplex test has been shown to give straightforward diagnosis in three different analytical systems: standard polyacrylamide gel electrophoresis (PAGE), mini-gel PAGE and capillary electrophoresis. The latter system is semiautomated, therefore rapid through-put of large sample numbers is now possible. PMID:9031460

  11. Genetics, diagnosis and management of colorectal cancer (Review)

    PubMed Central

    DE ROSA, MARINA; PACE, UGO; REGA, DANIELA; COSTABILE, VALERIA; DURATURO, FRANCESCA; IZZO, PAOLA; DELRIO, PAOLO

    2015-01-01

    Colorectal cancer (CRC) is the third most common type of cancer worldwide and a leading cause of cancer death. Surgery represents the mainstay of treatment in early cases but often patients are primarily diagnosed in an advanced stage of disease and sometimes also distant metastases are present. Neoadjuvant therapy is therefore needed but drug resistance may influence response and concur to recurrent disease. At molecular level, it is a very heterogeneous group of diseases with about 30% of hereditary or familial cases. During colorectal adenocarcinomas development, epithelial cells from gastrointestinal trait acquire sequential genetic and epigenetic mutations in specific oncogenes and/or tumour suppressor genes, causing CRC onset, progression and metastasis. Molecular characterization of cancer associated mutations gives valuable information about disease prognosis and response to the therapy. Very early diagnosis and personalized care, as well as a better knowledge of molecular basis of its onset and progression, are therefore crucial to obtain a cure of CRC. In this review, we describe updated genetics, current diagnosis and management of CRC pointing out the extreme need for a multidisciplinary approach to achieve the best results in patient outcomes. PMID:26151224

  12. Imposing genetic diversity.

    PubMed

    Sparrow, Robert

    2015-01-01

    The idea that a world in which everyone was born "perfect" would be a world in which something valuable was missing often comes up in debates about the ethics of technologies of prenatal testing and preimplantation genetic diagnosis (PGD). This thought plays an important role in the "disability critique" of prenatal testing. However, the idea that human genetic variation is an important good with significant benefits for society at large is also embraced by a wide range of figures writing in the bioethics literature, including some who are notoriously hostile to the idea that we should not select against disability. By developing a number of thought experiments wherein we are to contemplate increasing genetic diversity from a lower baseline in order to secure this value, I argue that this powerful intuition is more problematic than is generally recognized, especially where the price of diversity is the well-being of particular individuals. PMID:26030484

  13. Simple Genetic Transformation Assay for Rapid Diagnosis of Moraxella osloensis

    PubMed Central

    Juni, Elliot

    1974-01-01

    A genetic transformation assay for unequivocal identification of strains of Moraxella osloensis is described. In this assay a stable tryptophan auxotroph is transformed to prototrophy by deoxyribonucleic acid (DNA) samples from other strains of M. osloensis but not by DNA samples from unrelated bacteria. The test is simple to perform and definitive results can be obtained in less than 24 h. The procedure, which is suitable for routine diagnosis in a clinical laboratory, involves a rapid method for preparation of crude transforming DNA from small quantities of bacterial cells and permits simultaneous examination of large numbers of isolated cultures. The assay was shown to correctly identify 27 strains previously classified as M. osloensis. Forty-five other gram-negative, oxidase-positive, nonmotile coccobacilli, which might be confused with M. osloensis unless subject to more extensive testing, were shown to be unrelated genetically to M. osloensis. The transformation assay clearly distinguishes M. osloensis from Acinetobacter. Although most strains of M. osloensis are nonfastidious, being able to grow in a mineral medium supplemented with a single organic carbon source, one of the strains tested was only able to grow on fairly complex media and could not be transformed to grow on simple media. Inability to alkalize Simmons citrate agar was shown not to be characteristic of all strains of M. osloensis. Images PMID:4589126

  14. Legislation on Genetic Diagnosis: Comparison of South Korea and Germany

    PubMed Central

    Kim, Na-Kyoung

    2015-01-01

    This article explores the questions regarding PND and PID, especially the concrete legal conditions for the justification of PND and PID. As such, the German law stipulating PND and PID in a very concrete and detailed manner is introduced and explained in comparison with the corresponding South Korean law. The South Korean Bioethics and Biosafety Act (BBA) stipulates various types of gene testing and does not demonstrate a delicate sense of each type of gene testing. In contrast to the South Korean regulation, in Germany, there exist specific regulations for genetic counseling. Especially in the case of PND, GEKO stipulates the process of genetic counseling very concretely, based on GenDG. In the case of PND and PID, it is important that the people concerned understand the meaning of testing in various angles, and restructuralize it by combining it with their own values as the diagnosis is directly combined with pregnancy/abortion, which influences the whole life of a woman (and her partner). In this context, the South Korean BBA needs to be amended as soon as possible. The sections on informed consent also need to be amended to make them more concrete. Furthermore, guidelines for concretizing the regulation of BBA need to be continuously formulated and developed. PMID:27004267

  15. Genetic Analysis of Human Preimplantation Embryos.

    PubMed

    Garcia-Herrero, S; Cervero, A; Mateu, E; Mir, P; Póo, M E; Rodrigo, L; Vera, M; Rubio, C

    2016-01-01

    Preimplantation development comprises the initial stages of mammalian development, before the embryo implants into the mother's uterus. In normal conditions, after fertilization the embryo grows until reaching blastocyst stage. The blastocyst grows as the cells divide and the cavity expands, until it arrives at the uterus, where it "hatches" from the zona pellucida to implant into the uterine wall. Nevertheless, embryo quality and viability can be affected by chromosomal abnormalities, most of which occur during gametogenesis and early embryo development; human embryos produced in vitro are especially vulnerable. Therefore, the selection of chromosomally normal embryos for transfer in assisted reproduction can improve outcomes in poor-prognosis patients. Additionally, in couples with an inherited disorder, early diagnosis could prevent pregnancy with an affected child and would, thereby, avoid the therapeutic interruption of pregnancy. These concerns have prompted advancements in the use of preimplantation genetic diagnosis (PGD). Genetic testing is applied in two different scenarios: in couples with an inherited genetic disorder or carriers of a structural chromosomal abnormality, it is termed PGD; in infertile couples with increased risk of generating embryos with de novo chromosome abnormalities, it is termed preimplantation genetic screening, or PGS. PMID:27475859

  16. Genetics, diagnosis, and future treatment strategies for primary ciliary dyskinesia

    PubMed Central

    Daniels, M. Leigh Anne; Noone, Peadar G.

    2015-01-01

    Introduction Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder resulting in chronic oto-sino-pulmonary disease. While PCD is estimated to occur in 1 in 20,000 individuals, fewer than 1,000 patients in the US have a well-established diagnosis. Areas Covered We provide an overview of the clinical manifestations of PCD, describe the evolution of diagnostic methods, and critique the literature on management of PCD. Expert Opinion Although interest in clinical studies in non-CF bronchiectasis has increased in recent years, some of whom enroll patients with PCD, the literature regarding therapy for PCD as a distinct entity is lacking, as the numbers are small, and there have been no sub-analyses published. However, with improved screening and diagnostic methods, the development of clinical and research consortiums, and actively enrolling registries of PCD patients, the environment is conducive to perform longitudinal studies of disease course and therapeutic studies to alter that course. PMID:26998415

  17. Overcoming difficulty in diagnosis and differential diagnosis of Crohn's disease: the potential role of serological and genetic tests.

    PubMed

    Liu, Zhaoxiu; Shen, Bo

    2015-01-01

    Crohn's disease (CD) represents a heterogeneous group of chronic inflammatory disorders with various phenotypes. Establishing a definite diagnosis of CD should be based upon a combined assessment of clinical, endoscopic, radiological and pathological features. Although segmental disease distribution, transmural inflammation and non-caseating epithelioid granulomas have been considered as a 'hallmarks' for CD, clear diagnosis of CD in some patients has been challenging, due to overlapping endoscopic, radiographic and histologic features with other inflammatory bowel disease-like conditions. Laboratory markers (serological and genetic tests) may provide additional clues for the diagnosis and differential diagnosis of CD. This review focuses on the application of the currently available serological and genomic markers and in diagnosis and differential diagnosis of CD.

  18. Diagnosis of Wilson disease in young children: molecular genetic testing and a paradigm shift from the laboratory diagnosis.

    PubMed

    Seo, Jeong Kee

    2012-12-01

    Wilson disease (WD) is an autosomal recessive disorder of copper metabolism that results in accumulation of copper primarily in the liver, brain and cornea. Mutations in the WD gene, ATP7B, cause failure of copper excretion from hepatocyte into bile and a defective synthesis of ceruloplasmin. More than 500 mutations are now recognized, scattered throughout the ATP7B gene. Since WD has protean clinical presentations, awareness of WD in clinical practice is important for the early diagnosis and prevention of accumulated copper toxicity. Molecular genetic testing is playing an increasingly important role in the diagnosis of WD in uncertain cases and family screening. Siblings should be screened for WD once an index case has been diagnosed. Discrimination of heterozygotes from asymptomatic patients is essential to avoid inappropriate lifelong therapy for heterozygotes. Genetic testing, either by haplotype analysis or by mutation analysis, is the only definite solution for differentiating heterozygote carriers from affected asymptomatic patients. Routine genetic testing, because of the multitude of documented mutations, has been thought to be impractical until recently. However, genetic testing is now being more actively applied to the diagnosis of WD, particularly in young children in whom conventional biochemical diagnosis has much limitation and only genetic testing is able to confirm WD. Because advancement of modern biochemical technology now allows more rapid, easier, and less expensive mutation detection, direct DNA sequencing could be actively considered as the primary mode of diagnostic investigation rather than a supplementary test to the conventional biochemical tests. This review will focus on the recent advancement of molecular genetics and genetic diagnosis of WD in very young children on the basis of research data of the Seoul National University Children's Hospital and recent literature.

  19. ‘My funky genetics’: BRCA1/2 mutation carriers’ understanding of genetic inheritance and reproductive merger in the context of new repro-genetic technologies

    PubMed Central

    Rubin, Lisa R.; Doyle, Maya; Stern, Rikki; Savin, Katie; Hurley, Karen; Sagi, Michal

    2014-01-01

    INTRODUCTION Deleterious mutations in the BRCA1/BRCA2 genes elevate lifetime risk of breast and ovarian cancer. Each child of a mutation-positive parent has a 50% chance of inheriting it. Pre-implantation genetic diagnosis (PGD) permits prospective parents to avoid transmitting a BRCA1/2 mutation to a child, introducing predictability into a process historically defined by chance. This investigation explored how BRCA1/2 mutation carriers understand genetic inheritance and consider a child’s inheritance of a BRCA1/2 mutation, given the opportunities that exist to pursue PGD. METHOD 39 female and male BRCA1/2 mutation carriers of reproductive age were recruited from urban cancer and reproductive medical centers. Participants completed a standardized educational presentation on PGD and prenatal diagnosis, with pre- and post-test assessments. An interdisciplinary team of qualitative researchers analyzed data using grounded theory techniques. FINDINGS Participants expressed the belief that reproduction yields children with unique genetic strengths and challenges, including the BRCA1/2 mutation, family traits for which predictive tests do not exist, and hypothetical genetic risks. Participants expressed preference for biologically-related children, yet stated their genetically ‘well’ partner’s lineage would be marred through reproductive merger, requiring the well partner to assume the burden of the BRCA1/2 mutation via their children. Participants expressed diverse views of genetically ‘well’ partners’ participation in family planning and risk management decisions. DISCUSSION Pressure to use reprogenetic technology may grow as genetic susceptibility testing becomes more widely available. Work with individuals and couples across the disease spectrum must be attuned to they ways beliefs about genetic inheritance play into reproductive decision making. PMID:22709328

  20. PGD to reduce reproductive risk: the case of mitochondrial DNA disorders.

    PubMed

    Bredenoord, A L; Dondorp, W; Pennings, G; De Die-Smulders, C E M; De Wert, G

    2008-11-01

    This paper discusses the pros and cons of introducing PGD for mitochondrial DNA (mtDNA) disorders such as NARP (Neurogenic muscle weakness, Ataxia, Retinis Pigmentosa)/Leigh, MELAS (Mitochondrial myopathy, Encephalopathy, Lactic acidosis, and Stroke-like episodes), private mtDNA mutations and LHON (Leber Hereditary Optic Neuropathy). Although there is little experience with PGD for mtDNA disorders, it is reasonable to assume that in many cases, the best one can achieve is the selection of the 'least' affected embryos for transfer. So instead of 'promising' parents a healthy child, PGD in these cases can only aim at reducing reproductive risk. From an ethical point of view, this raises challenging questions about parental and medical responsibilities. The main argument in favour of PGD is that it offers couples at risk the opportunity of reducing their chances of having a severely affected child. Potential objections are manifold, but we conclude that none of them supplies convincing moral arguments to regard risk-reducing PGD as unacceptable. Nevertheless, introducing this new application of PGD in clinical practice will raise further complex issues of determining conditions for its responsible use.

  1. [First in the world application of next generation sequencing in preimplantation genetic diagnostics in clinical practice - a case report].

    PubMed

    Łukaszuk, Krzysztof; Kuczyńska, Agnieszka; Pukszta, Sebastian; Kuć, Paweł; Kuczyński, Waldemar; Łukaszuk, Jakub; Liss, Joanna; Wocławek-Potocka, Izabela

    2016-01-01

    Preimplantation genetic diagnosis (PGD) is a well established method for detecting genetic abnormalities during the course of infertility treatment, resulting in thousands of healthy newborns delivered worldwide. PGD with next generation sequencing (NGS) provides new possibilities for diagnosis and new parameters for evaluation. The use of next-generation DNA sequencing technique has lead to great progress in the human genome analysis. The aim of this study was molecular analysis using next generation sequencing technique of embryos from a couple suffering from recurrent pregnancy losses. As a result of in vitro fertilization procedure, seven embryos were created. Seven blastomeres, one from each embryo, were analyzed. Transfer of two blastocysts in a fresh cycle resulted in the singleton pregnancy. Healthy baby girl was delivered via caesarean section after 28 weeks of gestation (weight: 1250g, Apgar score: 8/9). The reason for the premature labor was likely caused by mother's pneumonia. This is the first case of clinical use of the NGS in PGD in fresh cycle after blastomere biopsy. PMID:27164286

  2. Preimplantation genetic testing in the 21st century: uncharted territory.

    PubMed

    Brezina, Paul R

    2013-02-10

    The past hundred years have given birth to arguably the most profound changes in society, medicine, and technology the world has ever witnessed. Genetics is one such field that has enjoyed a meteoric rise during this time. Progressing from Mendelian genetics to the discovery of DNA to the ability to sequence the human genome, perhaps no other discipline holds more promise to affect future change than genetics. Technology currently exists to evaluate some of the genetic information held by developing embryos in the context of an in vitro fertilization (IVF) cycle. This information is then used to determine which embryos are selected for uterine transfer. Many societies have enacted legislation to protect against possible abuses utilizing this technology. However, it is incumbent upon society to continue ensuring that preimplantation genetic diagnosis (PGD)-and genetic testing in general-is applied in a way that utilizes its potential in a responsible manner to improve health care. PMID:24453515

  3. The role of ultrasound in the diagnosis of fetal genetic syndromes

    PubMed Central

    Conner, Shayna N.; Longman, Ryan E.; Cahill, Alison G.

    2014-01-01

    The use of ultrasound in the prenatal diagnosis of fetal genetic syndromes is rapidly evolving. Advancing technology and new research findings are aiding in the increased accuracy of ultrasound-based diagnosis in combination with other methods of non-invasive and invasive fetal testing. Ultrasound as a screening tool for aneuploidy and other anomalies is increasingly being used throughout pregnancy, beginning in the first trimester. Given the number of recorded syndromes, it is important to identify patterns and establish a strategy for identifying abnormalities on ultrasound. These syndromes encompass a wide range of causes from viral, substance-linked, chromosomal, and other genetic syndromes. Despite the ability of those experienced in ultrasound, it is important to note that not all fetal genetic syndromes can be identified prenatally, and even common syndromes often have no associated ultrasound findings. Here, we review the role of ultrasound in the diagnosis of fetal genetic syndromes. PMID:24534428

  4. Molecular diagnosis of some common genetic diseases in Russia and the former USSR: present and future.

    PubMed Central

    Baranov, V S

    1993-01-01

    The current state of molecular diagnosis of some common genetic diseases, including cystic fibrosis, Duchenne muscular dystrophy, haemophilia A and B, phenylketonuria, and thalassaemia, in Russia and elsewhere in the former USSR is reviewed. Data on carrier detection and prenatal diagnosis are presented and some objective problems and obstacles hampering efficient molecular diagnosis in Russia are discussed. The necessity for molecular diagnosis of some other inherited diseases (for example, von Willebrand's disease, Martin-Bell syndrome, polycystic kidney disease, Huntington's disease, and myotonic dystrophy) is stressed. The need for establishing new diagnostic centres dealing with the most common diseases, as well as rare genetic diseases, is substantiated. Perspectives on the implementation of new molecular methods and new technical approaches (preimplantation embryo diagnosis, fetal cells selected from maternal blood) are briefly outlined. PMID:8445619

  5. A methodological overview on molecular preimplantation genetic diagnosis and screening: a genomic future?

    PubMed

    Vendrell, Xavier; Bautista-Llácer, Rosa

    2012-12-01

    The genetic diagnosis and screening of preimplantation embryos generated by assisted reproduction technology has been consolidated in the prenatal care framework. The rapid evolution of DNA technologies is tending to molecular approaches. Our intention is to present a detailed methodological view, showing different diagnostic strategies based on molecular techniques that are currently applied in preimplantation genetic diagnosis. The amount of DNA from one single, or a few cells, obtained by embryo biopsy is a limiting factor for the molecular analysis. In this sense, genetic laboratories have developed molecular protocols considering this restrictive condition. Nevertheless, the development of whole-genome amplification methods has allowed preimplantation genetic diagnosis for two or more indications simultaneously, like the selection of histocompatible embryos plus detection of monogenic diseases or aneuploidies. Moreover, molecular techniques have permitted preimplantation genetic screening to progress, by implementing microarray-based comparative genome hybridization. Finally, a future view of the embryo-genetics field based on molecular advances is proposed. The normalization, cost-effectiveness analysis, and new technological tools are the next topics for preimplantation genetic diagnosis and screening. Concomitantly, these additions to assisted reproduction technologies could have a positive effect on the schedules of preimplantation studies.

  6. Clinical Application of Antenatal Genetic Diagnosis of Osteogenesis Imperfecta Type IV

    PubMed Central

    Yuan, Jing; Li, Song; Xu, YeYe; Cong, Lin

    2015-01-01

    Background Clinical analysis and genetic testing of a family with osteogenesis imperfecta type IV were conducted, aiming to discuss antenatal genetic diagnosis of osteogenesis imperfecta type IV. Material/Methods Preliminary genotyping was performed based on clinical characteristics of the family members and then high-throughput sequencing was applied to rapidly and accurately detect the changes in candidate genes. Results Genetic testing of the III5 fetus and other family members revealed missense mutation in c.2746G>A, pGly916Arg in COL1A2 gene coding region and missense and synonymous mutation in COL1A1 gene coding region. Conclusions Application of antenatal genetic diagnosis provides fast and accurate genetic counseling and eugenics suggestions for patients with osteogenesis imperfecta type IV and their families. PMID:25835785

  7. Ethical and legal aspects of noninvasive prenatal genetic diagnosis.

    PubMed

    Dickens, Bernard M

    2014-02-01

    The new technology that will allow genetic testing of a fetus within the first trimester of pregnancy by isolating cell-free fetal DNA (cffDNA) in the mother's blood raises a range of ethical and legal issues. Considered noninvasive, this test is safe and reliable, and may avoid alternative genetic testing by amniocentesis or chorionic villus sampling, which risks causing spontaneous abortion. Ethical and legal issues of cffDNA testing will become more acute if testing expands to fetal whole-genome sequencing. Critical issues include the state of the science or diagnostic art; the appropriateness of offering the test; the implications of denying the test when it is available and appropriate; disclosure and counseling following test results; and management of patients' choices on acquiring test results. A challenge will be providing patients with appropriate counseling based on up-to-date genetic knowledge, and accommodating informed patients' legal choices.

  8. An efficient reduced-order method with PGD for solving journal bearing hydrodynamic lubrication problems

    NASA Astrophysics Data System (ADS)

    Cherabi, Bilal; Hamrani, Abderrachid; Belaidi, Idir; Khelladi, Sofiane; Bakir, Farid

    2016-10-01

    In the present work, a reduced-order method, "Proper Generalized Decomposition (PGD)" is extended and applied to the resolution of the Reynolds equation describing the behavior of the lubricant in hydrodynamic journal bearing. The PGD model is employed to solve the characteristic 'Reynolds' partial differential equation using the separation technique through the alternating direction strategy. The resulting separated-dimension system has a low computation cost compared to classical finite-difference resolution. Several numerical benchmark examples are investigated to verify the validity and accuracy of the proposed method. It has been found that numerical results obtained by the PGD method can achieve an improved convergence rate with a very low computation cost.

  9. Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy

    PubMed Central

    Kang, Hee Gyung; Lee, Hyun Kyung; Ahn, Yo Han; Joung, Je-Gun; Nam, Jaeyong; Kim, Nayoung K D; Ko, Jung Min; Cho, Min Hyun; Shin, Jae Il; Kim, Joon; Park, Hye Won; Park, Young Seo; Ha, Il-Soo; Chung, Woo Yeong; Lee, Dae-Yeol; Kim, Su Young; Park, Woong Yang; Cheong, Hae Il

    2016-01-01

    Nephronophthisis-related ciliopathy (NPHP-RC) is a common genetic cause of end-stage renal failure during childhood and adolescence and exhibits an autosomal recessive pattern of inheritance. Genetic diagnosis is quite limited owing to genetic heterogeneity in NPHP-RC. We designed a novel approach involving the step-wise screening of Sanger sequencing and targeted exome sequencing for the genetic diagnosis of 55 patients with NPHP-RC. First, five NPHP-RC genes were analyzed by Sanger sequencing in phenotypically classified patients. Known pathogenic mutations were identified in 12 patients (21.8%); homozygous deletions of NPHP1 in 4 juvenile nephronophthisis patients, IQCB1/NPHP5 mutations in 3 Senior–Løken syndrome patients, a CEP290/NPHP6 mutation in 1 Joubert syndrome patient, and TMEM67/MKS3 mutations in 4 Joubert syndrome patients with liver involvement. In the remaining undiagnosed patients, we applied targeted exome sequencing of 34 ciliopathy-related genes to detect known pathogenic mutations in 7 (16.3%) of 43 patients. Another 18 likely damaging heterozygous variants were identified in 13 NPHP-RC genes in 18 patients. In this study, we report a variety of pathogenic and candidate mutations identified in 55 patients with NPHP-RC in Korea using a step-wise application of two genetic tests. These results support the clinical utility of targeted exome sequencing to resolve the issue of allelic and genetic heterogeneity in NPHP-RC. PMID:27491411

  10. A tale worth telling: The impact of the diagnosis experience on disclosure of genetic disorders

    PubMed Central

    Goodwin, Jane; Schoch, Kelly; Shashi, Vandana; Hooper, Stephen R.; Gothelf, Doron; Zalevsky, Moran; Morad, Ola; Campbell, Linda E.

    2014-01-01

    Background Research suggests children with genetic disorders exhibit greater coping skills when they are aware of their condition and its heritability. While the experiences parents have at diagnosis may influence their decision to disclose the diagnosis to their children, there is little research into this communication. The aim of the current study was to examine the relationship between the diagnosis experience and the disclosure experience for parents of children with intellectual disabilities; with a child affected by 22q11.2 deletion syndrome (22q11DS) compared to a group of parents with children affected with other genetic diagnoses, with a similar age of diagnosis (e.g., Fragile X syndrome) and a group where diagnosis generally occurs early (i.e., Down syndrome). Method The sample comprised 559 parents and caregivers of children with genetic developmental disorders, and an online survey was utilised. Items from the questionnaire were combined to create variables for diagnosis experience, parental disclosure experience, child’s disclosure experience, and parental coping and self-efficacy. Results Across all groups parents reported that the diagnosis experience was negative and often accompanied by lack of support and appropriate information. Sixty-eight percent of those in the 22q11DS and 58.3% in the Similar Conditions groups had disclosed the diagnosis to their child, whereas only 32.7% of the Down syndrome group had. Eighty-six percent of the Down syndrome group felt they had sufficient information to talk to their child compared to 44.1% of the Similar Conditions group and 32.6% of the 22q11DS group. Parents reported disclosing the diagnosis to their child because they did not want to create secrets; and that they considered the child’s age when disclosing. In the 22q11DS and Similar Conditions groups, a poor diagnosis experience was significantly associated with negative parental disclosure experiences. In the Similar Conditions group, a poor

  11. The Role of Molecular Genetic Analysis in the Diagnosis of Primary Ciliary Dyskinesia

    PubMed Central

    Kim, Raymond H.; A. Hall, David; Cutz, Ernest; Knowles, Michael R.; Nelligan, Kathleen A.; Nykamp, Keith; Zariwala, Maimoona A.

    2014-01-01

    Rationale: Primary ciliary dyskinesia (PCD) is an autosomal recessive genetic disorder of motile cilia. The diagnosis of PCD has previously relied on ciliary analysis with transmission electron microscopy or video microscopy. However, patients with PCD may have normal ultrastructural appearance, and ciliary analysis has limited accessibility. Alternatively, PCD can be diagnosed by demonstrating biallelic mutations in known PCD genes. Genetic testing is emerging as a diagnostic tool to complement ciliary analysis where interpretation and access may delay diagnosis. Objectives: To determine the diagnostic yield of genetic testing of patients with a confirmed or suspected diagnosis of PCD in a multiethnic urban center. Methods: Twenty-eight individuals with confirmed PCD on transmission electron microscopy of ciliary ultrastructure and 24 individuals with a probable diagnosis of PCD based on a classical PCD phenotype and low nasal nitric oxide had molecular analysis of 12 genes associated with PCD. Results: Of 49 subjects who underwent ciliary biopsy, 28 (57%) were diagnosed with PCD through an ultrastructural defect. Of the 52 individuals who underwent molecular genetic analysis, 22 (42%) individuals had two mutations in known PCD genes. Twenty-four previously unreported mutations in known PCD genes were observed. Combining both diagnostic modalities of biopsy and molecular genetics, the diagnostic yield increased to 69% compared with 57% based on biopsy alone. Conclusions: The diagnosis of PCD is challenging and has traditionally relied on ciliary biopsy, which is unreliable as the sole criterion for a definitive diagnosis. Molecular genetic analysis can be used as a complementary test to increase the diagnostic yield. PMID:24498942

  12. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency

    PubMed Central

    Maffucci, Patrick; Filion, Charles A.; Boisson, Bertrand; Itan, Yuval; Shang, Lei; Casanova, Jean-Laurent; Cunningham-Rundles, Charlotte

    2016-01-01

    Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes. PMID:27379089

  13. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency.

    PubMed

    Maffucci, Patrick; Filion, Charles A; Boisson, Bertrand; Itan, Yuval; Shang, Lei; Casanova, Jean-Laurent; Cunningham-Rundles, Charlotte

    2016-01-01

    Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes. PMID:27379089

  14. Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology.

    PubMed

    Harper, Joyce C; Geraedts, Joep; Borry, Pascal; Cornel, Martina C; Dondorp, Wybo; Gianaroli, Luca; Harton, Gary; Milachich, Tanya; Kääriäinen, Helena; Liebaers, Inge; Morris, Michael; Sequeiros, Jorge; Sermon, Karen; Shenfield, Françoise; Skirton, Heather; Soini, Sirpa; Spits, Claudia; Veiga, Anna; Vermeesch, Joris Robert; Viville, Stéphane; de Wert, Guido; Macek, Milan

    2013-11-01

    In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide

  15. Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology.

    PubMed

    Harper, Joyce C; Geraedts, Joep; Borry, Pascal; Cornel, Martina C; Dondorp, Wybo; Gianaroli, Luca; Harton, Gary; Milachich, Tanya; Kääriäinen, Helena; Liebaers, Inge; Morris, Michael; Sequeiros, Jorge; Sermon, Karen; Shenfield, Françoise; Skirton, Heather; Soini, Sirpa; Spits, Claudia; Veiga, Anna; Vermeesch, Joris Robert; Viville, Stéphane; de Wert, Guido; Macek, Milan

    2013-11-01

    In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide

  16. BLOCKADE OF PGE2, PGD2 RECEPTORS CONFERS PROTECTION AGAINST PREPATENT SCHISTOSOMIASIS MANSONI IN MICE.

    PubMed

    Abdel-Ghany, Rasha; Rabia, Ibrahim; El-Ahwany, Eman; Saber, Sameh; Gamal, Rasha; Nagy, Faten; Mahmoud, Olaa; Hamad, Rabab Salem; Barakat, Walled

    2015-12-01

    Schistosomiasis is a chronic disease with considerable social impact. Despite the availability of affordable chemotherapy, drug treatment has not significantly reduced the overall number of disease cases. Among other mechanisms, the parasite produces PGE2 and PGD2 to evade host immune defenses. To investigate the role of PGE2 and PGD2 in schistosomiasis, we evaluated the effects of L-161,982, Ah6809 (PGE2 receptor antagonists alone of combined with each other) and MK-0524 (PGD2 receptor antagonist) during prepatent Schistosoma mansoni infection. Drugs were administered intraperitoneally an hour before and 24 hours after infection of C57BL/6 mice with 100 Schistosoma mansoni cercariae. L-161,982, Ah6809, their combination and MK-0524 caused partial protection against pre-patent S. mansoni infection which was mediated by biasing the immune response towards Th1 phenotype. These results showed that blockade of PGE2 and PGD2 receptors confers partial protection against pre-patent S. mansoni infection in mice and that they may be useful as adjunctive therapy to current anti-schistosomal drugs or vaccines. PMID:26939228

  17. Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy

    PubMed Central

    Harper, Joyce C; Geraedts, Joep; Borry, Pascal; Cornel, Martina C; Dondorp, Wybo; Gianaroli, Luca; Harton, Gary; Milachich, Tanya; Kääriäinen, Helena; Liebaers, Inge; Morris, Michael; Sequeiros, Jorge; Sermon, Karen; Shenfield, Françoise; Skirton, Heather; Soini, Sirpa; Spits, Claudia; Veiga, Anna; Vermeesch, Joris Robert; Viville, Stéphane; de Wert, Guido; Macek, Milan

    2013-01-01

    In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation – ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and

  18. Ethical challenges in assisted reproduction: the place of preimplantation genetic diagnosis in a just society.

    PubMed

    Whetstine, Leslie M

    2015-04-01

    The purpose of this article is to provide an overview of preimplantation genetic diagnosis and identify the relevant moral questions it raises. In the course of this discussion, the scope of parental rights and the inherent difficulty in defining disease/disability will be considered.

  19. [Genetic Aberration and Pathological Diagnosis in Bone and Soft-Tissue Tumors].

    PubMed

    Iura, Kunio; Oda, Yoshinao

    2016-03-01

    Bone and soft-tissue sarcomas comprise a rare, complex, and heterogeneous group of tumors for which it is difficult for even experienced pathologists to provide a conclusive diagnosis. The number of diagnoses made using genetic analysis has increased since the detection of fusion genes in several soft-tissue tumors in the 1990s. Moreover, other specific genetic aberrations have been reported in various bone and soft-tissue tumors. In addition, molecular therapeutic targets have been sought in advanced cases of soft-tissue and bone tumors similar to other organ malignancies. To enable the pathological diagnosis of bone and soft-tissue tumors, it is necessary to combine histological diagnosis with immunohistochemistry and gene analysis findings including fusion gene or other genetic aberrations. In this review, we describe the fusion genes recently reported in bone and soft-tissue tumors such as solitary fibrous tumor, aneurysmal bone cyst, nodular fasciitis, CIC-DUX4 fusion gene-positive small round cell tumors, or BCOR-CCNB3-positive sarcoma as well as other genetic aberrations in dedifferentiated liposarcoma, malignant rhabdoid tumor, cartilaginous tumor, Langerhans cell histiocytosis chondroblastoma, or giant cell tumor of the bone. We also demonstrate their association with pathological diagnosis. PMID:27067846

  20. Automated Test Assembly for Cognitive Diagnosis Models Using a Genetic Algorithm

    ERIC Educational Resources Information Center

    Finkelman, Matthew; Kim, Wonsuk; Roussos, Louis A.

    2009-01-01

    Much recent psychometric literature has focused on cognitive diagnosis models (CDMs), a promising class of instruments used to measure the strengths and weaknesses of examinees. This article introduces a genetic algorithm to perform automated test assembly alongside CDMs. The algorithm is flexible in that it can be applied whether the goal is to…

  1. Ethical challenges in assisted reproduction: the place of preimplantation genetic diagnosis in a just society.

    PubMed

    Whetstine, Leslie M

    2015-04-01

    The purpose of this article is to provide an overview of preimplantation genetic diagnosis and identify the relevant moral questions it raises. In the course of this discussion, the scope of parental rights and the inherent difficulty in defining disease/disability will be considered. PMID:24334349

  2. Clinical features and genetic diagnosis of hereditary spinocerebellar ataxia 3.

    PubMed

    Wang, Yaoguang; Yang, Xiaokai; Ma, Weide; Li, Jinxin; Zhang, Qingyuan; Xia, Shuqi; Wang, Hai; Zhang, Chenghui; Xu, Xiaomin; Zheng, Jiayong

    2016-10-01

    Spinocerebellar ataxia type 3 (SCA3) is a rare inherited autosomal dominant progressive neurological disorder, which results from a CAG‑repeat expansion in the gene encoding the deubiquitinating enzyme, ataxin‑3. At present, no effective treatment is available for this fatal disorder; however, certain studies have suggested that reducing the levels of mutant ataxin‑3 protein may reverse or halt the progression of disease in patients with SCA3. In the present study, clinical examinations were performed on a patient with SCA3 who exhibited disease features including coughing, expectoration and was bedridden with mobility limitation. CAG repetitions at SCA‑associated genes were detected in the patient's family by performing standard polymerase chain reaction (PCR) and triple‑repeat primed PCR. The numbers of CAG‑repeats within the two alleles of the gene of interest in the patient were 15 and 78. Notably, the patient's brother, who harbored 76 CAG‑repeats in one allele of the gene of interest, did not exhibit severe disease symptoms. These results suggest that the number of CAG‑repeats is a critical for determination of SCA3 disease severity and time of onset. In addition, the defined phenotypic characteristics of the patient in the present study provide useful insight for more accurate clinical diagnosis and genotyping of future patients. PMID:27600091

  3. Blastocystis: Genetic diversity and molecular methods for diagnosis and epidemiology.

    PubMed

    Stensvold, Christen Rune

    2013-01-01

    Blastocystis, an unusual anaerobic, single-celled stramenopile, is a remarkably successful intestinal parasite of a vast array of host species including humans. Fecal Deoxyribonucleic acid (DNA) analysis by nucleic-acid based methods in particular has led to significant advances in Blastocystis diagnostics and research over the past few years enabling accurate identification of carriers and molecular characterization by high discriminatory power. Moreover, Blastocystis comprises a multitude of subtypes (STs) (arguably species) many of which have been identified only recently and molecular epidemiological studies have revealed a significant difference in the distribution of STs across host species and geographical regions. Having a cosmopolitan distribution, the parasite is a common laboratory finding in the stools of individuals with and without intestinal symptoms across the entire globe and while the parasite remains extremely difficult to eradicate and isolate in culture, appropriate molecular tools are now available to resolve important questions such as whether the clinical outcome of colonization is linked to ST and whether Blastocystis is transmitted zoonotically. This review summarizes some of the recent advances in the molecular diagnosis of Blastocystis and gives an introduction to Blastocystis STs, including a recommendation of subtyping methodology based on recent data and method comparisons. A few suggestions for future directions and research areas are given in the light of relevant technological advances and the availability of mitochondrial and nuclear genomes.

  4. Role of molecular genetics in transforming diagnosis of diabetes mellitus.

    PubMed

    Molven, Anders; Njølstad, Pål R

    2011-04-01

    Most common diseases also run in families as rare, monogenic forms. Diabetes is no exception. Mutations in approximately 20 different genes are now known to cause monogenic diabetes, a disease group that can be subclassified into maturity-onset diabetes of the young, neonatal diabetes and mitochondrial diabetes. In some families, additional features, such as urogenital malformations, exocrine pancreatic dysfunction and neurological abnormalities, are present and may aid the diagnostic classification. The finding of a mutation in monogenic diabetes may have implications for the prediction of prognosis and choice of treatment. Mutations in the GCK gene cause a mild form of diabetes, which seldom needs insulin and has a low risk for complications. By contrast, HNF1A mutations lead to a diabetes form that in severity, treatment and complication risk resembles Type 1 diabetes, although these patients may experience a good effect of sulfonylurea treatment. The majority of neonatal diabetes cases are caused by mutations in the K(ATP) channel genes ABCC8 and KCNJ11, and sulfonylurea therapy is then usually superior to insulin. Diseases with a considerable genetic component may now be explored by genome-wide approaches using next-generation DNA sequencing technology. We expect that within a few years important breakthroughs will be made in mapping cases of diabetes with a suspected, but still unsolved monogenic basis.

  5. [Diagnosis of MDS: morphology, chromosome abnormalities and genetic mutations].

    PubMed

    Hata, Tomoko

    2015-10-01

    Myelodysplastic syndromes (MDS) are a group of hematological neoplasms associated with ineffective hematopoiesis and that can transform into acute leukemia. The clinical classification of MDS which is defined by cytopenia, the rate of blasts in peripheral blood and bone marrow, dysplasia, and chromosomal abnormalities, has undergone continuous revision. To increase the accuracy of dysplastic evaluation, IWGM-MDS and the Research Committee for Idiopathic Hematopoietic Disorders, Ministry of Health, Labour and Welfare, Japan have proposed a quantitative and qualitative definition of dysplasia. Recently, refining the definition of dysgranulopoiesis was proposed by IWGM-MDS. Neutrophils with abnormal clumping of chromatin, and harboring more than 4 nuclear projections, were recognized as dysplastic features. At present, karyotypic abnormalities are detected in approximately 50% of de novo MDS and these remain the most critical prognostic factor. In the new cytogenetic scoring system, cytogenetic abnormalities were classified into five prognostic subgroups. This new classification was adopted by the revised IPSS. Approximately 80% to 90% of MDS patients have detectable mutations by whole-exon sequencing or whole genome sequencing. Many genetic mutations had biological and prognostic significance. It is important to further understand the utility of this factor in determining prognosis and in selecting among therapeutic options. PMID:26458436

  6. Genetic diagnosis of patients with esophageal cancer using FISH

    PubMed Central

    AWUT, IDIRIS; NIYAZ, MADINIYET; HUIZHONG, XIE; BIEKEMITOUFU, HADETI; YAN, ZHANG HONG; ZHU, ZHANG; SHEYHEDIN, ILYAR; CHANGMIN, ZHANG; WEI, ZHANGLI; HAO, WEN

    2010-01-01

    This study aimed to the clarify the diagnostic efficacy of fluorescence in situ hybridization (FISH) in Kazakh patients with esophageal cancer (EC). FISH was compared with the pathological examination of biopsy specimens with DNA probes. We enrolled 20 patients, of which 15 were males and 5 females, with an average age of 58.3 years, who had abnormal esophaguses on barium radiological digital imaging. Touch preparations were performed on biopsy specimens from all of the patients and were examined using FISH for chromosomal abnormalities. We compared the FISH results with the pathology slides stained with hematoxylin and eosin. Classification, according to pathology, identified 2 cases of class II, 3 cases of IIIa, 1 case of IIIb, 2 cases of IV, 12 cases of class V and no cases of class I. The cases classified as class IIIb or higher were considered to be positive for cancer. Using histopathology, 10 cases were diagnosed with squamous cell carcinoma and 5 were diagnosed as adenocarcinoma, with one case being false-negative. Thus, the sensitivity of the pathological examination was 93% and the specificity was 100%. Using FISH, 16 cases showed aberrant copy numbers in either chromosome 3 or 17. By comparison, pathology did not reveal any false-positive or false-negative cases with a sensitivity and specificity of 100%. The centromeres of chromosome 3 copy numbers was significantly higher (p=0.035) than the centromeres of chromosome 17. Our study compared FISH to diagnose aneusomic esophageal cancer cells with the pathology of biopsied tissue. Our findings suggest that FISH is a useful and objective assay for the detection of malignant cells of esophageal cancer. In our study, the centromeres of chromosome 3 was the more sensitive probe for the diagnosis of esophageal cancer in Kazakh patients. PMID:22966385

  7. New Advances of Preimplantation and Prenatal Genetic Screening and Noninvasive Testing as a Potential Predictor of Health Status of Babies

    PubMed Central

    2014-01-01

    The current morphologically based selection of human embryos for transfer cannot detect chromosome aneuploidies. So far, only biopsy techniques have been able to screen for chromosomal aneuploidies in the in vitro fertilization (IVF) embryos. Preimplantation genetic diagnosis (PGD) or screening (PGS) involves the biopsy of oocyte polar bodies or embryonic cells and has become a routine clinical procedure in many IVF clinics worldwide, including recent development of comprehensive chromosome screening of all 23 pairs of chromosomes by microarrays for aneuploidy screening. The routine preimplantation and prenatal genetic diagnosis (PND) require testing in an aggressive manner. These procedures may be invasive to the growing embryo and fetus and potentially could compromise the clinical outcome. Therefore the aim of this review is to summarize not only the new knowledge on preimplantation and prenatal genetic diagnosis in humans, but also on the development of potential noninvasive embryo and fetal testing that might play an important role in the future. PMID:24783200

  8. [Prenatal diagnosis. I: Prenatal diagnosis program at the Medical Genetics Unit of the Universidad de Zulia, Maracaibo, Venezuela].

    PubMed

    Prieto-Carrasquero, M; Molero, A; Carrasquero, N; Paz, V; González, S; Pineda-Del Villar, L; Del Villar, A; Rojas-Atencio, A; Quintero, M; Fulcado, W; Mena, R; Morales-Machin, A

    1998-06-01

    The Prenatal Diagnosis Program of the Medical Genetic Unit of University of Zulia has the following objectives: Identification of Genetic Risk Factors (GRF) in those couples who attend to the Prenatal Genetic Clinic, application of different prenatal diagnostic procedures (PDP), and providing adequate genetic counseling. The goal of this paper is to show preliminary results obtained between January 1993 and December 1996. Three hundred and twenty one pregnant women were analyzed by determining the GRF and taking into account the genetic clinical history. The GRF analyzed were: Advanced maternal age (AMA), congenital malformation history (CMH), previous child with chromosomic anomalies (PCCA), defects of neural tube history (DNTH), congenital heart disease history (CHDH), any parent carrier of chromosomic anomaly (PCA), habitual abortion (HA), abnormal fetal echography (AFE), altered maternal serum levels of alpha-feto-protein (AMSAFP) and OTHERS: exposure to teratogenic agents, history of Mendelian diseases, maternal systemic diseases and anxiety in the mother or in her partner. The PDP was designed according to the GRF, which included fetal echography (FE), fetal echocardiography (FEc), amniocentesis (AMN), chordocentesis (CCT) and AMSAFP. Results showed that 58.4% of the expectant mothers asked for counseling during the 2nd trimester, 70% of the total showed only one GRF, and AMA was the most frequent GRF found (40.3%), followed by PCCA, AFE, CHDH, HA, DNTH, PCA, and OTHERS in that order. The specific PDP applied to the identified GRF allowed a health evaluation of the fetus. The GRF identification gave the opportunity of establishing a Prenatal Diagnostic Program producing a response to the couple's needs and showed the utility of an integral and multidisciplinary management directed to any expecting mother in order to identify any high GRF.

  9. A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies

    PubMed Central

    Leventer, Richard J.; van der Knaap, Marjo S.; van Hove, Johan; Pizzino, Amy; McNeill, Nathan H.; Helman, Guy; Simons, Cas; Schmidt, Johanna L.; Rizzo, William B.

    2015-01-01

    Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive – many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroim-aging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders. PMID:25655951

  10. Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units

    PubMed Central

    Saunders, Carol Jean; Miller, Neil Andrew; Soden, Sarah Elizabeth; Dinwiddie, Darrell Lee; Noll, Aaron; Alnadi, Noor Abu; Andraws, Nevene; Patterson, Melanie LeAnn; Krivohlavek, Lisa Ann; Fellis, Joel; Humphray, Sean; Saffrey, Peter; Kingsbury, Zoya; Weir, Jacqueline Claire; Betley, Jason; Grocock, Russell James; Margulies, Elliott Harrison; Farrow, Emily Gwendolyn; Artman, Michael; Safina, Nicole Pauline; Petrikin, Joshua Erin; Hall, Kevin Peter; Kingsmore, Stephen Francis

    2014-01-01

    Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. Hence, an immense unmet need exists for improved molecular diagnosis in infants. Because disease progression is extremely rapid, albeit heterogeneous, in newborns, molecular diagnoses must occur quickly to be relevant for clinical decision-making. We describe 50-hour differential diagnosis of genetic disorders by whole-genome sequencing (WGS) that features automated bioinformatic analysis and is intended to be a prototype for use in neonatal intensive care units. Retrospective 50-hour WGS identified known molecular diagnoses in two children. Prospective WGS disclosed potential molecular diagnosis of a severe GJB2-related skin disease in one neonate; BRAT1-related lethal neonatal rigidity and multifocal seizure syndrome in another infant; identified BCL9L as a novel, recessive visceral heterotaxy gene (HTX6) in a pedigree; and ruled out known candidate genes in one infant. Sequencing of parents or affected siblings expedited the identification of disease genes in prospective cases. Thus, rapid WGS can potentially broaden and foreshorten differential diagnosis, resulting in fewer empirical treatments and faster progression to genetic and prognostic counseling. PMID:23035047

  11. Genetic testing and counseling in the case of an autism diagnosis: A caregivers perspective.

    PubMed

    Hens, Kristien; Peeters, Hilde; Dierickx, Kris

    2016-09-01

    The search for genes that can explain the development of autism is ongoing. At the same time, genetic counselling and genetic testing can be offered to families with a child diagnosed with autism. However, given the complexity of autism, both with respect to its aetiology as well as with respect to its heterogeneity, such genetic counselling and testing raises specific ethical questions regarding the aim and scope. In order to map these questions and opinions we interviewed 15 Belgian autism professionals. We found that they believed that genetic counselling and genetic testing have certain benefits for families confronted with an autism diagnosis, but also that direct benefit to the child is limited to those cases where a genetic finding offers a certain prognosis and intervention plan. In cases where autism is the result of a syndrome or a known genetic variant that is associated with other health problems, detection can also enable prevention of these health issues. Benefits of genetic testing, such as relief of guilt and reproductive choice, are primarily benefits to the parents, although indirectly they may affect the wellbeing of the person diagnosed. These benefits are associated with ethical questions.

  12. Genetic testing and counseling in the case of an autism diagnosis: A caregivers perspective.

    PubMed

    Hens, Kristien; Peeters, Hilde; Dierickx, Kris

    2016-09-01

    The search for genes that can explain the development of autism is ongoing. At the same time, genetic counselling and genetic testing can be offered to families with a child diagnosed with autism. However, given the complexity of autism, both with respect to its aetiology as well as with respect to its heterogeneity, such genetic counselling and testing raises specific ethical questions regarding the aim and scope. In order to map these questions and opinions we interviewed 15 Belgian autism professionals. We found that they believed that genetic counselling and genetic testing have certain benefits for families confronted with an autism diagnosis, but also that direct benefit to the child is limited to those cases where a genetic finding offers a certain prognosis and intervention plan. In cases where autism is the result of a syndrome or a known genetic variant that is associated with other health problems, detection can also enable prevention of these health issues. Benefits of genetic testing, such as relief of guilt and reproductive choice, are primarily benefits to the parents, although indirectly they may affect the wellbeing of the person diagnosed. These benefits are associated with ethical questions. PMID:27544064

  13. EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH)

    PubMed Central

    Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

    2016-01-01

    Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines. PMID:26153218

  14. Beyond the Genetic Diagnosis: Providing Parents What They Want to Know.

    PubMed

    Saul, Robert A; Meredith, Stephanie Hall

    2016-07-01

    Clinicians need to provide accurate, up-to-date, and balanced information to parents following a prenatal or postnatal diagnosis of Down syndrome and other genetic conditions. Families want information about the genomic outcomes and medical issues, but they also want information about life outcomes and social supports. Because the anticipated outcomes of a condition can change significantly based on available social support, health care, and services, it is important for clinicians to stay up-to-date about new developments and credible, medically reviewed information about Down syndrome and other genetic conditions to access resources for clinical care. PMID:27368358

  15. Gene scene: Earlier, eventually more specific, prenatal genetic diagnosis in realm of possibility

    SciTech Connect

    Randall, T.

    1990-12-26

    A new genetic technique that can amplify the DNA of a single cell has flung open the window of opportunity for prenatal genetic diagnosis to just 3 days after conception, and even to the unfertilized egg. In vitro fertilization (IVF) specialists at the Institute of Obstetrics and Gynecology at London's Postgraduate medical School, Hammersmith Hospital have determined the sex of human embryos at the eight-cell stage of development from five couples at risk for X chromosome-linked diseases. The female embryos, which do not risk inheriting the disease, were then successfully implanted in the uterus and carried to full term.

  16. Prenatal Diagnosis: A Directive Approach to Genetic Counseling Using Decision Analysis 1

    PubMed Central

    Pauker, Susan P.; Pauker, Stephen G.

    1977-01-01

    The decision which prospective parents face concerning mid-trimester amniocentesis for prenatal diagnosis was examined by decision analysis. The prospective parents' decision depends on the likelihood of the birth of a child affected by a genetic disorder, the risk of amniocentesis, and the probability that the diagnoses provided by the amniocentesis will be correct. The couple's decision must also depend on their attitudes toward each possible outcome. The likelihoods of the outcomes can be obtained from appropriate medical consultation, while the relative costs or burdens of the outcomes should be obtained from the prospective parents. A truly informed decision for this couple can then be formulated from these probabilities and values, thus allowing genetic counseling to be more directive. The technique is illustrated for the prenatal diagnosis of Down's syndrome, meningomyelocele, and Duchenne muscular dystrophy. PMID:142379

  17. Integration of PGD-virtual charts into an engineering design process

    NASA Astrophysics Data System (ADS)

    Courard, Amaury; Néron, David; Ladevèze, Pierre; Ballere, Ludovic

    2016-04-01

    This article deals with the efficient construction of approximations of fields and quantities of interest used in geometric optimisation of complex shapes that can be encountered in engineering structures. The strategy, which is developed herein, is based on the construction of virtual charts that allow, once computed offline, to optimise the structure for a negligible online CPU cost. These virtual charts can be used as a powerful numerical decision support tool during the design of industrial structures. They are built using the proper generalized decomposition (PGD) that offers a very convenient framework to solve parametrised problems. In this paper, particular attention has been paid to the integration of the procedure into a genuine engineering design process. In particular, a dedicated methodology is proposed to interface the PGD approach with commercial software.

  18. MEGA-MD: molecular evolutionary genetics analysis software with mutational diagnosis of amino acid variation.

    PubMed

    Stecher, Glen; Liu, Li; Sanderford, Maxwell; Peterson, Daniel; Tamura, Koichiro; Kumar, Sudhir

    2014-05-01

    Computational diagnosis of amino acid variants in the human exome is the first step in assessing the disruptive impacts of non-synonymous single nucleotide variants (nsSNVs) on human health and disease. The Molecular Evolutionary Genetics Analysis software with mutational diagnosis (MEGA-MD) is a suite of tools developed to forecast the deleteriousness of nsSNVs using multiple methods and to explore nsSNVs in the context of the variability permitted in the long-term evolution of the affected position. In its graphical interface for use on desktops, it enables interactive computational diagnosis and evolutionary exploration of nsSNVs. As a web service, MEGA-MD is suitable for diagnosing variants on an exome scale. The MEGA-MD suite intends to serve the needs for conducting low- and high-throughput analysis of nsSNVs in diverse applications.

  19. Genetic Testing as a New Standard for Clinical Diagnosis of Color Vision Deficiencies

    PubMed Central

    Davidoff, Candice; Neitz, Maureen; Neitz, Jay

    2016-01-01

    Purpose The genetics underlying inherited color vision deficiencies is well understood: causative mutations change the copy number or sequence of the long (L), middle (M), or short (S) wavelength sensitive cone opsin genes. This study evaluated the potential of opsin gene analyses for use in clinical diagnosis of color vision defects. Methods We tested 1872 human subjects using direct sequencing of opsin genes and a novel genetic assay that characterizes single nucleotide polymorphisms (SNPs) using the MassArray system. Of the subjects, 1074 also were given standard psychophysical color vision tests for a direct comparison with current clinical methods. Results Protan and deutan deficiencies were classified correctly in all subjects identified by MassArray as having red–green defects. Estimates of defect severity based on SNPs that control photopigment spectral tuning correlated with estimates derived from Nagel anomaloscopy. Conclusions The MassArray assay provides genetic information that can be useful in the diagnosis of inherited color vision deficiency including presence versus absence, type, and severity, and it provides information to patients about the underlying pathobiology of their disease. Translational Relevance The MassArray assay provides a method that directly analyzes the molecular substrates of color vision that could be used in combination with, or as an alternative to current clinical diagnosis of color defects.

  20. Genetic Diagnosis of Two Dopa-Responsive Dystonia Families by Exome Sequencing

    PubMed Central

    Sun, Zhan-fang; Zhang, Yu-han; Guo, Ji-feng; Sun, Qi-ying; Mei, Jun-pu; Zhou, Han-lin; Guan, Li-ping; Tian, Jin-yong; Hu, Zheng-mao; Li, Jia-da; Xia, Kun; Yan, Xin-xiang; Tang, Bei-sha

    2014-01-01

    Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes. PMID:25181484

  1. Genetic Testing as a New Standard for Clinical Diagnosis of Color Vision Deficiencies

    PubMed Central

    Davidoff, Candice; Neitz, Maureen; Neitz, Jay

    2016-01-01

    Purpose The genetics underlying inherited color vision deficiencies is well understood: causative mutations change the copy number or sequence of the long (L), middle (M), or short (S) wavelength sensitive cone opsin genes. This study evaluated the potential of opsin gene analyses for use in clinical diagnosis of color vision defects. Methods We tested 1872 human subjects using direct sequencing of opsin genes and a novel genetic assay that characterizes single nucleotide polymorphisms (SNPs) using the MassArray system. Of the subjects, 1074 also were given standard psychophysical color vision tests for a direct comparison with current clinical methods. Results Protan and deutan deficiencies were classified correctly in all subjects identified by MassArray as having red–green defects. Estimates of defect severity based on SNPs that control photopigment spectral tuning correlated with estimates derived from Nagel anomaloscopy. Conclusions The MassArray assay provides genetic information that can be useful in the diagnosis of inherited color vision deficiency including presence versus absence, type, and severity, and it provides information to patients about the underlying pathobiology of their disease. Translational Relevance The MassArray assay provides a method that directly analyzes the molecular substrates of color vision that could be used in combination with, or as an alternative to current clinical diagnosis of color defects. PMID:27622081

  2. Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis

    PubMed Central

    Walne, Amanda J.; Collopy, Laura; Cardoso, Shirleny; Ellison, Alicia; Plagnol, Vincent; Albayrak, Canan; Albayrak, Davut; Kilic, Sara Sebnem; Patıroglu, Turkan; Akar, Haluk; Godfrey, Keith; Carter, Tina; Marafie, Makia; Vora, Ajay; Sundin, Mikael; Vulliamy, Thomas; Tummala, Hemanth; Dokal, Inderjeet

    2016-01-01

    Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate management. The aim of this study was to determine the underlying genetic basis in patients presenting with features of dyskeratosis congenita and who were negative for mutations in the classical dyskeratosis congenita genes. By whole exome and targeted sequencing, we identified biallelic variants in genes that are not associated with dyskeratosis congenita in 17 individuals from 12 families. Specifically, these were homozygous variants in USB1 (8 families), homozygous missense variants in GRHL2 (2 families) and identical compound heterozygous variants in LIG4 (2 families). All patients had multiple somatic features of dyskeratosis congenita but not the characteristic short telomeres. Our case series shows that biallelic variants in USB1, LIG4 and GRHL2, the genes mutated in poikiloderma with neutropenia, LIG4/Dubowitz syndrome and the recently recognized ectodermal dysplasia/short stature syndrome, respectively, cause features that overlap with dyskeratosis congenita. Strikingly, these genes also overlap in their biological function with the known dyskeratosis congenita genes that are implicated in telomere maintenance and DNA repair pathways. Collectively, these observations demonstrate the marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. This has important implications for establishing a genetic diagnosis when a new patient presents in the clinic. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements. PMID:27612988

  3. [The use of genetic engineering in veterinary medicine with examples from epidemiology, diagnosis and drug production].

    PubMed

    Mayr, A; Hübert, P

    1990-04-01

    The results of genetic engineering have reached practical veterinary medicine already. Nevertheless there is a great lack of knowledge among those veterinarians who usually do not work with these methods. Therefore we want to give an introduction into the advantages and dangers of this technology concerning veterinary medicine. Some important analytical methods are explained. Related viruses such as WEE and EEE or canine parvovirus, feline parvovirus and mink enteritis virus, or the related coronaviruses FIPV and TGEV serve as examples for the possibilities in molecular diagnosis and epidemic monitoring. The history of the gl- mutants of PRV, now prescribed as vaccine strains in the FRG, is an example of the development of genetic engineered vaccines. A new generation of vaccines based on recombinant vaccinia viruses is imminent. Thus we have to be aware of the high risks and responsibility of everybody who is involved in these new systems, especially the scientist who produces genetically altered organisms. PMID:2112273

  4. Protein quantitative trait loci analysis identifies genetic variation in the innate immune regulator TOLLIP in post lung transplant primary graft dysfunction risk

    PubMed Central

    Cantu, Edward; Suzuki, Yoshikazu; Diamond, Joshua M.; Ellis, John; Tiwari, Jaya; Beduhn, Ben; Nellen, James R.; Shah, Rupal; Meyer, Nuala J.; Lederer, David J.; Kawut, Steven M.; Palmer, Scott M.; Snyder, Laurie D.; Hartwig, Matthew G.; Lama, Vibha N.; Bhorade, Sangeeta; Crespo, Maria; Demissie, Ejigayehu; Wille, Keith; Orens, Jonathan; Shah, Pali D.; Weinacker, Ann; Weill, David; Wilkes, David; Roe, David; Ware, Lorraine B.; Wang, Fan; Feng, Rui; Christie, Jason D.

    2016-01-01

    Summary We previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in PGD. We hypothesized plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A 2-stage cohort study was performed. In stage 1, we tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p<5×10−4 cutoff were carried forward and tested in Stage 2 for association with PGD. 297 enrollees were evaluated in Stage 1. 6 loci, associated with PAI-1, were carried forward to Stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein, TOLLIP) was significantly associated with PGD (p=0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% [95% CI: 4.9%, 18.5%]. The false positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP, and supports a role for toll-like receptors in PGD pathogenesis. PMID:26663441

  5. [Noninvasive prenatal genetic diagnosis: a bioethical reflection on the use of noninvasive prenatal diagnosis from the analysis of nucleic acids present in maternal peripheral blood].

    PubMed

    González-Melado, Fermín J; Di Pietro, Maria Luisa

    2011-01-01

    The use of techniques that analyse the fetal nucleic acids present in maternal peripheral blood for the preparation of non-invasive prenatal genetic diagnosis, is a clinical reality in the case of certain diseases. In the coming years, it will become part of the routine monitoring for fetal diagnosis. This study analyzes the current status of these techniques as well as the major ethical issues arising from the relationship between - prenatal diagnosis and eugenic abortion, and the specific problems posed by - prenatal genetic diagnosis based an analysis of the nucleic acids present in maternal peripheral blood. Among the conclusions are the following: we make a positive ethical evaluation of the technique when it is aimed at pregnant women who are in a situation of high risk, defined on the basis of medical standards and ethics, without compromising the integrity of the fetus. We make a negative ethical evaluation when non-invasive prenatal genetic diagnosis has a eugenic purpose and will establish a connection between prenatal diagnosis and eugenic abortion in case of a positive result. Non-invasive prenatal diagnosis increases the image of the disabled person as an individual that has to be excluded from society. The widespread use of non-invasive prenatal diagnosis will decrease the autonomy of women / couples when it comes to making decisions. Health authorities may use non-invasive prenatal diagnosis as a way of ″preventing″ genetic diseases, since it will lower costs, increase the number of malformed fetuses detected and a decrease the number of indirect abortions involving invasive techniques. PMID:21692554

  6. Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing

    PubMed Central

    Drew, Alexander P; Zhu, Danqing; Kidambi, Aditi; Ly, Carolyn; Tey, Shelisa; Brewer, Megan H; Ahmad-Annuar, Azlina; Nicholson, Garth A; Kennerson, Marina L

    2015-01-01

    Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype–phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c.7640T>C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive

  7. Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome.

    PubMed

    Zemojtel, Tomasz; Köhler, Sebastian; Mackenroth, Luisa; Jäger, Marten; Hecht, Jochen; Krawitz, Peter; Graul-Neumann, Luitgard; Doelken, Sandra; Ehmke, Nadja; Spielmann, Malte; Oien, Nancy Christine; Schweiger, Michal R; Krüger, Ulrike; Frommer, Götz; Fischer, Björn; Kornak, Uwe; Flöttmann, Ricarda; Ardeshirdavani, Amin; Moreau, Yves; Lewis, Suzanna E; Haendel, Melissa; Smedley, Damian; Horn, Denise; Mundlos, Stefan; Robinson, Peter N

    2014-09-01

    Less than half of patients with suspected genetic disease receive a molecular diagnosis. We have therefore integrated next-generation sequencing (NGS), bioinformatics, and clinical data into an effective diagnostic workflow. We used variants in the 2741 established Mendelian disease genes [the disease-associated genome (DAG)] to develop a targeted enrichment DAG panel (7.1 Mb), which achieves a coverage of 20-fold or better for 98% of bases. Furthermore, we established a computational method [Phenotypic Interpretation of eXomes (PhenIX)] that evaluated and ranked variants based on pathogenicity and semantic similarity of patients' phenotype described by Human Phenotype Ontology (HPO) terms to those of 3991 Mendelian diseases. In computer simulations, ranking genes based on the variant score put the true gene in first place less than 5% of the time; PhenIX placed the correct gene in first place more than 86% of the time. In a retrospective test of PhenIX on 52 patients with previously identified mutations and known diagnoses, the correct gene achieved a mean rank of 2.1. In a prospective study on 40 individuals without a diagnosis, PhenIX analysis enabled a diagnosis in 11 cases (28%, at a mean rank of 2.4). Thus, the NGS of the DAG followed by phenotype-driven bioinformatic analysis allows quick and effective differential diagnostics in medical genetics.

  8. Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome.

    PubMed

    Zemojtel, Tomasz; Köhler, Sebastian; Mackenroth, Luisa; Jäger, Marten; Hecht, Jochen; Krawitz, Peter; Graul-Neumann, Luitgard; Doelken, Sandra; Ehmke, Nadja; Spielmann, Malte; Oien, Nancy Christine; Schweiger, Michal R; Krüger, Ulrike; Frommer, Götz; Fischer, Björn; Kornak, Uwe; Flöttmann, Ricarda; Ardeshirdavani, Amin; Moreau, Yves; Lewis, Suzanna E; Haendel, Melissa; Smedley, Damian; Horn, Denise; Mundlos, Stefan; Robinson, Peter N

    2014-09-01

    Less than half of patients with suspected genetic disease receive a molecular diagnosis. We have therefore integrated next-generation sequencing (NGS), bioinformatics, and clinical data into an effective diagnostic workflow. We used variants in the 2741 established Mendelian disease genes [the disease-associated genome (DAG)] to develop a targeted enrichment DAG panel (7.1 Mb), which achieves a coverage of 20-fold or better for 98% of bases. Furthermore, we established a computational method [Phenotypic Interpretation of eXomes (PhenIX)] that evaluated and ranked variants based on pathogenicity and semantic similarity of patients' phenotype described by Human Phenotype Ontology (HPO) terms to those of 3991 Mendelian diseases. In computer simulations, ranking genes based on the variant score put the true gene in first place less than 5% of the time; PhenIX placed the correct gene in first place more than 86% of the time. In a retrospective test of PhenIX on 52 patients with previously identified mutations and known diagnoses, the correct gene achieved a mean rank of 2.1. In a prospective study on 40 individuals without a diagnosis, PhenIX analysis enabled a diagnosis in 11 cases (28%, at a mean rank of 2.4). Thus, the NGS of the DAG followed by phenotype-driven bioinformatic analysis allows quick and effective differential diagnostics in medical genetics. PMID:25186178

  9. Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the National Society of Genetic Counselors.

    PubMed

    Devers, Patricia L; Cronister, Amy; Ormond, Kelly E; Facio, Flavia; Brasington, Campbell K; Flodman, Pamela

    2013-06-01

    The 1997 discovery of free fetal DNA in maternal plasma launched clinical researchers' efforts to establish a reliable method for non-invasive prenatal testing for fetal genetic conditions. Various methods, including, but not limited to, massively parallel sequencing (MPS) and selective analysis of cell-free fetal DNA in maternal plasma, have recently been developed as highly sensitive and specific noninvasive screening tools for common fetal chromosome aneuploidies. Incorporating these new noninvasive technologies into clinical practice will impact the current prenatal screening paradigm for fetal aneuploidy, in which genetic counseling plays an integral role. The National Society of Genetic Counselors (NSGC) currently supports Noninvasive Prenatal Testing/Noninvasive Prenatal Diagnosis (NIPT/NIPD) as an option for patients whose pregnancies are considered to be at an increased risk for certain chromosome abnormalities. NSGC urges that NIPT/NIPD only be offered in the context of informed consent, education, and counseling by a qualified provider, such as a certified genetic counselor. Patients whose NIPT/NIPD results are abnormal, or who have other factors suggestive of a chromosome abnormality, should receive genetic counseling and be given the option of standard confirmatory diagnostic testing.

  10. Current molecular genetics strategies for the diagnosis of lysosomal storage disorders.

    PubMed

    Giugliani, Roberto; Brusius-Facchin, Ana-Carolina; Pasqualim, Gabriela; Leistner-Segal, Sandra; Riegel, Mariluce; Matte, Ursula

    2016-01-01

    Lysosomal storage disorders (LSDs) are a group of almost 50 monogenic diseases characterized by mutations causing deficiency of lysosomal enzymes or non-enzyme proteins involved in transport across the lysosomal membrane, protein maturation or lysosomal biogenesis. Usually, affected patients are normal at birth and have a progressive and severe disease with high morbidity and reduced life expectancy. The overall incidence of LSDs is usually estimated as 1:5000, but newborn screening studies are indicating that it could be much higher. Specific therapies were already developed for selected LSDs, making the timely and correct diagnosis very important for successful treatment and also for genetic counseling. In most LSD cases the biochemical techniques provide a reliable diagnosis. However, the identification of pathogenic mutations by genetic analysis is being increasingly recommended to provide additional information. In this paper we discuss the conventional methods for genetic analysis used in the LSDs [restriction fragment length polymorphism (RFLP), amplification-refractory mutation system (ARMS), single strand conformation polymorphism (SSCP), denaturing high performance liquid chromatography (dHPLC), real-time polymerase chain reaction, high resolution melting (HRM), multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing] and also the newer approaches [massive parallel sequencing, array comparative genomic hybridization (CGH)]. PMID:26567866

  11. Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

    PubMed

    Drougat, Ludivine; Espiard, Stéphanie; Bertherat, Jerôme

    2015-10-01

    Long-term consequences of cortisol excess are frequent despite appropriate treatment after cure of Cushing's syndrome. This might be due to diagnostic delay, often difficult to reduce in rare diseases. The identification of a genetic predisposing factor might help to improve early diagnosis by familial screening. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Hypercortisolism in PBMAH is most often diagnosed between the fifth and sixth decades of life. The bilateral nature of the adrenocortical tumors and the occurrence of rare clear familial forms suggest a genetic origin. Indeed, a limited subset of PBMAH can be observed as part of multiple tumors syndromes due to alterations of the APC, Menin or Fumarate Hydratase genes. Rare variants of the phosphodiesterases PDE11A have been associated with PBMAH. The recent identification of ARMC5 germline alterations in 25-50% of PBMAH patients without obvious familial history or associated tumors opens new perspectives. ARMC5 alterations follow the model of a tumor suppressor gene: a first germline inactivating mutation of this 16p located gene is followed by a somatic secondary hit on the other allele (inactivating mutation or allelic loss). Functional studies demonstrate that ARMC5 controls apoptosis and steroid synthesis. The phenotype of index cases patients with the mutation seems more severe than the one of WT index cases. However, phenotype variability within a family is often observed. This review summarizes the genetics of PBMAH, focusing on ARMC5, which offer new perspectives for early diagnosis of Cushing's syndrome.

  12. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome: a treatable genetic liver disease warranting urgent diagnosis.

    PubMed

    Lee, Hencher H C; Poon, K H; Lai, C K; Au, K M; Siu, T S; Lai, Judy P S; Mak, Chloe M; Yuen, Y P; Lam, C W; Chan, Albert Y W

    2014-02-01

    Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is an autosomal recessive disorder caused by a defect in ornithine translocase. This condition leads to variable clinical presentations, including episodic hyperammonaemia, hepatic derangement, and chronic neurological manifestations. Fewer than 100 affected patients have been reported worldwide. Here we report the first two cases in Hong Kong Chinese, who were compound heterozygous siblings for c.535C>T (p.Arg179*) and c.815C>T (p.Thr272Ile) in the SLC25A15 gene. When the mother refused prenatal diagnosis for the second pregnancy, urgent genetic testing provided the definitive diagnosis within 24 hours to enable specific treatment. Optimal management of these two patients relied on the concerted efforts of a multidisciplinary team and illustrates the importance of an expanded newborn screening service for early detection and treatment of inherited metabolic diseases. PMID:24473688

  13. AB033. Preimplantation genetic diagnosis of spinal muscular atrophy in Vietnam

    PubMed Central

    Khoa, Tran Van; Nga, Nguyen Thi Thanh; Tao, Nguyen Dinh; Sang, Trieu Tien; Giang, Ngo Truong; Dung, Vu Chi

    2015-01-01

    Objective Spinal muscular atrophy (SMA) is a severe neurodegenerative autosomal recessive disorder. Most of patients are caused by the homozygous absence of exon 7 of the telomeric copy of the SMN gene (SMNt) on chromosome 5. Setting up a molecular diagnostic protocol for detecting exon 7 gen SMNT homozygous deletion in single cell is basic to preimplantation genetic diagnosis of spinal muscular atrophy. Methods This study was carried out on 17 patients and their parents. Firstly, lymphocytes of patients and their parents were isolated from fresh blood by ficoll. Taking a lymphocyte on stereoscopic microscope, lysing the cell, amplifying whole genome, then amplifying exon 7 of SMNT gene by using a polymerase chain reaction, followed by HinfI restriction digest enzyme of the PCR enabling the important SMNT gene to be distinguished from the centromic SMN gene (SMNc) which has no clinical phenotype to detect mutation. Electrophoresis PCR products after digesting by restriction enzyme and analysis. Besides, the minisequencing technique has also been used to detect the absence of exon 7 of SMNT gene based on the difference of one nucleotide at 214-position in exon 7 (C-SMNT, T-SMNc). Secondly, the application of the protocol was set up on one lymphocyte to preimplantation genetic diagnosis of spinal muscular atrophy on biopsied blastomeres. Results Two different protocols which were PCR-RFLP and minisequencing, were set up on 200 lymphocytes from 17 patients and their parents to screen the homozygous deletion in exon 7 SMNT gene with the PCR efficiency in 96%. The results were similar with the gene diagnosed from fresh blood. The methods were also efficient, providing interpretable result in 96.55% (28/29) of the blastomeres tested. Three couples were treated using this method. Three normal embryos were transfer which resulted in one clinical pregnancy. Conclusions We have successfully applied the technique of PCR-RFLP and minisequencing for the preimplantation genetic

  14. Comorbidity of intellectual disability confounds ascertainment of autism: implications for genetic diagnosis.

    PubMed

    Polyak, Andrew; Kubina, Richard M; Girirajan, Santhosh

    2015-10-01

    While recent studies suggest a converging role for genetic factors towards risk for nosologically distinct disorders including autism, intellectual disability (ID), and epilepsy, current estimates of autism prevalence fail to take into account the impact of comorbidity of these disorders on autism diagnosis. We aimed to assess the effect of comorbidity on the diagnosis and prevalence of autism by analyzing 11 years (2000-2010) of special education enrollment data on approximately 6.2 million children per year. We found a 331% increase in the prevalence of autism from 2000 to 2010 within special education, potentially due to a diagnostic recategorization from frequently comorbid features such as ID. The decrease in ID prevalence equaled an average of 64.2% of the increase of autism prevalence for children aged 3-18 years. The proportion of ID cases potentially undergoing recategorization to autism was higher (P = 0.007) among older children (75%) than younger children (48%). Some US states showed significant negative correlations between the prevalence of autism compared to that of ID while others did not, suggesting state-specific health policy to be a major factor in categorizing autism. Further, a high frequency of autistic features was observed when individuals with classically defined genetic syndromes were evaluated for autism using standardized instruments. Our results suggest that current ascertainment practices are based on a single facet of autism-specific clinical features and do not consider associated comorbidities that may confound diagnosis. Longitudinal studies with detailed phenotyping and deep molecular genetic analyses are necessary to completely understand the cause of this complex disorder.

  15. Harlequin Ichthyosis: Prenatal Diagnosis of a Rare Yet Severe Genetic Dermatosis

    PubMed Central

    David, Liji Sarah; Beck, Manisha Madhai; Bindra, Mandeep Singh; Arunachal, Gautham

    2015-01-01

    Harlequin Ichthyosis (HI) is an extremely rare genetic skin disorder. It is the most severe type of ichthyosis. It is characterized by thickened, dry, rough and armor like plates of skin with deep cracks in between. Alternative names for HI include- keratosis diffusafetalis, ichthyosis congenital, icthyosis fetalis, harlequin fetus and icthyosis congenital gravior. It is an autosomal recessive disorder with the majority of affected individuals being homozygous for mutation in the ABCA 12 gene. This condition presents with a wide range of severity and symptoms. Affected neonates usually do not survive beyond first few days of life. We are presenting prenatal diagnosis of a case of this rare condition. PMID:26675324

  16. Multiplex ligation-dependent probe amplification: a novel approach for genetic diagnosis of Porphyria.

    PubMed

    Di Pierro, Elena; Brancaleoni, Valentina; Besana, Valeria; Cappellini, Maria Domenica

    2009-08-01

    Porphyrias are disorders caused by the genetic defects of enzymes of the heme pathway and are characterized by such a wide genetic heterogeneity that even the molecular analysis is not always decisive for a correct diagnosis. In the past few years, deletion with a size range of few kilobase pairs have been reported. These peculiar mutations, missed by both sequencing and cytogenetic techniques, have been identified by time consuming and technically demanding methods. To provide a rapid and sensitive method for the detection of deletions responsible for porphyria, we successfully designed and tested seven chemically synthesized probe sets specific for each heme gene and their flanking regions, to be used in multiplex ligation-dependent probe amplification technique.

  17. Use of genetic algorithms for computer-aided diagnosis of breast cancers from image features

    NASA Astrophysics Data System (ADS)

    Floyd, Carey E., Jr.; Tourassi, Georgia D.; Baker, Jay A.

    1996-04-01

    In this investigation we explore genetic algorithms as a technique to train the weights in a feed forward neural network designed to predict breast cancer based on mammographic findings and patient history. Mammograms were obtained from 206 patients who obtained breast biopsies. Mammographic findings were recorded by radiologists for each patient. In addition, the outcome of the biopsy was recorded. Of the 206 cases, 73 were malignant while 133 were benign at the time of biopsy. A genetic algorithm (GA) was developed to adjust the weights of an artificial neural network (ANN) so that the ANN would output the outcome of the biopsy when the mammographic findings were given as inputs. The GA is a technique for function optimization that reflects biological genetic evolution. The ANN was a fully connected feed- forward network using a sigmoid activation with 11 inputs, one hidden layer with 10 nodes, and one output node (benign/malignant). The GA approach allows much flexibility in selecting the function to be optimized. In this work both mean-squared error (MSE) and receiver operating characteristic (ROC) curve area (Az) were explored as optimization criteria. The system was trained using a bootstrap sampling. Optimizing for the two criteria result in different solutions. The 'best' solution was obtained by minimizing a linear combination of MSE and (1-Az). ROC areas were 0.82 plus or minus 0.07, somewhat less than those obtained using backpropagation for ANN training: 0.90 plus or minus 0.05. This is the first description of a genetic algorithm for breast cancer diagnosis. The novel advantage of this technique is the ability to optimize the system for maximizing ROC area rather than minimizing mean squared error. A new technique for computer-aided diagnosis of breast cancer has been explored. The flexibility of the GA approach allows optimization of cost functions that have relevance to breast cancer prediction.

  18. Rolling element bearing fault diagnosis based on the combination of genetic algorithms and fast kurtogram

    NASA Astrophysics Data System (ADS)

    Zhang, Yongxiang; Randall, R. B.

    2009-07-01

    The rolling element bearing is a key part in many mechanical facilities and the diagnosis of its faults is very important in the field of predictive maintenance. Till date, the resonant demodulation technique (envelope analysis) has been widely exploited in practice. However, much practical diagnostic equipment for carrying out the analysis gives little flexibility to change the analysis parameters for different working conditions, such as variation in rotating speed and different fault types. Because the signals from a flawed bearing have features of non-stationarity, wide frequency range and weak strength, it can be very difficult to choose the best analysis parameters for diagnosis. However, the kurtosis of the vibration signals of a bearing is different from normal to bad condition, and is robust in varying conditions. The fast kurtogram gives rough analysis parameters very efficiently, but filter centre frequency and bandwidth cannot be chosen entirely independently. Genetic algorithms have a strong ability for optimization, but are slow unless initial parameters are close to optimal. Therefore, the authors present a model and algorithm to design the parameters for optimal resonance demodulation using the combination of fast kurtogram for initial estimates, and a genetic algorithm for final optimization. The feasibility and the effectiveness of the proposed method are demonstrated by experiment and give better results than the classical method of arbitrarily choosing a resonance to demodulate. The method gives more flexibility in choosing optimal parameters than the fast kurtogram alone.

  19. Inflammation, Genetics, Dysbiosis, and the Environment: New Paradigms for Diagnosis in Complex Chronic Gut Syndromes.

    PubMed

    Walker, Marjorie M

    2016-10-01

    Chronic and complex gut syndromes are complex to diagnose and manage, but good clinicopathologic correlation, recognition of new entities, understanding (and understanding the limits) of genetic susceptibility and the importance of the microbiome, dysbiosis and influence of the environmental allows development of new models for diagnosis. An awareness of overlap in chronic gut syndromes has been clarified by the realization that inflammatory pathways involved in chronic gut disease can arise through variable gene expression that is influenced by the environment in susceptible individuals. Recent advances in diagnosis of inflammatory bowel disease and diverticular disease may be aided by genetic tests but at present, pathology and some simple biomarkers such as C-reactive protein and fecal calprotectin are still mainstream investigative measures. When made aware of the importance of these recent developments in chronic gut disease, histopathologists can easily recognize colonic spirochetosis and microscopic colitis. The role of the microbiome alongside interaction with the environment, are now recognized as key players in complex diseases. Integration of appropriate and cost-effective tests into new paradigms will surely advance patients' well-being and allow development of curative-targeted therapies rather than current treatments which, in many cases, merely alleviate symptoms. PMID:27622361

  20. Fault diagnosis in spur gears based on genetic algorithm and random forest

    NASA Astrophysics Data System (ADS)

    Cerrada, Mariela; Zurita, Grover; Cabrera, Diego; Sánchez, René-Vinicio; Artés, Mariano; Li, Chuan

    2016-03-01

    There are growing demands for condition-based monitoring of gearboxes, and therefore new methods to improve the reliability, effectiveness, accuracy of the gear fault detection ought to be evaluated. Feature selection is still an important aspect in machine learning-based diagnosis in order to reach good performance of the diagnostic models. On the other hand, random forest classifiers are suitable models in industrial environments where large data-samples are not usually available for training such diagnostic models. The main aim of this research is to build up a robust system for the multi-class fault diagnosis in spur gears, by selecting the best set of condition parameters on time, frequency and time-frequency domains, which are extracted from vibration signals. The diagnostic system is performed by using genetic algorithms and a classifier based on random forest, in a supervised environment. The original set of condition parameters is reduced around 66% regarding the initial size by using genetic algorithms, and still get an acceptable classification precision over 97%. The approach is tested on real vibration signals by considering several fault classes, one of them being an incipient fault, under different running conditions of load and velocity.

  1. Recent advances in the diagnosis, genetics and treatment of restless legs syndrome.

    PubMed

    Trenkwalder, Claudia; Högl, Birgit; Winkelmann, Juliane

    2009-04-01

    Knowledge of restless legs syndrome (RLS) has greatly increased in recent years due to the many advances that have been made in diagnosis, management and genetics. Tools have been developed that facilitate the diagnosis and treatment of RLS, in particular the essential diagnostic criteria for RLS have been refined, severity scales (IRLS, RLS-6, JHSS) have been developed, as have instruments that improve diagnostic accuracy and assess for specific aspects of RLS such as augmentation. These newly developed tools have been used in recent population-based studies, which have provided a greater understanding of the epidemiology of RLS, and also within patient-based trials. As far as the genetics of RLS is concerned, linkage studies in RLS families have revealed eight loci but no causally related sequence variant has yet been identified using this approach. Recent genome-wide association studies have identified variants within intronic or intergenic regions of MEIS1, BTBD9, and MAP2K5/LBXCOR1, and PTPRD, raising new pathological hypotheses for RLS. An overview on therapeutic options and recent trials is given based on evidence-based management strategies for this common disorder.

  2. Molecular genetics of the sickling syndromes: evolution of new strategies for improved diagnosis.

    PubMed

    Benz, E J

    1984-01-01

    This survey is intended to illustrate some major areas relevant to the diagnosis and treatment of sickle cell syndromes that have benefited by the input of molecular genetic approaches. The development of gene mapping techniques has permitted the direct examination of the effect of co-inheritance of alpha-thalassemia and sickle cell anemia on clinical severity, providing, for the first time, a direct strategy for investigation of the clinical heterogeneity of these syndromes. In addition, antenatal diagnosis of these disorders is now best done by direct gene mapping whenever appropriate facilities are available. Treatment by manipulation of gamma-globin gene expression has been shown to be an effective means of achieving at least partial reversal of the hemoglobin F to hemoglobin A switch. Whether the magnitude of this reversal is sufficient to interfere with the clinical phenotype of sickle cell disease remains to be determined. Moreover, the agent currently available to accomplish this goal, 5-azacytidine, remains unsuitable for wide-spread clinical application for a variety of reasons. Nonetheless, the molecular geneticist has already demonstrated that desirable effects can be achieved by building on the knowledge of globin gene physiology. This knowledge is best acquired by application of the concepts and methodologies of molecular genetics.

  3. Inflammation, Genetics, Dysbiosis, and the Environment: New Paradigms for Diagnosis in Complex Chronic Gut Syndromes.

    PubMed

    Walker, Marjorie M

    2016-10-01

    Chronic and complex gut syndromes are complex to diagnose and manage, but good clinicopathologic correlation, recognition of new entities, understanding (and understanding the limits) of genetic susceptibility and the importance of the microbiome, dysbiosis and influence of the environmental allows development of new models for diagnosis. An awareness of overlap in chronic gut syndromes has been clarified by the realization that inflammatory pathways involved in chronic gut disease can arise through variable gene expression that is influenced by the environment in susceptible individuals. Recent advances in diagnosis of inflammatory bowel disease and diverticular disease may be aided by genetic tests but at present, pathology and some simple biomarkers such as C-reactive protein and fecal calprotectin are still mainstream investigative measures. When made aware of the importance of these recent developments in chronic gut disease, histopathologists can easily recognize colonic spirochetosis and microscopic colitis. The role of the microbiome alongside interaction with the environment, are now recognized as key players in complex diseases. Integration of appropriate and cost-effective tests into new paradigms will surely advance patients' well-being and allow development of curative-targeted therapies rather than current treatments which, in many cases, merely alleviate symptoms.

  4. Immunohistochemical Markers of Soft Tissue Tumors: Pathologic Diagnosis, Genetic Contributions, and Therapeutic Options

    PubMed Central

    Parham, David M

    2015-01-01

    After ~30 years of widespread usage, immunohistochemistry (IHC) has become a standard method of diagnosis for surgical pathology. Because of the plethora of diagnoses and often subtle nature of diagnostic criteria, IHC finds particular utility in soft tissue tumors. The use of progressively small amounts of tissue for diagnosis highlights the importance of this method. The sensitivity and crispness of IHC stains have progressively improved with the advent of new techniques. Traditionally, IHC detects cell-typic markers that characterize cell phenotypes, such as chromogranin for neuroectodermal tissue, myogenin for skeletal muscle, and cytokeratin for epithelium. However, the advent of genetic discoveries have led to IHC testing for detection of fusion gene products or overexpressed oncogenes associated with deletions and mutations. Proliferation-based markers such as Ki-67 can also be used for prognosis and grading, but more standardization is needed. Development of monoclonal antibody-based pharmaceuticals, such as imatinib or crizotinib, holds the promise of tailored anticancer therapy. IHC thus has assumed importance not only for diagnosis but also for guidance of personalized medicine. PMID:26549970

  5. Genetic analysis of Tunisian families with Usher syndrome type 1: toward improving early molecular diagnosis

    PubMed Central

    Ben-Rebeh, Imen; Bonnet, Crystel; Bouassida, Walid; Hadjamor, Imen; Ayadi, Hammadi; Ghorbel, Abdelmonem; Petit, Christine; Masmoudi, Saber

    2016-01-01

    Purpose Usher syndrome accounts for about 50% of all hereditary deaf-blindness cases. The most severe form of this syndrome, Usher syndrome type I (USH1), is characterized by profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. Six USH1 genes have been identified, MYO7A, CDH23, PCDH15, USH1C, SANS, and CIB2, encoding myosin VIIA, cadherin-23, protocadherin-15, harmonin, scaffold protein containing ankyrin repeats and a sterile alpha motif (SAM) domain, and calcium- and integrin-binding member 2, respectively. Methods In the present study, we recruited four Tunisian families with a diagnosis of USH1, together with healthy unrelated controls. Affected members underwent detailed audiologic and ocular examinations. We used the North African Deafness (NADf) chip to search for known North African mutations associated with USH. Then, we selected microsatellite markers covering USH1 known loci to genotype the DNA samples. Finally, we performed DNA sequencing of three known USH1 genes: MYO7A, PCDH15, and USH1C. Results Four biallelic mutations, all single base changes, were found in the MYO7A, USH1C, and PCDH15 genes. These mutations consist of a previously reported splicing defect c.470+1G>A in MYO7A, three novel variants, including two nonsense (p.Arg3X and p.Arg134X) in USH1C and PCDH15, respectively, and one frameshift (p.Lys615Asnfs*6) in MYO7A. Conclusions We found a remarkable genetic heterogeneity in the studied families with USH1 with a variety of mutations, among which three were novel. These novel mutations will be included in the NADf mutation screening chip that will allow a higher diagnosis efficiency of this extremely genetically heterogeneous disease. Ultimately, efficient molecular diagnosis of USH in a patient’s early childhood is of utmost importance, allowing better educational and therapeutic management. PMID:27440999

  6. 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.

  7. Access to medical-assisted reproduction and pgd in Italian law: a deadly blow to an illiberal statute? commentary to the European Court on Human Rights's decision Costa and Pavan v Italy (ECtHR, 28 August 2012, App. 54270/2010).

    PubMed

    Biondi, Stefano

    2013-01-01

    This article provides an account of the European Court on Human Rights' Second Section decision in the case Costa and Pavan v Italy. The judgment found that the Italian Statute on Assisted Reproduction (Law 40/2004), and particularly its prohibition to use in vitro fertilisation and pre-implantation genetic diagnosis (PGD) to prevent the birth of children affected by genetically transmissible conditions, breached Article 8 of the European Convention on Human Rights (ECHR). In fact, the statute in question permits only infertile people to access medically assisted reproduction techniques and forbids PGD and embryo selection. The Court regarded that the rationale of these prohibitions-identified by the Italian Government with the need to prevent eugenic practices as well as to protect the health of the unborn and of the woman-was at odds with the fact that Italian law allows pre-natal screening and therapeutic abortions in case foetal abnormalities are diagnosed. In order to clarify the decision's significance, the paper goes on to analyse the rationale of Law 40/2004 in the Italian legal and political context. Emphasis is placed on the fact that this statute is extremely controversial at domestic level, because many of its provisions-including those considered by the Strasbourg Court-are inherently contradictory and contrast with the settled constitutional principles on abortion, as many domestic authorities highlighted. In this context, should the commented decision be confirmed by the Grand Chamber, it may provide a basis to bring consistency back to the Italian regulation of assisted reproduction. Finally, the paper considers the appeal lodged by the Italian Government to the Grand Chamber, and in particular the contention that the European Court had failed to respect Italy's margin of appreciation. In this regard, it is argued that, under Law 40/2004, individuals face illogical and discriminatory restrictions to their right to private and family life and that

  8. Lethal autonomy: the malfunction of the informed consent mechanism within the context of prenatal diagnosis of genetic variants.

    PubMed

    Dunne, C; Warren, C

    1998-01-01

    In this article, Cara Dunne and Catherine Warren challenge the current role of genetic counselors in advising expectant mothers about potential genetic defects of their fetuses. They show that genetic counselors sometimes provide one-sided negative information to women undergoing prenatal diagnosis of genetic variants. This biased information promotes abortion of what are considered "defective" fetuses. The misleading information provided by the genetic counselors and the termination of the pregnancies is akin to the eugenics movement. The authors describe the early 20th century eugenics movement, explore the origin and development of the Human Genome Project, analyze the current role of genetic counseling, and explain the importance of the informed consent process to the exercise of autonomy. Dunne and Warren conclude by offering methods by which to restructure the informed consent mechanism to offer a more balanced assessment of the risks and benefits associated with genetic disability.

  9. Comparing targeted exome and whole exome approaches for genetic diagnosis of neuromuscular disorders

    PubMed Central

    Gorokhova, Svetlana; Cerino, Mathieu; Mathieu, Yves; Courrier, Sébastien; Desvignes, Jean-Pierre; Salgado, David; Béroud, Christophe; Krahn, Martin; Bartoli, Marc

    2015-01-01

    Massively parallel sequencing is rapidly becoming a widely used method in genetic diagnostics. However, there is still no clear consensus as to which approach can most efficiently identify the pathogenic mutations carried by a given patient, while avoiding false negative and false positive results. We developed a targeted exome approach (MyoPanel2) in order to optimize genetic diagnosis of neuromuscular disorders. Using this approach, we were able to analyse 306 genes known to be mutated in myopathies as well as in related disorders, obtaining 98.8% target sequence coverage at 20 ×. Moreover, MyoPanel2 was able to detect 99.7% of 11,467 known mutations responsible for neuromuscular disorders. We have then used several quality control parameters to compare performance of the targeted exome approach with that of whole exome sequencing. The results of this pilot study of 140 DNA samples suggest that targeted exome sequencing approach is an efficient genetic diagnostic test for most neuromuscular diseases. PMID:27054082

  10. A model of genetic guidance for hemoglobinopathy patients and laboratory diagnosis of family members as educational and preventive measures

    PubMed Central

    Ferreira, Tatiana Dela-Sávia; Freire, Adriana Sousa; Silveira-Lacerda, Elisângela de Paula; García-Zapata, Marco Túlio Antônio

    2012-01-01

    Background: The high frequency of hemoglobinopathies in Brazil constitutes a public health problem and thus educational and preventive measures are necessary to reduce the incidence. Genetic guidance, a modality of genetic counseling, and family screening are measures that can assist in reproductive decisions and mitigate clinical, psychological and social problems of families with these disorders. Objetive: The objective of the current study was to evaluate the effectiveness of educational and preventive measures for hemoglobinopathies using genetic guidance and laboratory screening of families. Methods: The diagnoses of patients with hemoglobinopathies were confirmed and then the level of knowledge about their disease was evaluated and genetic guidance was provided. Three months later, the level of assimilated information of these patients was evaluated. In addition, laboratory diagnosis of family members was carried out. Results: Diagnosis of sickle cell anemia was confirmed for most patients. Moreover, the majority of the patients who had a low level of knowledge before genetic guidance (68.8%) demonstrated a higher level of assimilated information after the process (81.8%). Almost 70% of the family members had hemoglobin changes and some had hemoglobinopathies(2.6%). They were duly informed about the results of the examinations, which made it possible to investigate further. Conclusion: Genetic guidance and family screening were effective preventive and educational measures that improved the quality of life of patients, preventing complications and sequels and allowed the referral of those who may transmit altered genes for clinical diagnosis and to genetic counseling services. PMID:23125541

  11. Angelman-Like Syndrome: A Genetic Approach to Diagnosis with Illustrative Cases

    PubMed Central

    Luk, Ho-Ming

    2016-01-01

    Epigenetic abnormalities in 15q11-13 imprinted region and UBE3A mutation are the two major mechanisms for molecularly confirmed Angelman Syndrome. However, there is 10% of clinically diagnosed Angelman Syndrome remaining test negative. With the advancement of genomic technology like array comparative genomic hybridization and next generation sequencing methods, it is found that some patients of these test negative Angelman-like Syndromes actually have alternative diagnoses. Accurate molecular diagnosis is paramount for genetic counseling and subsequent management. Despite overlapping phenotypes between Angelman and Angelman-like Syndrome, there are some subtle but distinct features which could differentiate them clinically. It would provide important clue during the diagnostic process for clinicians. PMID:26942024

  12. Preimplantation genetic diagnosis of a large pericentric inversion of chromosome 5.

    PubMed

    Iwarsson, E; Ahrlund-Richter, L; Inzunza, J; Rosenlund, B; Fridström, M; Hillensjö, T; Sjöblom, P; Nordenskjöld, M; Blennow, E

    1998-07-01

    We report the first established pregnancy using preimplantation genetic diagnosis in order to avoid chromosomal imbalance in the progeny of a woman carrying a large inversion of chromosome 5. This is also the first time where it has been possible to study the distribution of balanced and unbalanced gametes in a female inversion carrier. In total, 23 embryos were biopsied in two separate treatments and analysed by fluorescent in-situ hybridization. Of these, 10 were unbalanced, nine were balanced and for four the analysis was inconclusive. The diagnostic procedure was performed within 3.5 h. This allowed the biopsied embryos to be transferred the same day as the biopsy was taken (day 3). Two embryos were transferred each time, and in the second treatment a twin pregnancy with two chromosomally balanced fetuses was established. Healthy twins were delivered at 34 weeks of gestation.

  13. Angelman-Like Syndrome: A Genetic Approach to Diagnosis with Illustrative Cases.

    PubMed

    Luk, Ho-Ming

    2016-01-01

    Epigenetic abnormalities in 15q11-13 imprinted region and UBE3A mutation are the two major mechanisms for molecularly confirmed Angelman Syndrome. However, there is 10% of clinically diagnosed Angelman Syndrome remaining test negative. With the advancement of genomic technology like array comparative genomic hybridization and next generation sequencing methods, it is found that some patients of these test negative Angelman-like Syndromes actually have alternative diagnoses. Accurate molecular diagnosis is paramount for genetic counseling and subsequent management. Despite overlapping phenotypes between Angelman and Angelman-like Syndrome, there are some subtle but distinct features which could differentiate them clinically. It would provide important clue during the diagnostic process for clinicians. PMID:26942024

  14. Peyronie’s disease: a literature review on epidemiology, genetics, pathophysiology, diagnosis and work-up

    PubMed Central

    Al-Thakafi, Sultan

    2016-01-01

    Peyronie’s disease (PD), a fibromatous disorder of the tunica albuginea of the penile corpus cavernosum, named after the French physician Francois de la Peyronie, is characterized by pain, plaque formation, penile curvature, and plaque calcification. The epidemiological data on PD is inconsistent, with recent reports stating a prevalence of up to 9%, and the condition affecting men of all ages, from teenagers to septuagenarians. We are just beginning to elucidate the role of genetics as a causative factor for PD. Chromosomal abnormalities and single-nucleotide polymorphisms have been shown to be associated with fibrotic diatheses. Tunical mechanical stress and microvascular trauma are major contributory factors to the pathophysiology of PD. The diagnosis of PD can be made using a combination of clinical history, physical examination and, sometimes, imaging modalities. A better understanding of the molecular pathophysiology of this condition remains paramount for the development of newer and more effective disease-targeted interventions. PMID:27298774

  15. Prenatal Diagnosis of Congenital Lipoid Adrenal Hyperplasia (CLAH) by Molecular Genetic Testing in Korean Siblings

    PubMed Central

    Ko, Hyun Sun; Lee, Seungok; Chae, Hyojin; Choi, Sae Kyung; Kim, Myungshin; Park, In Yang; Suh, Byung Kyu

    2011-01-01

    Congenital lipoid adrenal hyperplasia (CLAH) is caused by mutations to the steroidogenic acute regulatory protein (StAR) gene associated with the inability to synthesize all adrenal and gonadal steroids. Inadequate treatment in an infant with this condition may result in sudden death from an adrenal crisis. We report a case in which CLAH developed in Korean siblings; the second child was prenatally diagnosed because the first child was affected and low maternal serum estriol was detected in a prenatal screening test. To our knowledge, this is the first prenatal diagnosis of the Q258X StAR mutation, which is the only consistent genetic cluster identified to date in Japanese and Korean populations. PMID:22028173

  16. Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis.

    PubMed

    Phipps, Amanda I; Passarelli, Michael N; Chan, Andrew T; Harrison, Tabitha A; Jeon, Jihyoun; Hutter, Carolyn M; Berndt, Sonja I; Brenner, Hermann; Caan, Bette J; Campbell, Peter T; Chang-Claude, Jenny; Chanock, Stephen J; Cheadle, Jeremy P; Curtis, Keith R; Duggan, David; Fisher, David; Fuchs, Charles S; Gala, Manish; Giovannucci, Edward L; Hayes, Richard B; Hoffmeister, Michael; Hsu, Li; Jacobs, Eric J; Jansen, Lina; Kaplan, Richard; Kap, Elisabeth J; Maughan, Timothy S; Potter, John D; Schoen, Robert E; Seminara, Daniela; Slattery, Martha L; West, Hannah; White, Emily; Peters, Ulrike; Newcomb, Polly A

    2016-01-01

    Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5×10(-8) in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6×10(-10) and HR = 1.8, P = 3.7×10(-9) for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest. PMID:26586795

  17. Feature selection using genetic algorithm for breast cancer diagnosis: experiment on three different datasets

    PubMed Central

    Aalaei, Shokoufeh; Shahraki, Hadi; Rowhanimanesh, Alireza; Eslami, Saeid

    2016-01-01

    Objective(s): This study addresses feature selection for breast cancer diagnosis. The present process uses a wrapper approach using GA-based on feature selection and PS-classifier. The results of experiment show that the proposed model is comparable to the other models on Wisconsin breast cancer datasets. Materials and Methods: To evaluate effectiveness of proposed feature selection method, we employed three different classifiers artificial neural network (ANN) and PS-classifier and genetic algorithm based classifier (GA-classifier) on Wisconsin breast cancer datasets include Wisconsin breast cancer dataset (WBC), Wisconsin diagnosis breast cancer (WDBC), and Wisconsin prognosis breast cancer (WPBC). Results: For WBC dataset, it is observed that feature selection improved the accuracy of all classifiers expect of ANN and the best accuracy with feature selection achieved by PS-classifier. For WDBC and WPBC, results show feature selection improved accuracy of all three classifiers and the best accuracy with feature selection achieved by ANN. Also specificity and sensitivity improved after feature selection. Conclusion: The results show that feature selection can improve accuracy, specificity and sensitivity of classifiers. Result of this study is comparable with the other studies on Wisconsin breast cancer datasets. PMID:27403253

  18. Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy

    PubMed Central

    Roma-Rodrigues, Catarina; Fernandes, Alexandra R

    2014-01-01

    Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle that occurs mainly due to mutations (>1,400 variants) in genes encoding for the cardiac sarcomere. HCM, the most common familial form of cardiomyopathy, affecting one in every 500 people in the general population, is typically inherited in an autosomal dominant pattern, and presents variable expressivity and age-related penetrance. Due to the morphological and pathological heterogeneity of the disease, the appearance and progression of symptoms is not straightforward. Most HCM patients are asymptomatic, but up to 25% develop significant symptoms, including chest pain and sudden cardiac death. Sudden cardiac death is a dramatic event, since it occurs without warning and mainly in younger people, including trained athletes. Molecular diagnosis of HCM is of the outmost importance, since it may allow detection of subjects carrying mutations on HCM-associated genes before development of clinical symptoms of HCM. However, due to the genetic heterogeneity of HCM, molecular diagnosis is difficult. Currently, there are mainly four techniques used for molecular diagnosis of HCM, including Sanger sequencing, high resolution melting, mutation detection using DNA arrays, and next-generation sequencing techniques. Application of these methods has proven successful for identification of mutations on HCM-related genes. This review summarizes the features of these technologies, highlighting their strengths and weaknesses. Furthermore, current therapeutics for HCM patients are correlated with clinically observed phenotypes and are based on the alleviation of symptoms. This is mainly due to insufficient knowledge on the mechanisms involved in the onset of HCM. Tissue engineering alongside regenerative medicine coupled with nanotherapeutics may allow fulfillment of those gaps, together with screening of novel therapeutic drugs and target delivery systems. PMID:25328416

  19. Beware! Preimplantation genetic diagnosis may solve some old problems but it also raises new ones.

    PubMed Central

    Draper, H; Chadwick, R

    1999-01-01

    Preimplantation genetic diagnosis (PIGD) goes some way to meeting the clinical, psychological and ethical problems of antenatal testing. We should guard, however, against the assumption that PIGD is the answer to all our problems. It also presents some new problems and leaves some old problems untouched. This paper will provide an overview of how PIGD meets some of the old problems but will concentrate on two new challenges for ethics (and, indeed, law). First we look at whether we should always suppose that it is wrong for a clinician to implant a genetically abnormal zygote. The second concern is particularly important in the UK. The Human Fertilisation and Embryology Act (1990) gives clinicians a statutory obligation to consider the interests of the future children they help to create using in vitro fertilisation (IVF) techniques. Does this mean that because PIGD is based on IVF techniques the balance of power for determining the best interests of the future child shifts from the mother to the clinician? PMID:10226915

  20. Invited commentary: the politics of human embryo research and the motivation to achieve PGD.

    PubMed

    Yovich, John L

    2011-05-01

    The idea that biomedical research can be influenced by political events implies a teleological basis indicating that scientific achievements occur because there is a political need. Such a concept appears to have been the reason PGD was fast-tracked to emerge as a biomedical achievement well before its due date, occurring at a time when human embryology was still struggling to reach a reasonable level of efficiency and become adopted as a clinically relevant advance around the world. One story underlying the historical achievement of the HFE Act 1990, enabling regulated embryo research, steps outside the firm ground of biomedical science and encourages the idea that Reproductive BioMedicine Online should embrace a further section enabling articles dealing with 'History, politics and personalities' where these influence biomedical research. PMID:21393061

  1. Preimplantation genetic diagnosis of chromosome balance in embryos from a patient with a balanced reciprocal translocation.

    PubMed

    Pierce, K E; Fitzgerald, L M; Seibel, M M; Zilberstein, M

    1998-02-01

    Duplications or deletions are present in a high percentage of the gametes produced by individuals carrying balanced translocations. Preimplantation genetic diagnosis was used to examine chromosome balance in embryos from a patient having a reciprocal translocation within the short arms of chromosomes 5 and 8 (46,XX,t(5;8)(p13;p23)). This woman has two sisters with the translocation unbalanced, resulting in a partial trisomy for chromosome 5 and partial monosomy for chromosome 8 (46,XX,-8, +der(8)t(5;8)(p13;p23)) with associated mental retardation and physical abnormalities. The patient and her husband desired to have children without the abnormal chromosome balance and wished to reduce the likelihood of spontaneous abortion or need for therapeutic abortion. Fluorescence in-situ hybridization (FISH) probes for the alpha-satellite region of chromosome 8 and for a region on the short arm of chromosome 5 (5p15.2) were tested initially on lymphocytes from the patient and her sisters. The hybridization signal for chromosome 5 was detected in the expected two copies for the patient and three copies for the sisters in 87% of the cells. Two hybridization signals for chromosome 8 were detected in 96% of the cells from all individuals. Additional probe testing was done using blastomeres from polyspermic embryos. The couple then proceeded with a stimulated in-vitro fertilization (IVF) cycle and biopsies were done on 13 embryos at the 7-10-cell stage using a method of zona drilling and fluid displacement. Diagnosis was possible on at least one blastomere for nine embryos. Three embryos had nuclei with three hybridization signals for chromosome 5, three had fewer than two signals for one or both chromosomes, one was mosaic, and two had two signals for each chromosome. The latter were transferred to the patient, but pregnancy was not achieved. The results demonstrate that preimplantation genetic diagnosis for patients with reciprocal translocations can be used to identify embryos

  2. Assisted procreation and its relationship to genetics and eugenics.

    PubMed

    Ricci, Mariella Lombardi

    2009-01-01

    The article below is intended to reflect on whether or not a eugenic tendency constitutes an intrinsic element of human fertilization in vitro. The author outlines ideas and circumstances which characterized the foundation and propagation of eugenics between the eighteenth and nineteenth centuries. A brief discussion follows on some of the standard procedures of in vitro fertilization, and in particular, those which manifest a trace or hint of eugenics--heterologous fertilization and sperm banking, preimplantation genetic diagnosis (PGD) and embryo selection--practices which, nonetheless, are used on a large scale and shed light on both the essence of procreative medicine and on the current cultural environment. The objective of the article is to explore whether it is possible to eliminate the eugenic connotations without foregoing the benefits of technical and scientific progress.

  3. Prenatal diagnosis as a tool and support for eugenics: myth or reality in contemporary French society?

    PubMed

    Gaille, Marie; Viot, Géraldine

    2013-02-01

    Today, French public debate and bioethics research reflect an ongoing controversy about eugenics. The field of reproductive medicine is often targeted as pre-implantation genetic diagnosis (PGD), prenatal diagnosis, and prenatal detection are accused of drifting towards eugenics or being driven by eugenics considerations. This article aims at understanding why the charge against eugenics came at the forefront of the ethical debate. Above all, it aims at showing that the charge against prenatal diagnosis is groundless. The point of view presented in this article has been elaborated jointly by a geneticist and a philosopher. Besides a survey of the medical, bioethical, philosophical and social sciences literature on the topic, the methodology is founded on a joint analysis of geneticist's various consults. Evidence from office visits demonstrated that prenatal diagnosis leads to case-by-case decisions. As we have suggested, this conclusion does not mean that prenatal diagnosis is devoid of ethical issues, and we have identified at least two. The first is related to the evaluation of a decision to abort. The second line of ethical questions arises from the fact that the claim for "normality" hardly hides normative and ambiguous views about disability. As a conclusion, ethical dilemmas keep being noticeable in the field of reproductive medicine and genetic counselling, but an enquiry about eugenic tendencies probably does not allow us to understand them in the proper way.

  4. Improved access to life insurance after genetic diagnosis of familial hypercholesterolaemia: cross-sectional postal questionnaire study.

    PubMed

    Huijgen, Roeland; Homsma, Sietske J M; Hutten, Barbara A; Kindt, Iris; Vissers, Maud N; Kastelein, John J P; van Rijckevorsel, Jan L A

    2012-07-01

    A decade ago, in the initial stage of genetic testing for familial hypercholesterolaemia (FH) in The Netherlands, it was reported that such screening decreased access to affordable life insurance for mutation carriers. In 2003, in order to improve access to insurance for FH mutation carriers, insurers agreed to underwrite according to a set of guidelines. In this cross-sectional study, we assessed whether access to insurance has improved since the advent of these guidelines. We approached 2825 subjects that had participated in the genetic testing for FH between 1998 and 2003. We compared unconditional acceptance rates before and after FH diagnosis and before and after the guidelines were issued by means of logistic regression analysis. Our study outcome pertains to 414 FH patients who applied for life insurance. Unconditional acceptance of a policy before DNA diagnosis and before the issue of guidelines occurred in 182 out of 255 (71%) cases, versus 27 out of 35 (77%) cases after DNA diagnosis, but before the issue of guidelines. De facto, 107 out of 124 (86%) patients received unconditional acceptance after DNA diagnosis and after the issue of guidelines (P for trend=0.002). Access to life insurance improved for FH patients after molecular diagnosis and it improved even further after the guidelines were issued. Therefore, we argue that limited access to life insurance on the basis of 'DNA discrimination' is no longer a valid argument against genetic cascade testing for FH, at least not in our country.

  5. Low utilization of prenatal and pre-implantation genetic diagnosis in Huntington disease - risk discounting in preventive genetics.

    PubMed

    Schulman, J D; Stern, H J

    2015-09-01

    Huntington disease (HD) is a late-onset, fatal neurodegenerative disorder caused by a (CAG) triplet repeat expansion in the Huntingtin gene that enlarges during male meiosis. In 1996 in this journal, one of us (J. D. S.) presented a methodology to perform pre-implantation genetic diagnosis in families at-risk for HD without revealing the genetic status of the at-risk parent. Despite the introduction of accurate prenatal and pre-implantation genetic testing which can prevent transmission of the abnormal HD gene in the family permanently, utilization of these options is extremely low. In this article, we examine the decision-making process regarding genetic testing in families with HD and discuss the possible reasons for the low uptake among this group.

  6. Comparison between ultrasound and genetic testing for the early diagnosis of polycystic kidney disease in Persian and Exotic Shorthair cats.

    PubMed

    Bonazzi, Mattia; Volta, Antonella; Gnudi, Giacomo; Cozzi, Maria C; Strillacci, Maria G; Polli, Michele; Longeri, Maria; Manfredi, Sabrina; Bertoni, Giorgio

    2009-06-01

    Autosomal-dominant polycystic kidney disease (AD-PKD) is common in Persians and Persians-related breeds. The aims of this study were to evaluate the sensitivity and specificity of early ultrasound examination and to compare ultrasound and genetic testing for early diagnosis. Sixty-three Persians and seven Exotic Shorthairs were considered. All underwent ultrasonographic and genetic testing (polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) assay) between 2.5 and 3.5 months of age (10-14 weeks). With ultrasound, 41.4% showed renal cysts, while 37.1% were PKD positive by genetic testing and DNA sequencing. Six cats with at least one renal cyst were negative by genetic testing, while only one cat negative at ultrasound resulted positive at genetic test. DNA sequencing of three polycystic cats, negative by genetic test, revealed they were heterozygous for the mutation. Agreement was described by Cohen's kappa that resulted 0.85, considering genetic test and DNA sequencing. Sensitivity and specificity of ultrasound were 96.2% and 91%, respectively. Sensitivity was higher and specificity lower than reported previously. The higher sensitivity could be due to improved technical capabilities of ultrasound machines and transducers. Other causes of PKD could explain the lower specificity. In conclusion, ultrasound resulted in a reliable diagnostic method for feline AD-PKD1 at early age and it should always be used with genetic testing, in order to reach a complete screening programme and eventually to identify other genetic mutations. PMID:19046910

  7. Panel of Genetic Variations as a Potential Non-invasive Biomarker for Early Diagnosis of Alzheimer's Disease

    PubMed Central

    Lam, Linda Chiu Wa

    2011-01-01

    Alzheimer's disease (AD) is the most prevalent form of dementia. Biomarkers such as levels of amyloid beta (Aβ) in cerebrospinal fluid and ApoE genotyping were suggested for the diagnosis of AD, however, the result is either non-conclusive or with invasive procedure. Genome-wide association studies (GWASs) for AD suggested single nucleotide polymorphisms (SNPs) in many genes are associated with the risk of AD, but each only contributed with small effect to the disease. By incorporating a panel of established genetic susceptibility factors, the risk of an individual in getting AD could be better estimated. Further research will be required to reveal if adding to the current well-developed clinical diagnosis protocol, the accuracy and specificity of diagnosis of AD would be greatly improved and if this might also be beneficial in identifying pre-symptomatic AD patients for early diagnosis and intervention of the disease. PMID:23429712

  8. Defined morphological criteria allow reliable diagnosis of colorectal serrated polyps and predict polyp genetics.

    PubMed

    Rau, Tilman T; Agaimy, Abbas; Gehoff, Anastasia; Geppert, Carol; Jung, Klaus; Knobloch, Katharina; Langner, Cord; Lugli, Alessandro; Groenbus-Lurkin, Irene; Nagtegaal, Iris D; Rüschoff, Josef; Saegert, Xavier; Sarbia, Mario; Schneider-Stock, Regine; Vieth, Michael; Zwarthoff, Ellen C; Hartmann, Arndt

    2014-06-01

    Criteria for the diagnosis of serrated colorectal lesions (hyperplastic polyp, sessile serrated adenoma without or with dysplasia--which we called mixed polyp--and traditional serrated adenoma) for which consensus has been reached should be validated for applicability in daily practice in terms of inter-observer reproducibility and their association with clinical features and (epi)genetic events. A study set was created from a consecutive series of colorectal polyps (n = 1,926) by selecting all sessile serrated adenomas, traditional serrated adenomas and mixed polyps. We added consecutive series of hyperplastic polyps, classical adenomas and normal mucosa samples for a total of 200 specimens. With this series, we conducted an inter-observer study, encompassing ten pathologists with gastrointestinal pathology experience from five European countries, in three rounds in which all cases were microscopically evaluated. An assessment of single morphological criteria was included, and these were correlated with clinical parameters and the mutation status of KRAS, BRAF and PIK3CA and the methylation status of MLH1. Gender, age and localisation were significantly associated with certain types of lesions. Kappa statistics revealed moderate to good inter-observer agreement for polyp classification (κ = 0.56 to 0.63), but for single criteria, this varied considerably (κ = 0.06 to 0.82). BRAF mutations were frequently found in hyperplastic polyps (86 %, 62/72) and sessile serrated adenomas (80 %, 41/51). KRAS mutations occurred more frequently in traditional serrated adenomas (78 %, 7/9) and less so in classical adenomas (20 %, 10/51). Single morphological criteria for sessile serrated adenomas showed significant correlation with BRAF mutation (all p ≤ 0.001), and those for classical adenomas or traditional serrated adenoma correlated significantly with KRAS mutation (all p < 0.001). Therefore, single well-defined morphological criteria are predictive for

  9. Identification of defensin-encoding genes of Picea glauca: characterization of PgD5, a conserved spruce defensin with strong antifungal activity

    PubMed Central

    2012-01-01

    Background Plant defensins represent a major innate immune protein superfamily that displays strong inhibitory effects on filamentous fungi. The total number of plant defensins in a conifer species is unknown since there are no sequenced conifer genomes published, however the genomes of several angiosperm species provide an insight on the diversity of plant defensins. Here we report the identification of five new defensin-encoding genes from the Picea glauca genome and the characterization of two of their gene products, named PgD5 and endopiceasin. Results Screening of a P. glauca EST database with sequences of known plant defensins identified four genes with homology to the known P. glauca defensin PgD1, which were designated PgD2-5. Whereas in the mature PgD2-4 only 7–9 amino acids differed from PgD1, PgD5 had only 64% sequence identity. PgD5 was amplified from P. glauca genomic DNA by PCR. It codes for a precursor of 77-amino acid that is fully conserved within the Picea genus and has similarity to plant defensins. Recombinant PgD5, produced in Escherichia coli, had a molecular mass of 5.721 kDa, as determined by mass spectrometry. The PgD5 peptide exhibited strong antifungal activity against several phytopathogens without any effect on the morphology of the treated fungal hyphae, but strongly inhibited hyphal elongation. A SYTOX uptake assay suggested that the inhibitory activity of PgD5 could be associated with altering the permeability of the fungal membranes. Another completely unrelated defensin gene was identified in the EST library and named endopiceasin. Its gene codes for a 6-cysteine peptide that shares high similarity with the fungal defensin plectasin. Conclusions Screening of a P. glauca EST database resulted in the identification of five new defensin-encoding genes. PgD5 codes for a plant defensin that displays non-morphogenic antifungal activity against the phytopathogens tested, probably by altering membrane permeability. PgD5 has potential for

  10. DIAGNOSIS-GUIDED METHOD FOR IDENTIFYING MULTI-MODALITY NEUROIMAGING BIOMARKERS ASSOCIATED WITH GENETIC RISK FACTORS IN ALZHEIMER'S DISEASE.

    PubMed

    Hao, Xiaoke; Yan, Jingwen; Yao, Xiaohui; Risacher, Shannon L; Saykin, Andrew J; Zhang, Daoqiang; Shen, Li

    2016-01-01

    Many recent imaging genetic studies focus on detecting the associations between genetic markers such as single nucleotide polymorphisms (SNPs) and quantitative traits (QTs). Although there exist a large number of generalized multivariate regression analysis methods, few of them have used diagnosis information in subjects to enhance the analysis performance. In addition, few of models have investigated the identification of multi-modality phenotypic patterns associated with interesting genotype groups in traditional methods. To reveal disease-relevant imaging genetic associations, we propose a novel diagnosis-guided multi-modality (DGMM) framework to discover multi-modality imaging QTs that are associated with both Alzheimer's disease (AD) and its top genetic risk factor (i.e., APOE SNP rs429358). The strength of our proposed method is that it explicitly models the priori diagnosis information among subjects in the objective function for selecting the disease-relevant and robust multi-modality QTs associated with the SNP. We evaluate our method on two modalities of imaging phenotypes, i.e., those extracted from structural magnetic resonance imaging (MRI) data and fluorodeoxyglucose positron emission tomography (FDG-PET) data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The experimental results demonstrate that our proposed method not only achieves better performances under the metrics of root mean squared error and correlation coefficient but also can identify common informative regions of interests (ROIs) across multiple modalities to guide the disease-induced biological interpretation, compared with other reference methods.

  11. Multi-Stage Feature Selection by Using Genetic Algorithms for Fault Diagnosis in Gearboxes Based on Vibration Signal.

    PubMed

    Cerrada, Mariela; Vinicio Sánchez, René; Cabrera, Diego; Zurita, Grover; Li, Chuan

    2015-01-01

    There are growing demands for condition-based monitoring of gearboxes, and techniques to improve the reliability, effectiveness and accuracy for fault diagnosis are considered valuable contributions. Feature selection is still an important aspect in machine learning-based diagnosis in order to reach good performance in the diagnosis system. The main aim of this research is to propose a multi-stage feature selection mechanism for selecting the best set of condition parameters on the time, frequency and time-frequency domains, which are extracted from vibration signals for fault diagnosis purposes in gearboxes. The selection is based on genetic algorithms, proposing in each stage a new subset of the best features regarding the classifier performance in a supervised environment. The selected features are augmented at each stage and used as input for a neural network classifier in the next step, while a new subset of feature candidates is treated by the selection process. As a result, the inherent exploration and exploitation of the genetic algorithms for finding the best solutions of the selection problem are locally focused. The Sensors 2015, 15 23904 approach is tested on a dataset from a real test bed with several fault classes under different running conditions of load and velocity. The model performance for diagnosis is over 98%. PMID:26393603

  12. Multi-Stage Feature Selection by Using Genetic Algorithms for Fault Diagnosis in Gearboxes Based on Vibration Signal.

    PubMed

    Cerrada, Mariela; Vinicio Sánchez, René; Cabrera, Diego; Zurita, Grover; Li, Chuan

    2015-09-18

    There are growing demands for condition-based monitoring of gearboxes, and techniques to improve the reliability, effectiveness and accuracy for fault diagnosis are considered valuable contributions. Feature selection is still an important aspect in machine learning-based diagnosis in order to reach good performance in the diagnosis system. The main aim of this research is to propose a multi-stage feature selection mechanism for selecting the best set of condition parameters on the time, frequency and time-frequency domains, which are extracted from vibration signals for fault diagnosis purposes in gearboxes. The selection is based on genetic algorithms, proposing in each stage a new subset of the best features regarding the classifier performance in a supervised environment. The selected features are augmented at each stage and used as input for a neural network classifier in the next step, while a new subset of feature candidates is treated by the selection process. As a result, the inherent exploration and exploitation of the genetic algorithms for finding the best solutions of the selection problem are locally focused. The Sensors 2015, 15 23904 approach is tested on a dataset from a real test bed with several fault classes under different running conditions of load and velocity. The model performance for diagnosis is over 98%.

  13. Multi-Stage Feature Selection by Using Genetic Algorithms for Fault Diagnosis in Gearboxes Based on Vibration Signal

    PubMed Central

    Cerrada, Mariela; Sánchez, René Vinicio; Cabrera, Diego; Zurita, Grover; Li, Chuan

    2015-01-01

    There are growing demands for condition-based monitoring of gearboxes, and techniques to improve the reliability, effectiveness and accuracy for fault diagnosis are considered valuable contributions. Feature selection is still an important aspect in machine learning-based diagnosis in order to reach good performance in the diagnosis system. The main aim of this research is to propose a multi-stage feature selection mechanism for selecting the best set of condition parameters on the time, frequency and time-frequency domains, which are extracted from vibration signals for fault diagnosis purposes in gearboxes. The selection is based on genetic algorithms, proposing in each stage a new subset of the best features regarding the classifier performance in a supervised environment. The selected features are augmented at each stage and used as input for a neural network classifier in the next step, while a new subset of feature candidates is treated by the selection process. As a result, the inherent exploration and exploitation of the genetic algorithms for finding the best solutions of the selection problem are locally focused. The approach is tested on a dataset from a real test bed with several fault classes under different running conditions of load and velocity. The model performance for diagnosis is over 98%. PMID:26393603

  14. Contribution of muscle biopsy and genetics to the diagnosis of chronic progressive external opthalmoplegia of mitochondrial origin.

    PubMed

    Sundaram, Challa; Meena, A K; Uppin, Megha S; Govindaraj, P; Vanniarajan, A; Thangaraj, K; Kaul, Subhash; Kekunnaya, Ramesh; Murthy, J M K

    2011-04-01

    Chronic progressive external opthalmoplegia (CPEO) is the most common phenotypic syndrome of the mitochondrial myopathies. Muscle biopsy, which provides important morphological clues for the diagnosis of mitochondrial disorders, is normal in approximately 25% of patients with CPEO, thus necessitating molecular genetic analysis for more accurate diagnosis. We aimed to study the utility of various histochemical stains in the diagnosis of CPEO on muscle biopsy and to correlate these results with genetic studies. Between May 2005 and November 2007 all 45 patients diagnosed with CPEO were included in the study (23 males; mean age at presentation, 35 years). Thirty-nine patients had CPEO only and six had CPEO plus; two had a positive family history but the remaining 39 patients had sporadic CPEO. Muscle biopsy samples were stained with hematoxylin and eosin, modified Gomori's trichrome stain, succinic dehydrogenase (SDH), cytochrome C oxidase (COX) and combined COX-SDH. Ragged red fibers were seen in 27 biopsies; seven showed characteristics of neurogenic atrophy only, and 11 were normal. The abnormal fibers were best identified on COX-SDH stain. A complete mitochondrial genome was amplified in muscle and blood samples of all patients. Mutations were found in transfer RNA, ribosomal RNA, ND, CYTB, COX I, II and III genes. Mitochondrial gene mutations were found in ten of the 11 patients with a normal muscle biopsy. The genetic mutations were classified according to their significance. The observed muscle biopsy findings were correlated with genetic mutations noted. Histological studies should be combined with genetic studies for the definitive diagnosis of CPEO syndrome.

  15. "I do not want my baby to suffer as I did"; prenatal and preimplantation genetic diagnosis for BRCA1/2 mutations: a case report and genetic counseling considerations.

    PubMed

    Dagan, Efrat; Gershoni-Baruch, Ruth; Kurolap, Alina; Goldberg, Yael; Fried, Georgeta

    2014-07-01

    This article presents the complexity of prenatal genetic diagnosis and preimplantation genetic diagnosis for hereditary breast-ovarian cancer syndrome. These issues are discussed using a case report to highlight the genetic counseling process, together with decision-making considerations, in light of the clinical, psychological, and ethical perspectives, of both the mutation carriers and health professionals; and the health policy regarding these procedures in Israel compared to several European countries.

  16. X-linked glucose-6-phosphate dehydrogenase (G6PD) and autosomal 6-phosphogluconate dehydrogenase (6PGD) polymorphisms in baboons

    SciTech Connect

    VandeBerg, J.L.; Aivaliotis, M.J.; Samollow, P.B. )

    1992-12-01

    Electrophoretic polymorphisms of glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) were examined in captive colonies of five subspecies of baboons (Papio hamadryas). Phenotype frequencies and family data verified the X-linked inheritance of the G6PD polymorphism. Insufficient family data were available to confirm autosomal inheritance of the 6PGD polymorphism, but the electrophoretic patterns of variant types (putative heterozygotes) suggested the codominant expression of alleles at an autosomal locus. Implications of the G6PD polymorphism are discussed with regard to its utility as a marker system for research on X-chromosome inactivation during baboon development and for studies of clonal cell proliferation and/or cell selection during the development of atherosclerotic lesions in the baboon model. 61 refs., 1 fig., 4 tabs.

  17. PKA regulatory IIα subunit is essential for PGD2-mediated resolution of inflammation.

    PubMed

    Kong, Deping; Shen, Yujun; Liu, Guizhu; Zuo, Shengkai; Ji, Yong; Lu, Ankang; Nakamura, Masataka; Lazarus, Michael; Stratakis, Constantine A; Breyer, Richard M; Yu, Ying

    2016-09-19

    The kinetic participation of macrophages is critical for inflammatory resolution and recovery from myocardial infarction (MI), particularly with respect to the transition from the M1 to the M2 phenotype; however, the underlying mechanisms are poorly understood. In this study, we found that the deletion of prostaglandin (PG) D2 receptor subtype 1 (DP1) in macrophages retarded M2 polarization, antiinflammatory cytokine production, and resolution in different inflammatory models, including the MI model. DP1 deletion up-regulated proinflammatory genes expression via JAK2/STAT1 signaling in macrophages, whereas its activation facilitated binding of the separated PKA regulatory IIα subunit (PRKAR2A) to the transmembrane domain of IFN-γ receptor, suppressed JAK2-STAT1 axis-mediated M1 polarization, and promoted resolution. PRKAR2A deficiency attenuated DP1 activation-mediated M2 polarization and resolution of inflammation. Collectively, PGD2-DP1 axis-induced M2 polarization facilitates resolution of inflammation through the PRKAR2A-mediated suppression of JAK2/STAT1 signaling. These observations indicate that macrophage DP1 activation represents a promising strategy in the management of inflammation-associated diseases, including post-MI healing. PMID:27621415

  18. KRT9 gene mutation as a reliable indicator in the prenatal molecular diagnosis of epidermolytic palmoplantar keratoderma.

    PubMed

    Ke, Hai-Ping; Jiang, Hu-Ling; Lv, Ya-Su; Huang, Yi-Zhou; Liu, Rong-Rong; Chen, Xiao-Ling; Du, Zhen-Fang; Luo, Yu-Qin; Xu, Chen-Ming; Fan, Qi-Hui; Zhang, Xian-Ning

    2014-08-01

    Epidermolytic palmoplantar keratoderma (EPPK) is the most frequent form of such keratodermas. It is inherited in an autosomal dominant pattern and is clinically characterized by diffuse yellowish thickening of the skin on the palms and soles with erythematous borders during the first weeks or months after birth. EPPK is generally caused by mutations of the KRT9 gene. More than 26 KRT9 gene mutations responsible for EPPK have been described (Human Intermediate Filament Database, www.interfil.org), and many of these variants are located within the highly-conserved coil 1A region of the α-helical rod domain of keratin 9. Unfortunately, there is no satisfactory treatment for EPPK. Thus, prenatal molecular diagnosis or pre-pregnancy diagnosis is crucial and benefits those affected who seek healthy descendants. In the present study, we performed amniotic fluid-DNA-based prenatal testing for three at-risk pregnant EPPK women from three unrelated southern Chinese families who carried the KRT9 missense mutations p.Arg163Trp and p.Arg163Gln, and successfully helped two families to bear normal daughters. We suggest that before the successful application of preimplantation genetic diagnosis (PGD), and noninvasive prenatal diagnosis of EPPK that analyzes fetal cells or cell-free DNA in maternal blood, prenatal genetic diagnosis by amniocentesis or chorionic villus sampling (CVS) offers a quite acceptable option for EPPK couples-at-risk to avoid the birth of affected offspring, especially in low- and middle-income countries.

  19. Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyDelta12 14 PGJ2.

    PubMed

    Rajakariar, Ravindra; Hilliard, Mark; Lawrence, Toby; Trivedi, Seema; Colville-Nash, Paul; Bellingan, Geoff; Fitzgerald, Desmond; Yaqoob, Muhammad M; Gilroy, Derek W

    2007-12-26

    Hematopoietic prostaglandin D(2) synthase (hPGD(2)S) metabolizes cyclooxygenase (COX)-derived PGH(2) to PGD(2) and 15-deoxyDelta(12-14) PGJ(2) (15d-PGJ(2)). Unlike COX, the role of hPGD(2)S in host defense is ambiguous. PGD(2) can be either pro- or antiinflammatory depending on disease etiology, whereas the existence of 15d-PGJ(2) and its relevance to pathophysiology remain controversial. Herein, studies on hPGD(2)S KO mice reveal that 15d-PGJ(2) is synthesized in a self-resolving peritonitis, detected by using liquid chromatography-tandem MS. Together with PGD(2) working on its DP1 receptor, 15d-PGJ(2) controls the balance of pro- vs. antiinflammatory cytokines that regulate leukocyte influx and monocyte-derived macrophage efflux from the inflamed peritoneal cavity to draining lymph nodes leading to resolution. Specifically, inflammation in hPGD(2)S KOs is more severe during the onset phase arising from a substantial cytokine imbalance resulting in enhanced polymorphonuclear leukocyte and monocyte trafficking. Moreover, resolution is impaired, characterized by macrophage and surprisingly lymphocyte accumulation. Data from this work place hPGD(2)S at the center of controlling the onset and the resolution of acute inflammation where it acts as a crucial checkpoint controller of cytokine/chemokine synthesis as well as leukocyte influx and efflux. Here, we provide definitive proof that 15d-PGJ(2) is synthesized during mammalian inflammatory responses, and we highlight DP1 receptor activation as a potential antiinflammatory strategy. PMID:18077391

  20. [Clinical symptoms, diagnosis and treatment of multiple endocrine neoplasia type 1. Results of genetic screening in Hungarian patients].

    PubMed

    Balogh, Katalin; Hunyady, László; Patócs, Attila; Valkusz, Zsuzsanna; Bertalan, Rita; Gergics, Péter; Majnik, Judit; Toke, Judit; Tóth, Miklós; Szucs, Nikolette; Gláz, Edit; Futo, László; Horányi, János; Rácz, Károly; Tulassay, Zsolt

    2005-10-23

    Multiple endocrine neoplasia type 1 syndrome is an autosomal dominant disorder characterized by endocrinopathies involving the parathyroid glands, anterior pituitary gland, and pancreas. Also, it may be associated with foregut carcinoid, adrenocortical tumors and non-endocrine tumors. After reviewing the prevalence, genetic background, clinical symptoms, diagnosis and treatment of the disorder, the authors present their genetic screening method used for the detection of mutations of the MEN1 gene (prescreening of polymerase chain reaction amplified exons using temporal temperature gradient gel electrophoresis followed by direct DNA sequencing). Using this method, the authors identified disease-causing MEN1 gene mutations in 9 probands (small deletions in 2 cases, insertion in 2 cases, nonsense mutations in 2 cases and missense mutations in 3 cases). Of the 9 mutations, 4 proved to be novel mutation not reported in the literature. Family screening indicated de novo mutations in 2 probands. In addition to mutations, several sequence polymorphisms were also detected. The authors conclude that one of the major advantages of genetic screening in families with MEN1 syndrome was the identification of family members carrying the mutation who should be regularly screened for disease manifestations and those not carrying the mutation in whom clinical screening is unnecessary. Also, genetic screening may be useful in cases when MEN1 syndrome is suspected, but the clinical manifestations do not fully establish the diagnosis of MEN1 syndrome. PMID:16323565

  1. Applicability of genetic polymorphism analysis for the diagnosis of Angelman syndrome and the correlation between language difficulties and disease phenotype.

    PubMed

    Wang, K; Li, Y T; Hou, M

    2016-01-01

    Angelman syndrome (AS) is a neurogenetic disorder caused by a defect in the expression of the maternally inherited ubiquitin protein ligase E3A (UBE3A) gene in chromosome 15. The most common genetic defects include maternal deletions in chromosome 15q11-13; however, paternal uniparental disomy and imprinting defects allow for the identification of mutations in UBE3A in 10% of patients with AS. The aim of this study was to validate the clinical features and genetic polymorphisms of AS, and to discuss the relationship between functional language lateralization and the arcuate fasciculus in the Broca's and Wernicke's areas. Six children with AS (mean age = 32.57 months) presenting characteristic behavioral patterns of AS (frequent laughter and happy demeanor, hand flapping, and hypermotor behavior) were recruited to this study. The patients underwent a clinical evaluation (clinical history, dysmorphological and neurological examinations, and psychological evaluations) and paraclinical investigations [genetic tests (fluorescence in situ hybridization and methylation polymerase chain reaction), electroencephalogram, and magnetic resonance imaging]. We conclude that AS diagnosis cannot rely solely on genetic testing for polymorphisms in UBE3A and must consider its clinical characteristics. Moreover, functional language lateralization and the arcuate fasciculus in the Broca's and Wernicke's areas were found to be closely correlated. Therefore, UBE3A gene mutation analysis combined with comprehensive clinical evaluations may be suitable for the diagnosis of AS. PMID:27323188

  2. Protein and genetic diagnosis of limb girdle muscular dystrophy type 2A: The yield and the pitfalls.

    PubMed

    Fanin, Marina; Angelini, Corrado

    2015-08-01

    Limb girdle muscular dystrophy type 2A (LGMD2A) is the most frequent form of LGMD worldwide. Comprehensive clinical assessment and laboratory testing is essential for diagnosis of LGMD2A. Muscle immunoblot analysis of calpain-3 is the most useful tool to direct genetic testing, as detection of calpain-3 deficiency has high diagnostic value. However, calpain-3 immunoblot testing lacks sensitivity in about 30% of cases due to gene mutations that inactivate the enzyme. The best diagnostic strategy should be determined on a case-by-case basis, depending on which tissues are available, and which molecular and/or genetic methods are adopted. In this work we survey the current knowledge, advantages, limitations, and pitfalls of protein testing and mutation detection in LGMD2A and provide an update of genetic epidemiology.

  3. Genetic Testing in the Diagnosis of Primary Ciliary Dyskinesia: State-of-the-Art and Future Perspectives

    PubMed Central

    Collins, Samuel A.; Walker, Woolf T.; Lucas, Jane S.

    2014-01-01

    Primary ciliary dyskinesia (PCD) is a heterogeneous autosomal recessive condition affecting around 1:15,000. In people with PCD, microscopic motile cilia do not move normally resulting in impaired clearance of mucus and debris leading to repeated sinopulmonary infection. If diagnosis is delayed, permanent bronchiectasis and deterioration of lung function occurs. Other complications associated with PCD include congenital heart disease, hearing impairment and infertility. A small number of longitudinal studies suggest that lung function deteriorates before diagnosis of PCD but may stabilise following diagnosis with subsequent specialist management. Early diagnosis is therefore essential, but for a number of reasons referral for diagnostic testing is often delayed until older childhood or even adulthood. Functional diagnostic tests for PCD are expensive, time consuming and require specialist equipment and scientists. In the last few years, there have been considerable developments to identify genes associated with PCD, currently enabling 65% of patients to be identified by bi-allelic mutations. The rapid identification of new genes continues. This review will consider the evidence that early diagnosis of PCD is beneficial. It will review the recent advances in identification of PCD-associated genes and will discuss the role of genetic testing in PCD. It will then consider whether screening for PCD antenatally or in the new born is likely to become a feasible and acceptable for this rare disease. PMID:26237387

  4. Pre-implantation diagnosis of aneuploidy by polar body and blastomere FISH analysis

    SciTech Connect

    Munne, S.; Cohen, J.; Grifo, J.

    1994-09-01

    For preimplantation genetic diagnosis (PGD) of aneuploidy in human in-vitro fertilization (IVF), two blastomeres per embryo should be analyzed to minimize errors caused by FISH and mosaicism. But the biopsy of two cells from an 8-cell embryo can be detrimental. This can be substituted by initial FISH analysis of the first polar body (PB) and subsequent single blastomere analysis. Simultaneous FISH analysis of chromosomes X, Y, 18, 13/21 was used for first polar body aneuploidy analysis. Normal divalents appeared as single-dotted signals corresponding to their two chromatids. We found that pre-division of chromatids increased dramatically with time in culture. All but three pre-division events involved separation of chromatids within the PB or the egg, with a total of two chromatids in each. We concluded that PB aneuploidy analysis is safe when performed within 6 hours after egg retrieval. For our first clinical case we chose a 39 year-old female carrier of an X-linked disease already selected for FISH pre-implantation diagnosis. Eight polar bodies from 12 eggs were analyzed: six showed a normal X181321 complement of divalents; one had an extra chromatid for 13/21 (egg {number_sign}8); and one had a missing chromatid for 13/21 (egg {number_sign}10). After insemination, six fertilized eggs developed into embryos, including egg {number_sign}10 but not egg {number_sign}8. At day 3 of development, a single blastomere per embryo was analyzed by FISH. According to the blastomere analysis, one embryo was haploid, one tetraploid. The two normal female embryos were replaced and pregnancy and CFS results are pending. These results suggest that this technique can be successfully applied for PGD of major aneuploidies in IVF patients over 35. In addition, it indicates that studies on pre-division should be performed on eggs within six hours of retrieval.

  5. Genetic Testing Confirmed the Early Diagnosis of X-Linked Hypophosphatemic Rickets in a 7-Month-Old Infant

    PubMed Central

    Poon, Kok Siong; Sng, Andrew Anjian; Ho, Cindy Weili; Koay, Evelyn Siew-Chuan

    2015-01-01

    Loss-of-function mutations in the phosphate regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) have been causally associated with X-linked hypophosphatemic rickets (XLHR). The early diagnosis of XLHR in infants is challenging when it is based solely on clinical features and biochemical findings. We report a 7-month-old boy with a family history of hypophosphatemic rickets., who demonstrated early clinical evidence of rickets, although serial biochemical findings could not definitively confirm rickets. A sequencing assay targeting the PHEX gene was first performed on the mother’s DNA to screen for mutations in the 5′UTR, 22 coding exons, and the exon-intron junctions. Targeted mutation analysis and mRNA studies were subsequently performed on the boys’ DNA to investigate the pathogenicity of the identified mutation. Genetic screening of the PHEX gene revealed a novel mutation, c.1080-2A>C, at the splice acceptor site in intron 9. The detection of an aberrant mRNA transcript with skipped (loss of) exon 10 establishes its pathogenicity and confirms the diagnosis of XLHR in this infant. Genetic testing of the PHEX gene resulted in early diagnosis of XLHR, thus enabling initiation of therapy and prevention of progressive rachitic changes in the infant. PMID:26904698

  6. American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss.

    PubMed

    Alford, Raye L; Arnos, Kathleen S; Fox, Michelle; Lin, Jerry W; Palmer, Christina G; Pandya, Arti; Rehm, Heidi L; Robin, Nathaniel H; Scott, Daryl A; Yoshinaga-Itano, Christine

    2014-04-01

    Hearing loss is a common and complex condition that can occur at any age, can be inherited or acquired, and is associated with a remarkably wide array of etiologies. The diverse causes of hearing loss, combined with the highly variable and often overlapping presentations of different forms of hearing loss, challenge the ability of traditional clinical evaluations to arrive at an etiologic diagnosis for many deaf and hard-of-hearing individuals. However, identifying the etiology of a hearing loss may affect clinical management, improve prognostic accuracy, and refine genetic counseling and assessment of the likelihood of recurrence for relatives of deaf and hard-of-hearing individuals. Linguistic and cultural identities associated with being deaf or hard of hearing can complicate access to and the effectiveness of clinical care. These concerns can be minimized when genetic and other health-care services are provided in a linguistically and culturally sensitive manner. This guideline offers information about the frequency, causes, and presentations of hearing loss and suggests approaches to the clinical evaluation of deaf and hard-of-hearing individuals aimed at identifying an etiologic diagnosis and providing informative and effective patient education and genetic counseling.

  7. [THE GENETIC EXAMINATION OF BRONCHIAL LAVAGE ENABLES THE PROMPT DIAGNOSIS OF PULMONARY MYCOBACTERIUM KANSASII--A CASE REPORT].

    PubMed

    Mori, Masahide; Ageshio, Fumitaka; Kagawa, Hiroyuki; Oshitani, Yohei; Fujikawa, Takeya; Saito, Haruko; Sako, Hajime; Yano, Yukihiro; Kitada, Seigo; Maekura, Ryoji

    2015-08-01

    A 59-year-old man with chronic obstructive pulmonary disease and bronchial asthma presented at our hospital with an abnormal shadow on the chest radiograph, which was obtained as part of a routine medical examination. Computed tomography of the chest revealed two nodules in the right upper lung with the longest diameter measuring 29 mm and 10 mm, respectively. A granulomatous disease was strongly suspected based on the histological features of the transbronchial lung biopsy specimen. Results of smear examination for mycobacteria and genetic examination of the bronchial lavage aspirate by the transcription reverse transcription concerted (TRC) reaction method for Mycobacterium tuberculosis and M. avium complex (MAC), were both negative. However, three days after the bronchoscopic examination, an additional genetic examination by the TRC method confirmed the diagnosis of M. kansasii infection. About two weeks later, the culture results were positive and M. kansasii infection was re-confirmed with the DNA probe method. The patient responded well to treatment with a combination of isoniazid, rifampicin, and ethambutol. In Japan, among the nontuberculous mycobacterial infections, the prevalence of pulmonary M.kansasii disease is second only to infection with MAC. However, it is often difficult to distinguish this disease from pulmonary tuberculosis. In this patient, a genetic examination with the TRC method enabled a prompt diagnosis of M. kansasii infection. The TRC method appears to be a useful tool for diagnosing nontubercular mycobacterial infections. PMID:26665518

  8. Long-range mapping in the research and diagnosis of genetic disease.

    PubMed

    van Ommen, G J; Pearson, P L

    1989-01-01

    This paper reviews current genetic and molecular biological methods that may be used in the so-called "reverse genetics" approach. These methods are the mapping, isolation, and study of the chromosomal DNA containing a previously unidentified gene responsible for a genetic disease, beginning with its chromosomal localization. In principle, the reverse genetics methodology follows the same path for different diseases studied. An overall outline of the steps to be undertaken is given and discussed. Several stages are illustrated with reference to current research in the fields of Duchenne muscular dystrophy, Huntington's disease, and polycystic kidney disease.

  9. An automatic scanning method for high throughput microscopic system to facilitate medical genetic diagnosis: an initial study

    NASA Astrophysics Data System (ADS)

    Qiu, Yuchen; Chen, Xiaodong; Li, Zheng; Li, Yuhua; Chen, Wei R.; Zheng, Bin; Li, Shibo; Liu, Hong

    2012-03-01

    The purpose of this paper is to report a new automatic scanning scheme for high throughput microscopic systems aiming to facilitate disease diagnosis in genetic laboratories. To minimize the impact of the random vibration and mechanical drifting of the scanning stage in microscopic image acquisition, auto-focusing operations are usually applied repeatedly during the scanning process. Such methods ensure the acquisition of well focused images for clinical diagnosis, but are time consuming. The technique investigated in this preliminary study applies the auto-focusing operations at a limited number of locations on the slide. For the rest of the imaging field, the focusing position is quickly adjusted through linear interpolation. In this initial validation study, blood pathological slides containing both metaphase and interphase cells are scanned. For a selected area of 6.9mm×6.9mm, a number of 2×2, 3×2, 3×3, and 4×4 positions are evenly sampled for auto-focusing operations. Respectively, 25, 29, 40, and 41 clinically meaningful cells are identified for each sampling scheme. For the specific case investigated, the results demonstrate that the 4 position auto-focusing scheme could obtain the adequate number of clinically meaningful cells for the diagnosis. The schemes with more auto-focusing operations provide an option for high reliability diagnosis when clinically necessary. More comprehensive research is planned, and that may lead to optimal design of trade-off for developing the scanning scheme of the high throughput microscopic systems.

  10. A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement

    PubMed Central

    Prasad, Megana K; Geoffroy, Véronique; Vicaire, Serge; Jost, Bernard; Dumas, Michael; Le Gras, Stéphanie; Switala, Marzena; Gasse, Barbara; Laugel-Haushalter, Virginie; Paschaki, Marie; Leheup, Bruno; Droz, Dominique; Dalstein, Amelie; Loing, Adeline; Grollemund, Bruno; Muller-Bolla, Michèle; Lopez-Cazaux, Séréna; Minoux, Maryline; Jung, Sophie; Obry, Frédéric; Vogt, Vincent; Davideau, Jean-Luc; Davit-Beal, Tiphaine; Kaiser, Anne-Sophie; Moog, Ute; Richard, Béatrice; Morrier, Jean-Jacques; Duprez, Jean-Pierre; Odent, Sylvie; Bailleul-Forestier, Isabelle; Rousset, Monique Marie; Merametdijan, Laure; Toutain, Annick; Joseph, Clara; Giuliano, Fabienne; Dahlet, Jean-Christophe; Courval, Aymeric; El Alloussi, Mustapha; Laouina, Samir; Soskin, Sylvie; Guffon, Nathalie; Dieux, Anne; Doray, Bérénice; Feierabend, Stephanie; Ginglinger, Emmanuelle; Fournier, Benjamin; de la Dure Molla, Muriel; Alembik, Yves; Tardieu, Corinne; Clauss, François; Berdal, Ariane; Stoetzel, Corinne; Manière, Marie Cécile; Dollfus, Hélène; Bloch-Zupan, Agnès

    2016-01-01

    Background Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. Methods We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. Results We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. Conclusions We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. Trial registration numbers NCT01746121 and NCT02397824. PMID:26502894

  11. Genetics of Tinnitus: An Emerging Area for Molecular Diagnosis and Drug Development

    PubMed Central

    Lopez-Escamez, Jose A.; Bibas, Thanos; Cima, Rilana F. F.; Van de Heyning, Paul; Knipper, Marlies; Mazurek, Birgit; Szczepek, Agnieszka J.; Cederroth, Christopher R.

    2016-01-01

    Subjective tinnitus is the perception of sound in the absence of external or bodily-generated sounds. Chronic tinnitus is a highly prevalent condition affecting over 70 million people in Europe. A wide variety of comorbidities, including hearing loss, psychiatric disorders, neurodegenerative disorders, and temporomandibular joint (TMJ) dysfunction, have been suggested to contribute to the onset or progression of tinnitus; however, the precise molecular mechanisms of tinnitus are not well understood and the contribution of genetic and epigenetic factors remains unknown. Human genetic studies could enable the identification of novel molecular therapeutic targets, possibly leading to the development of novel pharmaceutical therapeutics. In this article, we briefly discuss the available evidence for a role of genetics in tinnitus and consider potential hurdles in designing genetic studies for tinnitus. Since multiple diseases have tinnitus as a symptom and the supporting genetic evidence is sparse, we propose various strategies to investigate the genetic underpinnings of tinnitus, first by showing evidence of heritability using concordance studies in twins, and second by improving patient selection according to phenotype and/or etiology in order to control potential biases and optimize genetic data output. The increased knowledge resulting from this endeavor could ultimately improve the drug development process and lead to the preventive or curative treatment of tinnitus. PMID:27594824

  12. Genetics of Tinnitus: An Emerging Area for Molecular Diagnosis and Drug Development

    PubMed Central

    Lopez-Escamez, Jose A.; Bibas, Thanos; Cima, Rilana F. F.; Van de Heyning, Paul; Knipper, Marlies; Mazurek, Birgit; Szczepek, Agnieszka J.; Cederroth, Christopher R.

    2016-01-01

    Subjective tinnitus is the perception of sound in the absence of external or bodily-generated sounds. Chronic tinnitus is a highly prevalent condition affecting over 70 million people in Europe. A wide variety of comorbidities, including hearing loss, psychiatric disorders, neurodegenerative disorders, and temporomandibular joint (TMJ) dysfunction, have been suggested to contribute to the onset or progression of tinnitus; however, the precise molecular mechanisms of tinnitus are not well understood and the contribution of genetic and epigenetic factors remains unknown. Human genetic studies could enable the identification of novel molecular therapeutic targets, possibly leading to the development of novel pharmaceutical therapeutics. In this article, we briefly discuss the available evidence for a role of genetics in tinnitus and consider potential hurdles in designing genetic studies for tinnitus. Since multiple diseases have tinnitus as a symptom and the supporting genetic evidence is sparse, we propose various strategies to investigate the genetic underpinnings of tinnitus, first by showing evidence of heritability using concordance studies in twins, and second by improving patient selection according to phenotype and/or etiology in order to control potential biases and optimize genetic data output. The increased knowledge resulting from this endeavor could ultimately improve the drug development process and lead to the preventive or curative treatment of tinnitus.

  13. Genetics of Tinnitus: An Emerging Area for Molecular Diagnosis and Drug Development.

    PubMed

    Lopez-Escamez, Jose A; Bibas, Thanos; Cima, Rilana F F; Van de Heyning, Paul; Knipper, Marlies; Mazurek, Birgit; Szczepek, Agnieszka J; Cederroth, Christopher R

    2016-01-01

    Subjective tinnitus is the perception of sound in the absence of external or bodily-generated sounds. Chronic tinnitus is a highly prevalent condition affecting over 70 million people in Europe. A wide variety of comorbidities, including hearing loss, psychiatric disorders, neurodegenerative disorders, and temporomandibular joint (TMJ) dysfunction, have been suggested to contribute to the onset or progression of tinnitus; however, the precise molecular mechanisms of tinnitus are not well understood and the contribution of genetic and epigenetic factors remains unknown. Human genetic studies could enable the identification of novel molecular therapeutic targets, possibly leading to the development of novel pharmaceutical therapeutics. In this article, we briefly discuss the available evidence for a role of genetics in tinnitus and consider potential hurdles in designing genetic studies for tinnitus. Since multiple diseases have tinnitus as a symptom and the supporting genetic evidence is sparse, we propose various strategies to investigate the genetic underpinnings of tinnitus, first by showing evidence of heritability using concordance studies in twins, and second by improving patient selection according to phenotype and/or etiology in order to control potential biases and optimize genetic data output. The increased knowledge resulting from this endeavor could ultimately improve the drug development process and lead to the preventive or curative treatment of tinnitus. PMID:27594824

  14. Nanoparticles for brain-specific drug and genetic material delivery, imaging and diagnosis.

    PubMed

    Posadas, Inmaculada; Monteagudo, Silvia; Ceña, Valentín

    2016-04-01

    The poor access of therapeutic drugs and genetic material into the central nervous system due to the presence of the blood-brain barrier often limits the development of effective noninvasive treatments and diagnoses of neurological disorders. Moreover, the delivery of genetic material into neuronal cells remains a challenge because of the intrinsic difficulty in transfecting this cell type. Nanotechnology has arisen as a promising tool to provide solutions for this problem. This review will cover the different approaches that have been developed to deliver drugs and genetic material efficiently to the central nervous system as well as the main nanomaterials used to image the central nervous system and diagnose its disorders.

  15. Advanced Genetic Testing Comes to the Pain Clinic to Make a Diagnosis of Paroxysmal Extreme Pain Disorder

    PubMed Central

    Cannon, Ashley; Guthrie, Kimberly J.

    2016-01-01

    Objective. To describe the use of an advanced genetic testing technique, whole exome sequencing, to diagnose a patient and their family with a SCN9A channelopathy. Setting. Academic tertiary care center. Design. Case report. Case Report. A 61-year-old female with a history of acute facial pain, chronic pain, fibromyalgia, and constipation was found to have a gain of function SCN9A mutation by whole exome sequencing. This mutation resulted in an SCN9A channelopathy that is most consistent with a diagnosis of paroxysmal extreme pain disorder. In addition to the patient being diagnosed, four siblings have a clinical diagnosis of SCN9A channelopathy as they have consistent symptoms and a sister with a known mutation. For treatment, gabapentin was ineffective and carbamazepine was not tolerated. Nontraditional therapies improved symptoms and constipation resolved with pelvic floor retraining with biofeedback. Conclusion. Patients with a personal and family history of chronic pain may benefit from a referral to Medical Genetics. Pelvic floor retraining with biofeedback should be considered for patients with a SCN9A channelopathy and constipation. PMID:27525141

  16. Genetic diagnosis of Duchenne/Becker muscular dystrophy using next-generation sequencing: validation analysis of DMD mutations

    PubMed Central

    Okubo, Mariko; Minami, Narihiro; Goto, Kanako; Goto, Yuichi; Noguchi, Satoru; Mitsuhashi, Satomi; Nishino, Ichizo

    2016-01-01

    Duchenne and Becker muscular dystrophies (DMD/BMD) are the most common inherited neuromuscular disease. The genetic diagnosis is not easily made because of the large size of the dystrophin gene, complex mutational spectrum and high number of tests patients undergo for diagnosis. Multiplex ligation-dependent probe amplification (MLPA) has been used as the initial diagnostic test of choice. Although MLPA can diagnose 70% of DMD/BMD patients having deletions/duplications, the remaining 30% of patients with small mutations require further analysis, such as Sanger sequencing. We applied a high-throughput method using Ion Torrent next-generation sequencing technology and diagnosed 92% of patients with DMD/BMD in a single analysis. We designed a multiplex primer pool for DMD and sequenced 67 cases having different mutations: 37 with deletions/duplications and 30 with small mutations or short insertions/deletions in DMD, using an Ion PGM sequencer. The results were compared with those from MLPA or Sanger sequencing. All deletions were detected. In contrast, 50% of duplications were correctly identified compared with the MLPA method. Small insertions in consecutive bases could not be detected. We estimated that Ion Torrent sequencing could diagnose ~92% of DMD/BMD patients according to the mutational spectrum of our cohort. Our results clearly indicate that this method is suitable for routine clinical practice providing novel insights into comprehensive genetic information for future molecular therapy. PMID:26911353

  17. Discriminatory power of common genetic variants in personalized breast cancer diagnosis

    NASA Astrophysics Data System (ADS)

    Wu, Yirong; Abbey, Craig K.; Liu, Jie; Ong, Irene; Peissig, Peggy; Onitilo, Adedayo A.; Fan, Jun; Yuan, Ming; Burnside, Elizabeth S.

    2016-03-01

    Technology advances in genome-wide association studies (GWAS) has engendered optimism that we have entered a new age of precision medicine, in which the risk of breast cancer can be predicted on the basis of a person's genetic variants. The goal of this study is to evaluate the discriminatory power of common genetic variants in breast cancer risk estimation. We conducted a retrospective case-control study drawing from an existing personalized medicine data repository. We collected variables that predict breast cancer risk: 153 high-frequency/low-penetrance genetic variants, reflecting the state-of-the-art GWAS on breast cancer, mammography descriptors and BI-RADS assessment categories in the Breast Imaging Reporting and Data System (BI-RADS) lexicon. We trained and tested naïve Bayes models by using these predictive variables. We generated ROC curves and used the area under the ROC curve (AUC) to quantify predictive performance. We found that genetic variants achieved comparable predictive performance to BI-RADS assessment categories in terms of AUC (0.650 vs. 0.659, p-value = 0.742), but significantly lower predictive performance than the combination of BI-RADS assessment categories and mammography descriptors (0.650 vs. 0.751, p-value < 0.001). A better understanding of relative predictive capability of genetic variants and mammography data may benefit clinicians and patients to make appropriate decisions about breast cancer screening, prevention, and treatment in the era of precision medicine.

  18. Discriminatory power of common genetic variants in personalized breast cancer diagnosis

    PubMed Central

    Wu, Yirong; Abbey, Craig K.; Liu, Jie; Ong, Irene; Peissig, Peggy; Onitilo, Adedayo A.; Fan, Jun; Yuan, Ming; Burnside, Elizabeth S.

    2016-01-01

    Technology advances in genome-wide association studies (GWAS) has engendered optimism that we have entered a new age of precision medicine, in which the risk of breast cancer can be predicted on the basis of a person’s genetic variants. The goal of this study is to evaluate the discriminatory power of common genetic variants in breast cancer risk estimation. We conducted a retrospective case-control study drawing from an existing personalized medicine data repository. We collected variables that predict breast cancer risk: 153 high-frequency/low-penetrance genetic variants, reflecting the state-of-the-art GWAS on breast cancer, mammography descriptors and BI-RADS assessment categories in the Breast Imaging Reporting and Data System (BI-RADS) lexicon. We trained and tested naïve Bayes models by using these predictive variables. We generated ROC curves and used the area under the ROC curve (AUC) to quantify predictive performance. We found that genetic variants achieved comparable predictive performance to BI-RADS assessment categories in terms of AUC (0.650 vs. 0.659, p-value = 0.742), but significantly lower predictive performance than the combination of BI-RADS assessment categories and mammography descriptors (0.650 vs. 0.751, p-value < 0.001). A better understanding of relative predictive capability of genetic variants and mammography data may benefit clinicians and patients to make appropriate decisions about breast cancer screening, prevention, and treatment in the era of precision medicine. PMID:27279675

  19. The genetics of Charcot-Marie-Tooth disease: current trends and future implications for diagnosis and management.

    PubMed

    Hoyle, J Chad; Isfort, Michael C; Roggenbuck, Jennifer; Arnold, W David

    2015-01-01

    Charcot-Marie-Tooth (CMT) disease is the most common hereditary polyneuropathy and is classically associated with an insidious onset of distal predominant motor and sensory loss, muscle wasting, and pes cavus. Other forms of hereditary neuropathy, including sensory predominant or motor predominant forms, are sometimes included in the general classification of CMT, but for the purpose of this review, we will focus primarily on the forms associated with both sensory and motor deficits. CMT has a great deal of genetic heterogeneity, leading to diagnostic considerations that are still rapidly evolving for this disorder. Clinical features, inheritance pattern, gene mutation frequencies, and electrodiagnostic features all are helpful in formulating targeted testing algorithms in practical clinical settings, but these still have shortcomings. Next-generation sequencing (NGS), combined with multigene testing panels, is increasing the sensitivity and efficiency of genetic testing and is quickly overtaking targeted testing strategies. Currently, multigene panel testing and NGS can be considered first-line in many circumstances, although obtaining initial targeted testing for the PMP22 duplication in CMT patients with demyelinating conduction velocities is still a reasonable strategy. As technology improves and cost continues to fall, targeted testing will be completely replaced by multigene NGS panels that can detect the full spectrum of CMT mutations. Nevertheless, clinical acumen is still necessary given the variants of uncertain significance encountered with NGS. Despite the current limitations, the genetic diagnosis of CMT is critical for accurate prognostication, genetic counseling, and in the future, specific targeted therapies. Although whole exome and whole genome sequencing strategies have the power to further elucidate the genetics of CMT, continued technological advances are needed. PMID:26527893

  20. The genetics of Charcot–Marie–Tooth disease: current trends and future implications for diagnosis and management

    PubMed Central

    Hoyle, J Chad; Isfort, Michael C; Roggenbuck, Jennifer; Arnold, W David

    2015-01-01

    Charcot–Marie–Tooth (CMT) disease is the most common hereditary polyneuropathy and is classically associated with an insidious onset of distal predominant motor and sensory loss, muscle wasting, and pes cavus. Other forms of hereditary neuropathy, including sensory predominant or motor predominant forms, are sometimes included in the general classification of CMT, but for the purpose of this review, we will focus primarily on the forms associated with both sensory and motor deficits. CMT has a great deal of genetic heterogeneity, leading to diagnostic considerations that are still rapidly evolving for this disorder. Clinical features, inheritance pattern, gene mutation frequencies, and electrodiagnostic features all are helpful in formulating targeted testing algorithms in practical clinical settings, but these still have shortcomings. Next-generation sequencing (NGS), combined with multigene testing panels, is increasing the sensitivity and efficiency of genetic testing and is quickly overtaking targeted testing strategies. Currently, multigene panel testing and NGS can be considered first-line in many circumstances, although obtaining initial targeted testing for the PMP22 duplication in CMT patients with demyelinating conduction velocities is still a reasonable strategy. As technology improves and cost continues to fall, targeted testing will be completely replaced by multigene NGS panels that can detect the full spectrum of CMT mutations. Nevertheless, clinical acumen is still necessary given the variants of uncertain significance encountered with NGS. Despite the current limitations, the genetic diagnosis of CMT is critical for accurate prognostication, genetic counseling, and in the future, specific targeted therapies. Although whole exome and whole genome sequencing strategies have the power to further elucidate the genetics of CMT, continued technological advances are needed. PMID:26527893

  1. A Specially Designed Multi-Gene Panel Facilitates Genetic Diagnosis in Children with Intrahepatic Cholestasis: Simultaneous Test of Known Large Insertions/Deletions

    PubMed Central

    Wang, Neng-Li; Lu, Yu-Lan; Zhang, Ping; Zhang, Mei-Hong; Gong, Jing-Yu; Lu, Yi; Xie, Xin-Bao; Qiu, Yi-Ling; Yan, Yan-Yan; Wu, Bing-bing; Wang, Jian-She

    2016-01-01

    Background and Aims Large indels are commonly identified in patients but are not detectable by routine Sanger sequencing and panel sequencing. We specially designed a multi-gene panel that could simultaneously test known large indels in addition to ordinary variants, and reported the diagnostic yield in patients with intrahepatic cholestasis. Methods The panel contains 61 genes associated with cholestasis and 25 known recurrent large indels. The amplicon library was sequenced on Ion PGM system. Sequencing data were analyzed using a routine data analysis protocol and an internal program encoded for large indels test simultaneously. The validation phase was performed using 54 patients with known genetic diagnosis, including 5 with large insertions. At implement phase, 141 patients with intrahepatic cholestasis were evaluated. Results At validation phase, 99.6% of the variations identified by Sanger sequencing could be detected by panel sequencing. Following the routine protocol, 99.8% of false positives could be filtered and 98.8% of retained variations were true positives. Large insertions in the 5 patients with known genetic diagnosis could be correctly detected using the internal program. At implementation phase, 96.9% of the retained variations, following the routine protocol, were confirmed to be true. Twenty-nine patients received a potential genetic diagnosis when panel sequencing data were analyzed using the routine protocol. Two additional patients, who were found to harbor large insertions in SLC25A13, obtained a potential genetic diagnosis when sequencing data were further analyzed using the internal program. A total of 31 (22.0%) patients obtained a potential genetic diagnosis. Nine different genetic disorders were diagnosed, and citrin deficiency was the commonest. Conclusion Specially designed multi-gene panel can correctly detect large indels simultaneously. By using it, we assigned a potential genetic diagnosis to 22.0% of patients with intrahepatic

  2. Are There Cultural Differences in Parental Interest in Early Diagnosis and Genetic Risk Assessment for Autism Spectrum Disorder?

    PubMed Central

    Amiet, Claire; Couchon, Elizabeth; Carr, Kelly; Carayol, Jerôme; Cohen, David

    2014-01-01

    Background: There are many societal and cultural differences between healthcare systems and the use of genetic testing in the US and France. These differences may affect the diagnostic process for autism spectrum disorder (ASD) in each country and influence parental opinions regarding the use of genetic screening tools for ASD. Methods: Using an internet-based tool, a survey of parents with at least one child with ASD was conducted. A total of 162 participants from the US completed an English version of the survey and 469 participants from France completed a French version of the survey. Respondents were mainly females (90%) and biological parents (94.3% in the US and 97.2% in France). Results: The mean age of ASD diagnosis reported was not significantly different between France (57.5 ± 38.4 months) and the US (56.5 ± 52.7 months) (p = 0.82) despite significant difference in the average age at which a difference in development was first suspected [29.7 months (±28.4) vs. 21.4 months (±18.1), respectively, p = 7 × 10−4]. Only 27.8% of US participants indicated that their child diagnosed with ASD had undergone diagnostic genetic testing, whereas 61.7% of the French participants indicated this was the case (p = 2.7 × 10−12). In both countries, the majority of respondents (69.3% and 80% from France and the US, respectively) indicated high interest in the use of a genetic screening test for autism. Conclusion: Parents from France and the US report a persistent delay between the initial suspicion of a difference in development and the diagnosis of ASD. Significantly fewer US participants underwent genetic testing although this result should be regarded as exploratory given the limitations. The significance of these between country differences will be discussed. PMID:24795872

  3. Recent advances in molecular genetics of melanoma progression: implications for diagnosis and treatment.

    PubMed

    Yeh, Iwei

    2016-01-01

    According to the multi-step carcinogenesis model of cancer, initiation results in a benign tumor and subsequent genetic alterations lead to tumor progression and the acquisition of the hallmarks of cancer. This article will review recent discoveries in our understanding of initiation and progression in melanocytic neoplasia and the impact on diagnostic dermatopathology. PMID:27408703

  4. Recent advances in molecular genetics of melanoma progression: implications for diagnosis and treatment

    PubMed Central

    Yeh, Iwei

    2016-01-01

    According to the multi-step carcinogenesis model of cancer, initiation results in a benign tumor and subsequent genetic alterations lead to tumor progression and the acquisition of the hallmarks of cancer. This article will review recent discoveries in our understanding of initiation and progression in melanocytic neoplasia and the impact on diagnostic dermatopathology. PMID:27408703

  5. Aceruloplasminemia in an asymptomatic patient with a new mutation. Diagnosis and family genetic analysis.

    PubMed

    Pérez-Aguilar, Fernando; Burguera, Juan A; Benlloch, Salvador; Berenguer, Marina; Rayón, Jose M

    2005-06-01

    A 39-year-old asymptomatic man showed elevated serum ferritin levels, mild hypertransaminasemia and serum ceruloplasmin almost undetectable. There was histological iron accumulation within the hepatocytes and also in the central nervous system (MRI). A genetic analysis revealed a new missense mutation in the ceruloplasmin gene. Two of the other four siblings were also affected by this mutation.

  6. Tentative clinical diagnosis of Lujan-Fryns syndrome--A conglomeration of different genetic entities?

    PubMed

    Hackmann, Karl; Rump, Andreas; Haas, Stefan A; Lemke, Johannes R; Fryns, Jean-Pierre; Tzschach, Andreas; Wieczorek, Dagmar; Albrecht, Beate; Kuechler, Alma; Ripperger, Tim; Kobelt, Albrecht; Oexle, Konrad; Tinschert, Sigrid; Schrock, Evelin; Kalscheuer, Vera M; Di Donato, Nataliya

    2016-01-01

    The clinical diagnosis of Lujan-Fryns syndrome (LFS) comprises X-linked intellectual disability (XLID) with marfanoid habitus, distinct combination of minor facial anomalies and nasal speech. However the definition of syndrome was significantly broadened since the original report and implies ID with marfanoid habitus. Mutations of three genes (MED12, UPF3B, and ZDHHC9) have been reported in "broadly defined" LFS. We examined these genes in 28 individuals with a tentative clinical diagnosis of LFS but we did not identify any causative mutation. By molecular karyotyping we detected other disorders, i.e., Phelan-McDermid syndrome and 16p11.2 microduplication, each in one patient. One affected individual was carrier of a different recurrent duplication on 16p11.2 that has been reported several times to the DECIPHER and ISCA databases in individuals with autism, intellectual disability (ID), and developmental delay. It may represent a new duplication syndrome. We also identified previously unreported de novo duplication on chromosome 12p13.31 which we considered to be disease-causing. X-exome sequencing of four individuals revealed private or non-recurrent mutations in NKAP and LAS1L in one patient each. While LFS is defined as a form of XLID, there seem to be various conditions that have rather similar phenotypes. Therefore, the combination of ID and marfanoid habitus in a male patient is not sufficient for the diagnosis of LFS. We suggest that the diagnosis of LFS in patients with ID and marfanoid habitus should be made only in presence of specific facial features, nasal speech and obvious X-linked segregation of the disorder or an unambiguously pathogenic mutation in the MED12. PMID:26358559

  7. Tentative clinical diagnosis of Lujan-Fryns syndrome--A conglomeration of different genetic entities?

    PubMed

    Hackmann, Karl; Rump, Andreas; Haas, Stefan A; Lemke, Johannes R; Fryns, Jean-Pierre; Tzschach, Andreas; Wieczorek, Dagmar; Albrecht, Beate; Kuechler, Alma; Ripperger, Tim; Kobelt, Albrecht; Oexle, Konrad; Tinschert, Sigrid; Schrock, Evelin; Kalscheuer, Vera M; Di Donato, Nataliya

    2016-01-01

    The clinical diagnosis of Lujan-Fryns syndrome (LFS) comprises X-linked intellectual disability (XLID) with marfanoid habitus, distinct combination of minor facial anomalies and nasal speech. However the definition of syndrome was significantly broadened since the original report and implies ID with marfanoid habitus. Mutations of three genes (MED12, UPF3B, and ZDHHC9) have been reported in "broadly defined" LFS. We examined these genes in 28 individuals with a tentative clinical diagnosis of LFS but we did not identify any causative mutation. By molecular karyotyping we detected other disorders, i.e., Phelan-McDermid syndrome and 16p11.2 microduplication, each in one patient. One affected individual was carrier of a different recurrent duplication on 16p11.2 that has been reported several times to the DECIPHER and ISCA databases in individuals with autism, intellectual disability (ID), and developmental delay. It may represent a new duplication syndrome. We also identified previously unreported de novo duplication on chromosome 12p13.31 which we considered to be disease-causing. X-exome sequencing of four individuals revealed private or non-recurrent mutations in NKAP and LAS1L in one patient each. While LFS is defined as a form of XLID, there seem to be various conditions that have rather similar phenotypes. Therefore, the combination of ID and marfanoid habitus in a male patient is not sufficient for the diagnosis of LFS. We suggest that the diagnosis of LFS in patients with ID and marfanoid habitus should be made only in presence of specific facial features, nasal speech and obvious X-linked segregation of the disorder or an unambiguously pathogenic mutation in the MED12.

  8. ESHRE PGD Consortium data collection XI: cycles from January to December 2008 with pregnancy follow-up to October 2009.

    PubMed

    Goossens, V; Traeger-Synodinos, J; Coonen, E; De Rycke, M; Moutou, C; Pehlivan, T; Derks-Smeets, I A P; Harton, G

    2012-07-01

    The 11th report of the European Society of Human Reproduction and Embryology Preimplantation Genetic Diagnosis Consortium is presented, documenting cycles collected for the calendar year 2008 and follow-up of the pregnancies and babies born until October 2009 which resulted from these cycles. Since the beginning of the data collections, there has been a steady increase in the number of cycles, pregnancies and babies reported annually. For data collection XI, 53 centres have participated, reporting on 5641 cycles to oocyte retrieval (OR), along with details of the follow-up on 1418 pregnancies and 1169 babies born. A total of 774 OR were reported for chromosomal abnormalities, 96 OR for sexing for X-linked diseases, 1363 OR for monogenic diseases, 3401 OR for preimplantation genetic screening and 5 OR for social sexing. Data XI is compared with the cumulative data for data collections I-X. PMID:22572107

  9. The potential of genetic and gene expression analysis in the diagnosis of neuropsychiatric disorders.

    PubMed

    van de Leemput, Joyce; Glatt, Stephen J; Tsuang, Ming T

    2016-06-01

    Neuropsychiatric disorders are difficult to diagnose because of phenotypic heterogeneity within and symptomatic overlap between disorders. This review describes how genomics and blood-based gene expression have shown potential as biomarkers for neuropsychiatric disorders (schizophrenia, bipolar disorder, and major depressive disorder) yet also discusses how a complex genetic landscape has limited sole genetic diagnostic tools for these disorders. In addition to their potential use as classifiers for neuropsychiatric disorders, genomic and blood-based biomarkers have revealed clues to the molecular pathways contributing to etiology. A comprehensive overview of studies to date has been given, and the authors provide suggestions for steps to be taken to ultimately move the laboratory-based classifiers towards application in a clinical setting. Furthermore, they share their vision for the future of these classifiers, both in clinical application and in opening up new ways to gain insights into the underlying biology.

  10. Pituitary tumors in childhood: update of diagnosis, treatment and molecular genetics.

    PubMed

    Keil, Margaret F; Stratakis, Constantine A

    2008-04-01

    Pituitary tumors are rare in childhood and adolescence, with a reported prevalence of up to one per 1 million children. Only 2-6% of surgically treated pituitary tumors occur in children. Although pituitary tumors in children are almost never malignant and hormonal secretion is rare, these tumors may result in significant morbidity. Tumors within the pituitary fossa are mainly of two types: craniopharyngiomas and adenomas. Craniopharyngiomas cause symptoms by compressing normal pituitary, causing hormonal deficiencies and producing mass effects on surrounding tissues and the brain; adenomas produce a variety of hormonal conditions such as hyperprolactinemia, Cushing disease and acromegaly or gigantism. Little is known about the genetic causes of sporadic lesions, which comprise the majority of pituitary tumors, but in children, more frequently than in adults, pituitary tumors may be a manifestation of genetic conditions such as multiple endocrine neoplasia type 1, Carney complex, familial isolated pituitary adenoma and McCune-Albright syndrome. The study of pituitary tumorigenesis in the context of these genetic syndromes has advanced our knowledge of the molecular basis of pituitary tumors and may lead to new therapeutic developments. PMID:18416659

  11. Counseling Challenges with Variants of Uncertain Significance and Incidental Findings in Prenatal Genetic Screening and Diagnosis

    PubMed Central

    Westerfield, Lauren; Darilek, Sandra; van den Veyver, Ignatia B.

    2014-01-01

    Prenatal genetic screening and testing provides prospective parents information about the health of their fetus. It is offered to find or address an increased risk for chromosomal abnormalities or other genetic conditions in the fetus or to identify the cause of fetal structural abnormalities detected by prenatal imaging. Genome-wide tests, such as the already widely-used chromosomal microarray analysis and emerging diagnostic whole exome and whole genome sequencing, have improved the ability to detect clinically significant findings, but have also increased the chance of detecting incidental findings and variants of uncertain significance. There is an extensive ongoing discussion about optimal strategies for diagnostic laboratories to report such findings and for providers to communicate them with patients. While consensus opinions and guidelines are beginning to appear, they often exclude the prenatal setting, due to its unique set of challenging considerations. These include more limited knowledge of the impact of genetic variants when prospectively detected in an ongoing pregnancy, the absence or limitations of detecting clinically recognizable phenotypes at the time of testing and the different decision-making processes that will ensue from testing. In this review, we examine these challenges within the medical ethical framework unique to prenatal care. PMID:26237491

  12. Pituitary Tumors in Childhood: an update in their diagnosis, treatment and molecular genetics

    PubMed Central

    Keil, Margaret F.; Stratakis, Constantine A.

    2009-01-01

    Pituitary tumors are rare in childhood and adolescence, with a reported prevalence of up to 1 per million children. Only 2 - 6% of surgically treated pituitary tumors occur in children. Although pituitary tumors in children are almost never malignant and hormonal secretion is rare, these tumors may result in significant morbidity. Tumors within the pituitary fossa are of two types mainly, craniopharyngiomas and adenomas; craniopharyngiomas cause symptoms by compressing normal pituitary, causing hormonal deficiencies and producing mass effects on surrounding tissues and the brain; adenomas produce a variety of hormonal conditions such as hyperprolactinemia, Cushing disease and acromegaly or gigantism. Little is known about the genetic causes of sporadic lesions, which comprise the majority of pituitary tumors, but in children, more frequently than in adults, pituitary tumors may be a manifestation of genetic conditions such as multiple endocrine neoplasia type 1 (MEN 1), Carney complex, familial isolated pituitary adenoma (FIPA), and McCune-Albright syndrome. The study of pituitary tumorigenesis in the context of these genetic syndromes has advanced our knowledge of the molecular basis of pituitary tumors and may lead to new therapeutic developments. PMID:18416659

  13. [Molecular-genetic approaches to diagnosis and intraspecific typing of causative agents of glanders and melioidosis].

    PubMed

    Antonov, V A; Iliukhin, V I

    2005-01-01

    Pathogenic Burkholderia--Burkholderia mallei and Burkholderia pseudomallei--are causative agents of glanders and melioidosis, severe infectious diseases of man and animals. They are regarded as potential agents of bioterrorism. The existing bacteriological and immunological methods of identification of B. mallei and B. pseudomallei are not efficient enough for the rapid diagnosis and typing of strains. Described in the paper are molecular methods of detection of the agents by PCR, hybridization and strain typing made on the basis of bacterial total cell protein profiles, RAPD, ribotyping as well as of plasmid and DNA microrestriction analyses.

  14. Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes.

    PubMed

    Justino, Ana; Dias, Patrícia; João Pina, Maria; Sousa, Sónia; Cirnes, Luís; Berta Sousa, Ana; Carlos Machado, José; Costa, José Luis

    2015-03-01

    Variants in 11 genes of the RAS/MAPK signaling pathway have been causally linked to the neuro-cardio-facio-cutaneous syndromes group (NCFCS). Recently, A2ML1 and RIT1 were also associated with these syndromes. Because of the genetic and clinical heterogeneity of NCFCS, it is challenging to define strategies for their molecular diagnosis. The aim of this study was to develop and validate a massive parallel sequencing (MPS)-based strategy for the molecular diagnosis of NCFCS. A multiplex PCR-based strategy for the enrichment of the 13 genes and a variant prioritization pipeline was established. Two sets of genomic DNA samples were studied using the Ion PGM System: (1) training set (n =15) to optimize the strategy and (2) validation set (n = 20) to validate and evaluate the power of the new methodology. Sanger sequencing was performed to confirm all variants and low covered regions. All variants identified by Sanger sequencing were detected with our MPS approach. The methodology resulted in an experimental approach with a specificity of 99.0% and a maximum analytical sensitivity of ≥ 98.2% with a confidence of 99%. Importantly, two patients (out of 20) harbored described disease-causing variants in genes that are not routinely tested (RIT1 and SHOC2). The addition of less frequently altered genes increased in ≈ 10% the diagnostic yield of the strategy currently used. The presented workflow provides a comprehensive genetic screening strategy for patients with NCFCS in a fast and cost-efficient manner. This approach demonstrates the potential of a combined MPS-Sanger sequencing-based strategy as an effective diagnostic tool for heterogeneous diseases.

  15. Whole dystrophin gene analysis by next-generation sequencing: a comprehensive genetic diagnosis of Duchenne and Becker muscular dystrophy.

    PubMed

    Wang, Yan; Yang, Yao; Liu, Jing; Chen, Xiao-Chun; Liu, Xin; Wang, Chun-Zhi; He, Xi-Yu

    2014-10-01

    Duchenne/Becker muscular dystrophies are the most frequent inherited neuromuscular diseases caused by mutations of the dystrophin gene. However, approximately 30% of patients with the disease do not receive a molecular diagnosis because of the complex mutational spectrum and the large size of the gene. The introduction and use of next-generation sequencing have advanced clinical genetic research and might be a suitable method for the detection of various types of mutations in the dystrophin gene. To identify the mutational spectrum using a single platform, whole dystrophin gene sequencing was performed using next-generation sequencing. The entire dystrophin gene, including all exons, introns and promoter regions, was target enriched using a DMD whole gene enrichment kit. The enrichment libraries were sequenced on an Illumina HiSeq 2000 sequencer using paired read 100 bp sequencing. We studied 26 patients: 21 had known large deletion/duplications and 5 did not have detectable large deletion/duplications by multiplex ligation-dependent probe amplification technology (MLPA). We applied whole dystrophin gene analysis by next-generation sequencing to the five patients who did not have detectable large deletion/duplications and to five randomly chosen patients from the 21 who did have large deletion/duplications. The sequencing data covered almost 100% of the exonic region of the dystrophin gene by ≥10 reads with a mean read depth of 147. Five small mutations were identified in the first five patients, of which four variants were unreported in the dmd.nl database. The deleted or duplicated exons and the breakpoints in the five large deletion/duplication patients were precisely identified. Whole dystrophin gene sequencing by next-generation sequencing may be a useful tool for the genetic diagnosis of Duchenne and Becker muscular dystrophies.

  16. Genetics

    MedlinePlus

    ... Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  17. An Expert Diagnosis System for Parkinson Disease Based on Genetic Algorithm-Wavelet Kernel-Extreme Learning Machine

    PubMed Central

    Avci, Derya; Dogantekin, Akif

    2016-01-01

    Parkinson disease is a major public health problem all around the world. This paper proposes an expert disease diagnosis system for Parkinson disease based on genetic algorithm- (GA-) wavelet kernel- (WK-) Extreme Learning Machines (ELM). The classifier used in this paper is single layer neural network (SLNN) and it is trained by the ELM learning method. The Parkinson disease datasets are obtained from the UCI machine learning database. In wavelet kernel-Extreme Learning Machine (WK-ELM) structure, there are three adjustable parameters of wavelet kernel. These parameters and the numbers of hidden neurons play a major role in the performance of ELM. In this study, the optimum values of these parameters and the numbers of hidden neurons of ELM were obtained by using a genetic algorithm (GA). The performance of the proposed GA-WK-ELM method is evaluated using statical methods such as classification accuracy, sensitivity and specificity analysis, and ROC curves. The calculated highest classification accuracy of the proposed GA-WK-ELM method is found as 96.81%. PMID:27274882

  18. Technological advances in DNA sequence enrichment and sequencing for germline genetic diagnosis.

    PubMed

    Ku, Chee-Seng; Wu, Mengchu; Cooper, David N; Naidoo, Nasheen; Pawitan, Yudi; Pang, Brendan; Iacopetta, Barry; Soong, Richie

    2012-03-01

    The potential applications of next-generation sequencing technologies in diagnostic laboratories have become increasingly evident despite the various technical challenges that still need to be overcome to potentiate its widespread adoption in a clinical setting. Whole-genome sequencing is now both technically feasible and 'cost effective' using next-generation sequencing techniques. However, this approach is still considered to be 'expensive' for a diagnostic test. Although the goal of the US$1000 genome is fast approaching, neither the analytical hurdles nor the ethical issues involved are trivial. In addition, the cost of data analysis and storage has been much higher than initially expected. As a result, it is widely perceived that targeted sequencing and whole-exome sequencing are more likely to be adopted as diagnostic tools in the foreseeable future. However, the information-generating power of whole-exome sequencing has also sparked considerable debate in relation to its deployment in genetic diagnostics, particularly with reference to the revelation of incidental findings. In this review, we focus on the targeted sequencing approach and its potential as a genetic diagnostic tool.

  19. [Specifics of histopathological and genetical diagnosis and classification of lymphomas in children and adolescents].

    PubMed

    Klapper, W; Oschlies, I

    2012-04-01

    Malignant lymphoma along with leukemias account for nearly half of all malignancies arising in childhood and adolescence. The correct tissue-based histopathological diagnosis of lymphomas results from a close interdisciplinary exchange between pediatric oncologists and hematopathologists. We describe here relevant features of lymphoma subtypes arising in the young age group, Burkitt lymphoma, precursor/lymphoblastic lymphomas, anaplastic large cell lymphoma and diffuse large B-cell lymphoma as well as primary mediastinal B-cell lymphoma and the rare pediatric follicular lymphomas. Special focus is put on specific diagnostic difficulties as well as new insights into biological features of pediatric lymphomas in comparison with their adult counterpart. In addition the relevance of newly defined lymphoma entities of the WHO-classification 2008, e.g. greyzone lymphomas, will be discussed for the young age group. PMID:22513791

  20. Prenatal diagnosis of female monozygotic twins discordant for Turner syndrome: implications for prenatal genetic counselling.

    PubMed

    Gilbert, B; Yardin, C; Briault, S; Belin, V; Lienhardt, A; Aubard, Y; Battin, J; Servaud, M; Philippe, H J; Lacombe, D

    2002-08-01

    We describe a set of monozygotic (MZ) female twins, one of whom presented with a typical Turner syndrome (TS) phenotype and the other a normal female phenotype. Prenatal fetal ultrasonographic examination showed a monochorial diamniotic pregnancy with a hygroma colli and growth delay in Twin A and no anomalies in Twin B. Karyotypic analysis performed on fetal blood samples demonstrated a 46,XX/45,X (23/2) mosaicism in Twin A and a normal 46,XX chromosome constitution in Twin B. At birth, Twin A presented with a typical TS and Twin B had a normal female phenotype. Postnatal cytogenetic investigation of blood lymphocytes showed the same 46,XX/45,X mosaicism in both twins: 46,XX/45,X (40/7) in Twin A and 46,XX/45,X (40/5) in Twin B. Further investigations at the age of 10 months showed in Twin A a 46,XX/45,X (98/2) mosaicism in lymphocytes and 100% of 45,X (50 analysed cells) in fibroblasts, and in Twin B a normal 46,XX (100 analysed cells) chromosome constitution in lymphocytes but a mild 46,XX/45,X (78/2) mosaicism in fibroblasts. Monozygosity was confirmed by molecular analysis. To our knowledge, this is the first report of prenatal diagnosis of MZ female twins discordant for TS. Review of reported sets of MZ female twins (eight cases) or triplets (one case) discordant for TS shows, as in the present case, that the phenotype correlates better with the chromosomal distribution of mosaicism in fibroblasts than in lymphocytes. In the blood of MZ twins chimerism may modify the initial allocation of the mosaicism. These results suggest that, in cases of prenatal diagnosis of MZ female twins discordant for TS, the phenotype of each twin would be better predicted from karyotype analysis of cells from amniotic fluid than from fetal blood.

  1. [Medico-genetic study of isolates in Uzbekistan. IV. Clinico-biochemical diagnosis of hereditary diseases].

    PubMed

    Kozlova, S I; Diachenko, S S; Khannanova, F K; Kuleshov, N P; Khodzhaeva, G K

    1976-01-01

    An exhaustive clinico-biochemical examination of the population of two kishlaks of the Samarkand Region, viz. Karakent (210 persons) and Ishan (248 persons) was carried out. The program of this examination permitted to exclude over 160 forms of hereditary pathology. A total of 45 persons affected with diseases belonging to 12 nosological forms were revealed in the course of the examination. Among the diseases observed only 5 are hereditary sensu stricto, viz. myoclonus-epilepsy, Bonevi-Ulrich's syndrome, imperfect osteogenesis, pigment choreoretinite and Down's syndrome, others belong to diseases with a pronounced hereditary predisposition. The main part of this group comprises neuro-psychic diseases, such as non-differentiated olygophreny (5.0%), epilepsy (1.3%), schizophreny; many of these cases have a familial character, particularly in Karakent. Besides the persons suffering from diseases, 20 heterozygous carriers of beta-thalassemia and 17 heterozygous carriers of G6PD-deficiency were discovered in the kishlaks examined. On the whole the frequency of the diseases revealed did not exceed the level in the general population. Despite the different degree of isolation of the kishlaks examined (Karakent is isolated on a religious basis, F = 0.0064; while Ishan is a desintagrated isolate, F = = 0.0014), no substantial differences between them in the distribution of pathological phenomena were observed. On the basis of the experience of this expedition recomendations are proposed concerning the origination and accomplishment of medico-genetic expeditions. A scheme is proposed for the performance of medico-genetic examination through several stages. The first stage in the composition of tentative maps of the distribution of hereditary diseases within a region on the basis of the information obtained from the medical personnel and from the examination of the documents of district and regional hospitals. Subsequently the primary information is specified, the regions to

  2. Telethon Network of Genetic Biobanks: a key service for diagnosis and research on rare diseases.

    PubMed

    Filocamo, Mirella; Baldo, Chiara; Goldwurm, Stefano; Renieri, Alessandra; Angelini, Corrado; Moggio, Maurizio; Mora, Marina; Merla, Giuseppe; Politano, Luisa; Garavaglia, Barbara; Casareto, Lorena; Bricarelli, Francesca Dagna

    2013-08-30

    Several examples have always illustrated how access to large numbers of biospecimens and associated data plays a pivotal role in the identification of disease genes and the development of pharmaceuticals. Hence, allowing researchers to access to significant numbers of quality samples and data, genetic biobanks are a powerful tool in basic, translational and clinical research into rare diseases. Recently demand for well-annotated and properly-preserved specimens is growing at a high rate, and is expected to grow for years to come. The best effective solution to this issue is to enhance the potentialities of well-managed biobanks by building a network.Here we report a 5-year experience of the Telethon Network of Genetic Biobanks (TNGB), a non-profit association of Italian repositories created in 2008 to form a virtually unique catalogue of biospecimens and associated data, which presently lists more than 750 rare genetic defects. The process of TNGB harmonisation has been mainly achieved through the adoption of a unique, centrally coordinated, IT infrastructure, which has enabled (i) standardisation of all the TNGB procedures and activities; (ii) creation of an updated TNGB online catalogue, based on minimal data set and controlled terminologies; (iii) sample access policy managed via a shared request control panel at web portal. TNGB has been engaged in disseminating information on its services into both scientific/biomedical - national and international - contexts, as well as associations of patients and families. Indeed, during the last 5-years national and international scientists extensively used the TNGB with different purposes resulting in more than 250 scientific publications. In addition, since its inception the TNGB is an associated member of the Biobanking and Biomolecular Resources Research Infrastructure and recently joined the EuroBioBank network. Moreover, the involvement of patients and families, leading to the formalization of various agreements

  3. Genetic Counseling for a Prenatal Diagnosis of Structural Chromosomal Abnormality with High-Resolution Analysis Using a Single Nucleotide Polymorphism Microarray

    PubMed Central

    Takashima, Akiko; Takeshita, Naoki; Kinoshita, Toshihiko

    2016-01-01

    A 41-year old pregnant woman underwent amniocentesis to conduct a conventional karyotyping analysis; the analysis reported an abnormal karyotype: 46, XY, add(9)(p24). Chromosomal microarray analysis (CMA) is utilized in prenatal diagnoses. A single nucleotide polymorphism microarray revealed a male fetus with balanced chromosomal translocations on 9p and balanced chromosomal rearrangements, but another chromosomal abnormality was detected. The fetus had microduplication. The child was born as a phenotypically normal male. CMA is a simple and informative procedure for prenatal genetic diagnosis. CMA is the detection of chromosomal variants of unknown clinical significance; therefore, genetic counseling is important during prenatal genetic testing. PMID:27777709

  4. At the intersection of toxicology, psychiatry, and genetics: a diagnosis of ornithine transcarbamylase deficiency.

    PubMed

    Sloas, Harold Andrew; Ence, Thomas C; Mendez, Donna R; Cruz, Andrea T

    2013-09-01

    Ornithine transcarbamylase (OTC) deficiency is a genetic disorder involving a mutation of the ornithine transcarbamylase gene, located on the short arm of the X chromosome (Xp21.1). This makes the expression of the gene most common in homozygous males, but heterozygous females can also be affected and may be more likely to suffer from serious morbidity. Most males present early in the neonatal period with more devastating outcomes than their female counterparts. Up to 34% will present in the first 30 days of life (J Pediatr 2001;138:S30). Females often have partially functioning mitochondria due to uneven distribution of the mutant gene secondary to lyonization (“X-chromosome Inactivation”. Genetics Home Reference, 2012). Occasionally, symptomatic females may not even present until they are placed under metabolic stress such as a severe illness, fasting, pregnancy, or new medication (Roth KS, Steiner RD. “Ornithine Transcarbamylase Deficiency”. EMedicine, 2012). The urea cycle is the body's primary tool for the disposal of excess nitrogen, which is generated by the routine metabolism of proteins and amino acids. Mitochondrial dysfunction impairs urea production and result in hyperammonemia (Semin Neonatol 2002;7:27). The sine qua non among all degrees of OTC deficiency at presentation is hyperammonemia. As in adults, children will have similar symptoms of encephalopathy, but this may be expressed differently depending on the child's developmental level. We present an unusual case of OTC deficiency in an older child with undifferentiated symptoms of an anticholinergic toxidrome, liver failure, iron overdose, and mushroom poisoning.

  5. Histologic and Genetic Advances in Refining the Diagnosis of “Undifferentiated Pleomorphic Sarcoma”

    PubMed Central

    Kelleher, Fergal C.; Viterbo, Antonella

    2013-01-01

    Undifferentiated pleomorphic sarcoma (UPS) is an inclusive term used for sarcomas that defy formal sub-classification. The frequency with which this diagnosis is assigned has decreased in the last twenty years. This is because when implemented, careful histologic assessment, immunohistochemistry, and ultra-structural evaluation can often determine lineage of differentiation. Further attrition in the diagnostic frequency of UPS may arise by using array-comparative genomic hybridization. Gene expression arrays are also of potential use as they permit hierarchical gene clustering. Appraisal of the literature is difficult due to a historical perspective in which specific molecular diagnostic methods were previously unavailable. The American Joint Committee on Cancer (AJCC) classification has changed with different inclusion criteria. Taxonomy challenges also exist with the older term “malignant fibrous histiocytoma” being replaced by “UPS”. In 2010 an analysis of multiple sarcoma expression databases using a 170-gene predictor, re-classified most MFH and “not-otherwise-specified” (NOS) tumors as liposarcomas, leiomyosarcomas or fibrosarcomas. Interestingly, some of the classifier genes are potential molecular therapeutic targets including Insulin-like growth factor 1 (IGF-1), Peroxisome proliferator-activated receptor γ (PPARγ), Nerve growth factor β (NGF β) and Fibroblast growth factor receptor (FGFR). PMID:24216705

  6. [Genetic diagnosis of thalassemia mutations with free fetal DNA in pregnant plasma].

    PubMed

    Lin, Xiao-Rong; You, Liu-Xia; Chen, Yong

    2013-10-01

    This research was aimed to develop a simple, rapid, accurate and non-invasive method by means of flow-through hybridization technology, which can be used for molecular screening and early prenatal diagnosis for detecting common β-thalassemias mutational genotypes. By using PCR technology combined with flow-through hybridization of low-density gene chip technology, the 6 sets of PCR primer single tube multiplex PCR system and 29 types of DNA probes were designed, then the mutational thalassemias in foetus DNA was rapidly detected in total of 60 anaemia pregnant women plasma. The results showed that 4 cases with deletional α-thalassemias, 3 cases with β-thalassemias, 1 case with mixed type of α & β-thalassemias were detected in foetus DNA of 60 pregnant women plasmas. It is concluded that the method presented in this study is easy to handle, rapid, reliable and cost-effective for detecting 3 common deletional α-thalassemias and 17 common mutational β-thalassemia.

  7. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications

    PubMed Central

    Lynch, HT; Lynch, PM; Lanspa, SJ; Snyder, CL; Lynch, JF; Boland, CR

    2010-01-01

    More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (~30,700 cases) will have Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes (most frequently MLH1 or MSH2) and screening for CRC. Colonoscopy is mandated, given CRC’s proximal occurrence (70–80% proximal to the splenic flexure). Due to its early age of onset (average 45 years of age), colonoscopy needs to start by age 25, and because of its accelerated carcinogenesis, it should be repeated every 1 to 2 years through age 40 and then annually thereafter. Should CRC occur, subtotal colectomy may be necessary, given the marked frequency of synchronous and metachronous CRC. Because 40–60% of female patients will manifest endometrial cancer, tailored management is essential. Additional extracolonic cancers include ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir-Torre variant). LS explains only 10–25% of familial CRC. PMID:19659756

  8. Characterization and noninvasive diagnosis of bladder cancer with serum surface enhanced Raman spectroscopy and genetic algorithms

    PubMed Central

    Li, Shaoxin; Li, Linfang; Zeng, Qiuyao; Zhang, Yanjiao; Guo, Zhouyi; Liu, Zhiming; Jin, Mei; Su, Chengkang; Lin, Lin; Xu, Junfa; Liu, Songhao

    2015-01-01

    This study aims to characterize and classify serum surface-enhanced Raman spectroscopy (SERS) spectra between bladder cancer patients and normal volunteers by genetic algorithms (GAs) combined with linear discriminate analysis (LDA). Two group serum SERS spectra excited with nanoparticles are collected from healthy volunteers (n = 36) and bladder cancer patients (n = 55). Six diagnostic Raman bands in the regions of 481–486, 682–687, 1018–1034, 1313–1323, 1450–1459 and 1582–1587 cm−1 related to proteins, nucleic acids and lipids are picked out with the GAs and LDA. By the diagnostic models built with the identified six Raman bands, the improved diagnostic sensitivity of 90.9% and specificity of 100% were acquired for classifying bladder cancer patients from normal serum SERS spectra. The results are superior to the sensitivity of 74.6% and specificity of 97.2% obtained with principal component analysis by the same serum SERS spectra dataset. Receiver operating characteristic (ROC) curves further confirmed the efficiency of diagnostic algorithm based on GA-LDA technique. This exploratory work demonstrates that the serum SERS associated with GA-LDA technique has enormous potential to characterize and non-invasively detect bladder cancer through peripheral blood. PMID:25947114

  9. Characterization and noninvasive diagnosis of bladder cancer with serum surface enhanced Raman spectroscopy and genetic algorithms

    NASA Astrophysics Data System (ADS)

    Li, Shaoxin; Li, Linfang; Zeng, Qiuyao; Zhang, Yanjiao; Guo, Zhouyi; Liu, Zhiming; Jin, Mei; Su, Chengkang; Lin, Lin; Xu, Junfa; Liu, Songhao

    2015-05-01

    This study aims to characterize and classify serum surface-enhanced Raman spectroscopy (SERS) spectra between bladder cancer patients and normal volunteers by genetic algorithms (GAs) combined with linear discriminate analysis (LDA). Two group serum SERS spectra excited with nanoparticles are collected from healthy volunteers (n = 36) and bladder cancer patients (n = 55). Six diagnostic Raman bands in the regions of 481-486, 682-687, 1018-1034, 1313-1323, 1450-1459 and 1582-1587 cm-1 related to proteins, nucleic acids and lipids are picked out with the GAs and LDA. By the diagnostic models built with the identified six Raman bands, the improved diagnostic sensitivity of 90.9% and specificity of 100% were acquired for classifying bladder cancer patients from normal serum SERS spectra. The results are superior to the sensitivity of 74.6% and specificity of 97.2% obtained with principal component analysis by the same serum SERS spectra dataset. Receiver operating characteristic (ROC) curves further confirmed the efficiency of diagnostic algorithm based on GA-LDA technique. This exploratory work demonstrates that the serum SERS associated with GA-LDA technique has enormous potential to characterize and non-invasively detect bladder cancer through peripheral blood.

  10. Advances in pediatric restless legs syndrome: Iron, genetics, diagnosis and treatment.

    PubMed

    Picchietti, Matthew A; Picchietti, Daniel L

    2010-08-01

    A substantial literature characterizes pediatric restless legs syndrome (RLS), which occurs in about 1.9% of individuals between 8 and 18years of age. Diagnostic interview techniques and an updated inventory of pediatric RLS mimics are presented. Evidence for comorbidity of pediatric RLS with attention-deficit/hyperactivity disorder, depression, and anxiety is reviewed as is the relationship to periodic limb movements in sleep and periodic limb movement disorder. The role of relative iron deficiency in pediatric RLS is discussed, along with new data indicating the benefit of iron therapy in reducing symptoms. Five genetic variants have been linked to RLS, an important finding in a condition that is highly familial in early-onset cases. Numerous case reports and case series indicate benefit for moderate to severe pediatric RLS with medication. However, to date, there have been no double-blind, placebo-controlled studies of therapy for pediatric RLS published. These and other recent advances relevant to pediatric RLS research are reviewed. PMID:20620105

  11. SFE/SFHTA/AFCE consensus on primary aldosteronism, part 5: Genetic diagnosis of primary aldosteronism.

    PubMed

    Zennaro, Maria-Christina; Jeunemaitre, Xavier

    2016-07-01

    While the majority of cases of primary aldosteronism (PA) are sporadic, four forms of autosomal-dominant inheritance have been described: familial hyperaldosteronism (FH) types I to IV. FH-I, also called glucocorticoid-remediable aldosteronism, is characterized by early and severe hypertension, usually before the age of 20 years. It is due to the formation of a chimeric gene between the adjacent CYP11B2 and CYP11B1 genes (coding for aldosterone synthase and 11β-hydroxylase, respectively). FH-I is often associated with family history of stroke before 40years of age. FH-II is clinically and biochemically indistinguishable from sporadic forms of PA and is only diagnosed on the basis of two or more affected family members. No causal genes have been identified so far and no genetic test is available. FH-III is characterized by severe and early-onset hypertension in children and young adults, resistant to treatment and associated with severe hypokalemia. Mild forms, resembling FH-II, have been described. FH-III is due to gain-of-function mutations in the KCNJ5 gene. Recently, a new autosomal-dominant form of familial PA, FH-IV, associated with mutations in the CACNA1H gene, was described in patients with hypertension and PA before the age of 10years. In rare cases, PA may be associated with complex neurologic disorder involving epileptic seizures and cerebral palsy (Primary Aldosteronism, Seizures, and Neurologic Abnormalities [PASNA]) due to de novo germline CACNA1D mutations. PMID:27315758

  12. Genetic analysis in inherited metabolic disorders--from diagnosis to treatment. Own experience, current state of knowledge and perspectives.

    PubMed

    Wertheim-Tysarowska, Katarzyna; Gos, Monika; Sykut-Cegielska, Jolanta; Bal, Jerzy

    2015-01-01

    Inherited metabolic disorders, also referred to as inborn errors of metabolism (IEM), are a group of congenital disorders caused by mutation in genomic or mitochondrial DNA. IEM are mostly rare disorders with incidence ranging from 1/50,000-1/150,000), however in total IEM may affect even 1/1000 people. A particular mutation affects specific protein or enzyme that improper function leads to alterations in specific metabolic pathway. Inborn errors of metabolism are monogenic disorders that can be inherited in autosomal recessive manner or, less frequently, in autosomal dominant or X-linked patterns. Some exceptions to Mendelian rules of inheritance have also been described. Vast majority of mutations responsible for IEM are small DNA changes affecting single or several nucleotides, although larger rearrangements were also identified. Therefore, the methods used for the identification of pathogenic mutations are mainly based on molecular techniques, preferably on Sanger sequencing. Moreover, the next generation sequencing technique seems to be another prospective method that can be successfully implemented for the diagnosis of inborn errors of metabolism. The identification of the genetic defect underlying the disease is not only indispensable for genetic counseling, but also might be necessary to apply appropriate treatment to the patient. Therapeutic strategies for IEM are continuously elaborated and tested (eg. enzyme replacement therapy, specific cells or organ transplantation or gene therapy, both in vivo and ex vivo) and have already been implemented for several disorders. In this article we present current knowledge about various aspects of IEM on the basis of our own experience and literature review.

  13. [Modern algorithms of diagnosis of benign tumors of the mammary gland: the role of molecular-genetic methods].

    PubMed

    Dubinina, V G; Chetverikov, S G; Zavoloka, A V; Moroziuk, O N

    2014-01-01

    Experience of treatment in 2010-2012 yrs of the patients, suffering mammarial gland tumors, in The Center of Reconstructive and Restoration Medicine (The University Clinic) of The Odessa National Medical University was analyzed. There were examined 143 women with morphologically confirmed mammarial gland cancer (MGT), 56--benign mammary gland tumors and 50 healthy women. Molecular-genetic investigation was performed in the patients-women: there were determined the gene C634G polymorphism of VEGF and of the gene G308A of TNF--a with subsequent estimation of correlation of the mutations quantity and the mammarial gland diseases rate. Algorithm of differential diagnosis of benign tumors must include estimation of polymorphism of the VEGF gene C634G. While revealing of the heterozygous or homozygous bearers of mutation with the gene C634G polymorphism of VEGF the risk of the MGC occurrence is enhancing, what may serve as additional criterion for expedience for conduction of operative treatment in such patients.

  14. More parasitic myositis cases in humans in Australia, and the definition of genetic markers for the causative agents as a basis for molecular diagnosis.

    PubMed

    Koehler, Anson V; Spratt, David M; Norton, Robert; Warren, Sanchia; McEwan, Belinda; Urkude, Ravindra; Murthy, Suresh; Robertson, Thomas; McCallum, Naomi; Parsonson, Fiona; Bradbury, Richard S; Gasser, Robin B

    2016-10-01

    Since 1998, there have been six reported human cases of myositis in Australia, attributable to infection with the nematode Haycocknema perplexum. However, an unequivocal diagnosis of H. perplexum infection and associated disease has been seriously compromised by a lack of molecular markers for this nematode. Here, we report new cases of disseminated myositis in two male patients from the states of Queensland and Tasmania in Australia, respectively; genetically characterize the causative agent from each case; and, also establish a PCR-based sequencing approach as a tool to support the diagnosis of future cases and to underpin epidemiological studies.

  15. Prenatal diagnosis and genetic analysis of a fetus with 47,XX,+21/46,XX mosaicism and XX/XY chimerism.

    PubMed

    Hwa, Hsiao-Lin; Ko, Tsang-Ming; Huang, Chien-Hao; Chang, Li-Shu

    2006-08-01

    Prenatal diagnosis of simultaneous occurrence of chimerism and autosomal mosaicism is extremely rare. We report the prenatal diagnosis and genetic analysis of a fetus in a twin pregnancy with mosaic 47,XX,+21/46,XX with chimeric XX/XY. A 36-year-old, para 1, woman was referred for genetic counseling at 20 weeks' gestation because of abnormal karyotype (47,XX,+21/46,XX) in one fetus in a twin pregnancy. Cordocentesis revealed 47,XX,+21[3]/46,XX[35]/46,XY[7] in this fetus. Postnatal cytogenetic analysis of cord blood confirmed three cell lines in this twin (A) and 46,XY in the co-twin (B). Postmortem pathologic findings of both fetuses were normal. Fluorescence in situ hybridization identified three cell lines in the cord blood of twin A. Molecular genetic analysis using polymorphic DNA markers revealed parental origin of fetal tissue, and confirmed the chimeric status. Molecular genetic analysis with polymorphic DNA markers help to differentiate chimerism from mosaicism and define the origin of cell lines, which may have importance in genetic counseling.

  16. Aspirin-intolerant asthma (AIA) assessment using the urinary biomarkers, leukotriene E4 (LTE4) and prostaglandin D2 (PGD2) metabolites.

    PubMed

    Higashi, Noritaka; Taniguchi, Masami; Mita, Haruhisa; Yamaguchi, Hiromichi; Ono, Emiko; Akiyama, Kazuo

    2012-09-01

    The clinical syndrome of aspirin-intolerant asthma (AIA) is characterized by aspirin/nonsteroidal anti-inflammatory drug intolerance, bronchial asthma, and chronic rhinosinusitis with nasal polyposis. AIA reactions are evidently triggered by pharmacological effect of cyclooxygenase-1 inhibitors. Urine sampling is a non-invasive research tool for time-course measurements in clinical investigations. The urinary stable metabolite concentration of arachidonic acid products provides a time-integrated estimate of the production of the parent compounds in vivo. AIA patients exhibits significantly higher urinary concentrations of leukotriene E(4) (LTE(4)) and 1,15-dioxo-9α-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor-PGDM), a newly identified metabolite of PGD(2), at baseline. This finding suggests the possibility that increased mast cell activation is involved in the pathophysiology of AIA even in a clinically stable condition. In addition, lower urinary concentrations of primary prostaglandin E(2) and 15-epimer of lipoxin A(4) at baseline in the AIA patients suggest that the impaired anti-inflammatory elements may also contribute to the severe clinical outcome of AIA. During the AIA reaction, the urinary concentrations of LTE(4) and PGD(2) metabolites, including tetranor-PGDM significantly and correlatively increase. It is considered that mast cell activation probably is a pathophysiologic hallmark of AIA. However, despite the fact that cyclooxygenease-1 is the dominant in vivo PGD(2) biosynthetic pathway, the precise mechanism underlying the PGD(2) overproduction resulting from the pharmacological effect of cyclooxygenease-1 inhibitors in AIA remains unknown. A comprehensive analysis of the urinary concentration of inflammatory mediators may afford a new research target in elucidating the pathophysiology of AIA. PMID:22627848

  17. Implementation of next-generation sequencing for molecular diagnosis of hereditary breast and ovarian cancer highlights its genetic heterogeneity.

    PubMed

    Pinto, Pedro; Paulo, Paula; Santos, Catarina; Rocha, Patrícia; Pinto, Carla; Veiga, Isabel; Pinheiro, Manuela; Peixoto, Ana; Teixeira, Manuel R

    2016-09-01

    Molecular diagnosis of hereditary breast and ovarian cancer (HBOC) by standard methodologies has been limited to the BRCA1 and BRCA2 genes. With the recent development of new sequencing methodologies, the speed and efficiency of DNA testing have dramatically improved. The aim of this work was to validate the use of next-generation sequencing (NGS) for the detection of BRCA1/BRCA2 point mutations in a diagnostic setting and to study the role of other genes associated with HBOC in Portuguese families. A cohort of 94 high-risk families was included in the study, and they were initially screened for the two common founder mutations with variant-specific methods. Fourteen index patients were shown to carry the Portuguese founder mutation BRCA2 c.156_157insAlu, and the remaining 80 were analyzed in parallel by Sanger sequencing for the BRCA1/BRCA2 genes and by NGS for a panel of 17 genes that have been described as involved in predisposition to breast and/or ovarian cancer. A total of 506 variants in the BRCA1/BRCA2 genes were detected by both methodologies, with a 100 % concordance between them. This strategy allowed the detection of a total of 39 deleterious mutations in the 94 index patients, namely 10 in BRCA1 (25.6 %), 21 in BRCA2 (53.8 %), four in PALB2 (10.3 %), two in ATM (5.1 %), one in CHEK2 (2.6 %), and one in TP53 (2.6 %), with 20.5 % of the deleterious mutations being found in genes other than BRCA1/BRCA2. These results demonstrate the efficiency of NGS for the detection of BRCA1/BRCA2 point mutations and highlight the genetic heterogeneity of HBOC. PMID:27553368

  18. Functional testing strategy for coding genetic variants of unclear significance in MLH1 in Lynch syndrome diagnosis.

    PubMed

    Hinrichsen, Inga; Schäfer, Dieter; Langer, Deborah; Köger, Nicole; Wittmann, Margarethe; Aretz, Stefan; Steinke, Verena; Holzapfel, Stefanie; Trojan, Jörg; König, Rainer; Zeuzem, Stefan; Brieger, Angela; Plotz, Guido

    2015-02-01

    Lynch syndrome is caused by inactivating mutations in the MLH1 gene, but genetic variants of unclear significance frequently preclude diagnosis. Functional testing can reveal variant-conferred defects in gene or protein function. Based on functional defect frequencies and clinical applicability of test systems, we developed a functional testing strategy aimed at efficiently detecting pathogenic defects in coding MLH1 variants. In this strategy, tests of repair activity and expression are prioritized over analyses of subcellular protein localization and messenger RNA (mRNA) formation. This strategy was used for four unclear coding MLH1 variants (p.Asp41His, p.Leu507Phe, p.Gln689Arg, p.Glu605del + p.Val716Met). Expression was analyzed using a transfection system, mismatch repair (MMR) activity by complementation in vitro, mRNA formation by reverse transcriptase-PCR in carrier lymphocyte mRNA, and subcellular localization with dye-labeled fusion constructs. All tests included clinically meaningful controls. The strategy enabled efficient identification of defects in two unclear variants: the p.Asp41His variant showed loss of MMR activity, whereas the compound variant p.Glu605del + p.Val716Met had a defect of expression. This expression defect was significantly stronger than the pathogenic expression reference variant analyzed in parallel, therefore the defect of the compound variant is also pathogenic. Interestingly, the expression defect was caused additively by both of the compound variants, at least one of which is non-pathogenic when occurring by itself. Tests were neutral for p.Leu507Phe and p.Gln689Arg, and the results were consistent with available clinical data. We finally discuss the improved sensitivity and efficiency of the applied strategy and its limitations in analyzing unclear coding MLH1 variants.

  19. Medical genetics

    SciTech Connect

    Jorde, L.B.; Carey, J.C.; White, R.L.

    1995-10-01

    This book on the subject of medical genetics is a textbook aimed at a very broad audience: principally, medical students, nursing students, graduate, and undergraduate students. The book is actually a primer of general genetics as applied to humans and provides a well-balanced introduction to the scientific and clinical basis of human genetics. The twelve chapters include: Introduction, Basic Cell Biology, Genetic Variation, Autosomal Dominant and Recessive Inheritance, Sex-linked and Mitochondrial Inheritance, Clinical Cytogenetics, Gene Mapping, Immunogenetics, Cancer Genetics, Multifactorial Inheritance and Common Disease, Genetic Screening, Genetic Diagnosis and Gene Therapy, and Clinical Genetics and Genetic Counseling.

  20. Design of a high-sensitivity classifier based on a genetic algorithm: application to computer-aided diagnosis

    NASA Astrophysics Data System (ADS)

    Sahiner, Berkman; Chan, Heang-Ping; Petrick, Nicholas; Helvie, Mark A.; Goodsitt, Mitchell M.

    1998-10-01

    A genetic algorithm (GA) based feature selection method was developed for the design of high-sensitivity classifiers, which were tailored to yield high sensitivity with high specificity. The fitness function of the GA was based on the receiver operating characteristic (ROC) partial area index, which is defined as the average specificity above a given sensitivity threshold. The designed GA evolved towards the selection of feature combinations which yielded high specificity in the high-sensitivity region of the ROC curve, regardless of the performance at low sensitivity. This is a desirable quality of a classifier used for breast lesion characterization, since the focus in breast lesion characterization is to diagnose correctly as many benign lesions as possible without missing malignancies. The high-sensitivity classifier, formulated as the Fisher's linear discriminant using GA-selected feature variables, was employed to classify 255 biopsy-proven mammographic masses as malignant or benign. The mammograms were digitized at a pixel size of mm, and regions of interest (ROIs) containing the biopsied masses were extracted by an experienced radiologist. A recently developed image transformation technique, referred to as the rubber-band straightening transform, was applied to the ROIs. Texture features extracted from the spatial grey-level dependence and run-length statistics matrices of the transformed ROIs were used to distinguish malignant and benign masses. The classification accuracy of the high-sensitivity classifier was compared with that of linear discriminant analysis with stepwise feature selection . With proper GA training, the ROC partial area of the high-sensitivity classifier above a true-positive fraction of 0.95 was significantly larger than that of

  1. Single strand conformation polymorphism analysis of androgen receptor gene mutations in patients with androgen insensitivity syndromes: Application for diagnosis, genetic counseling, and therapy

    SciTech Connect

    Hiort, O. Tufts-New England Medical Center, Boston, MA ); Huang, Q. ); Sinnecker, G.H.G.; Kruse, K. ); Sadeghi-Nejad, A.; Wolfe, H.J. ); Yandell, D.W. ) Harvard School of Public Health, Boston, MA )

    1993-07-01

    Recent studies indicate that mutations in the androgen receptor gene are associated with androgen insensitivity syndromes, a heterogeneous group of related disorders involving defective sexual differentiation in karyotypic males. In this report, the authors address the possibility of rapid mutational analysis of the androgen receptor gene for initial diagnosis, genetic counseling, and molecular subclassification of affected patients and their families. DNA from peripheral blood leukocytes of six patients from five families with various degrees of androgen insensitivity was studied. Exons 2 to 8 of the androgen receptor gene were analyzed using a combination of single strand conformation polymorphism analysis and direct DNA sequencing. Female family members were also studied to identify heterozygote carriers. Point mutations in the AR gene were identified in all six patients, and all mutations caused amino acid substitutions. One patient with incomplete androgen insensitivity was a mosaic for the mutation. Four of the five mothers, as well as a young sister of one patient, were carriers of the mutation present in the affected child. The data show that new mutations may occur in the androgen receptor gene leading to sporadic androgen insensitivity syndrome. Molecular genetic characterization of the variant allele can serve as a primary tool for diagnosis and subsequent therapy, and can provide a basis for distinguishing heterozygous carriers in familial androgen resistance. The identification of carriers is of substantial clinical importance for genetic counseling. 29 refs., 2 figs., 1 tab.

  2. Genetics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The genus Capsicum represents one of several well characterized Solanaceous genera. A wealth of classical and molecular genetics research is available for the genus. Information gleaned from its cultivated relatives, tomato and potato, provide further insight for basic and applied studies. Early ...

  3. Genetics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Maintaining genetic variation in wild populations of Arctic organisms is fundamental to the long-term persistence of high latitude biodiversity. Variability is important because it provides options for species to respond to changing environmental conditions and novel challenges such as emerging path...

  4. Effects of Common Pesticides on Prostaglandin D2 (PGD2) Inhibition in SC5 Mouse Sertoli Cells, Evidence of Binding at the COX-2 Active Site, and Implications for Endocrine Disruption

    PubMed Central

    Kugathas, Subramaniam; Audouze, Karine; Ermler, Sibylle; Orton, Frances; Rosivatz, Erika; Scholze, Martin; Kortenkamp, Andreas

    2015-01-01

    Background: There are concerns that diminished prostaglandin action in fetal life could increase the risk of congenital malformations. Many endocrine-disrupting chemicals have been found to suppress prostaglandin synthesis, but to our knowledge, pesticides have never been tested for these effects. Objectives: We assessed the ability of pesticides that are commonly used in the European Union to suppress prostaglandin D2 (PGD2) synthesis. Methods: Changes in PGD2 secretion in juvenile mouse Sertoli cells (SC5 cells) were measured using an ELISA. Coincubation with arachidonic acid (AA) was conducted to determine the site of action in the PGD2 synthetic pathway. Molecular modeling studies were performed to assess whether pesticides identified as PGD2-active could serve as ligands of the cyclooxygenase-2 (COX-2) binding pocket. Results: The pesticides boscalid, chlorpropham, cypermethrin, cyprodinil, fenhexamid, fludioxonil, imazalil (enilconazole), imidacloprid, iprodione, linuron, methiocarb, o-phenylphenol, pirimiphos-methyl, pyrimethanil, and tebuconazole suppressed PGD2 production. Strikingly, some of these substances—o-phenylphenol, cypermethrin, cyprodinil, linuron, and imazalil (enilconazole)—showed potencies (IC50) in the range between 175 and 1,500 nM, similar to those of analgesics intended to block COX enzymes. Supplementation with AA failed to reverse this effect, suggesting that the sites of action of these pesticides are COX enzymes. The molecular modeling studies revealed that the COX-2 binding pocket can accommodate most of the pesticides shown to suppress PGD2 synthesis. Some of these pesticides are also capable of antagonizing the androgen receptor. Conclusions: Chemicals with structural features more varied than previously thought can suppress PGD2 synthesis. Our findings signal a need for in vivo studies to establish the extent of endocrine-disrupting effects that might arise from simultaneous interference with PGD2 signaling and androgen action

  5. How Are Genetic Conditions Diagnosed?

    MedlinePlus

    ... Consultation How are genetic conditions diagnosed? How are genetic conditions diagnosed? A doctor may suspect a diagnosis ... and advocacy resources. For more information about diagnosing genetic conditions: Genetics Home Reference provides information about genetic ...

  6. Presentation of Progressive Familial Intrahepatic Cholestasis Type 3 Mimicking Wilson Disease: Molecular Genetic Diagnosis and Response to Treatment

    PubMed Central

    Jain, Dhanpat; Schilsky, Michael L.

    2015-01-01

    Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal recessive disorder of cholestasis of hepatocellular origin, typically seen in infancy or childhood caused by a defect in the ABCB4 located on chromosome 7. Here we report on an older patient, aged 15, who presented with biochemical testing that led to an initial consideration of a diagnosis of Wilson disease (WD) resulting in a delayed diagnosis of PFIC3. Diagnosis of PFIC3 was later confirmed by molecular studies that identified novel mutations in the ABCB4 gene. Cholestasis due to PFIC3 can cause elevated hepatic copper and increased urine copper excretion that overlap with current diagnostic criteria for WD. Molecular diagnostics are very useful for establishing the diagnosis of PFIC3. Ursodeoxycholic acid ameliorates cholestasis in PFIC3, and may help mediate a reduction in hepatic copper content in response to treatment. PMID:26473142

  7. The role of aldo-keto reductase 1C3 (AKR1C3)-mediated prostaglandin D2 (PGD2) metabolism in keloids.

    PubMed

    Mantel, Alon; Newsome, Austin; Thekkudan, Theresa; Frazier, Robert; Katdare, Meena

    2016-01-01

    Keloids are progressively expanding scars, mostly prevalent in individuals of African descent. Previous data identified increased mast cell number and activation state in keloids suggesting a role in disease progression. The major eicosanoid secreted by mast cells is prostaglandin D2 (PGD2), a relatively unstable pro-inflammatory mediator which can be spontaneously converted to 15-deoxy-(Delta12,14)-prostaglandin J2(15d-PGJ2) or enzymatically metabolized to 9α,11β-PGF2 by aldo-keto reductase 1C3 (AKR1C3). In this work, we investigated the possible role of PGD2 and its metabolites in keloids using CRL1762 keloid fibroblasts (KF) and immunohistochemical staining. Our data suggested approximately 3-fold increase of tryptase-positive mast cell count in keloids compared with normal skin. Furthermore, AKR1C3 was overexpressed in the fibrotic area of keloids while relatively weak staining detected in normal skin. Metabolism of PGD2 to 9α,11β-PGF2 by both, KF and normal fibroblasts, was dependent on AKR1C3 as this reaction was attenuated in the presence of the AKR1C3 inhibitor, 2'-hydroxyflavanone, or in cells with decreased AKR1C3 expression. 15d-PGJ2, but not the other tested PGs, inhibited KF proliferation, attenuated KF-mediated collagen gel contraction and increased caspase-3 activation. In addition, treatment with 15d-PGJ2 activated P38-MAPK, induced reactive oxygen species and upregulated superoxide dismutase-1 (SOD-1). Finally, inhibition of P38-MAPK further augmented 15d-PGJ2-induced caspase-3 cleavage and attenuated its effect on SOD-1 transcription. This work suggests that localized dual inhibition of AKR1C3 and P38-MAPK may inhibit keloid progression. Inhibiting AKR1C3 activity may generate oxidative environment due to redirection of PGD2 metabolism towards 15d-PGJ2 while inhibition of P38-MAPK will sensitize keloid cells to ROS-induced apoptosis. PMID:26308156

  8. Oligonucleotide arrays vs. metaphase-comparative genomic hybridisation and BAC arrays for single-cell analysis: first applications to preimplantation genetic diagnosis for Robertsonian translocation carriers.

    PubMed

    Ramos, Laia; del Rey, Javier; Daina, Gemma; García-Aragonés, Manel; Armengol, Lluís; Fernandez-Encinas, Alba; Parriego, Mònica; Boada, Montserrat; Martinez-Passarell, Olga; Martorell, Maria Rosa; Casagran, Oriol; Benet, Jordi; Navarro, Joaquima

    2014-01-01

    Comprehensive chromosome analysis techniques such as metaphase-Comparative Genomic Hybridisation (CGH) and array-CGH are available for single-cell analysis. However, while metaphase-CGH and BAC array-CGH have been widely used for Preimplantation Genetic Diagnosis, oligonucleotide array-CGH has not been used in an extensive way. A comparison between oligonucleotide array-CGH and metaphase-CGH has been performed analysing 15 single fibroblasts from aneuploid cell-lines and 18 single blastomeres from human cleavage-stage embryos. Afterwards, oligonucleotide array-CGH and BAC array-CGH were also compared analysing 16 single blastomeres from human cleavage-stage embryos. All three comprehensive analysis techniques provided broadly similar cytogenetic profiles; however, non-identical profiles appeared when extensive aneuploidies were present in a cell. Both array techniques provided an optimised analysis procedure and a higher resolution than metaphase-CGH. Moreover, oligonucleotide array-CGH was able to define extra segmental imbalances in 14.7% of the blastomeres and it better determined the specific unbalanced chromosome regions due to a higher resolution of the technique (≈ 20 kb). Applicability of oligonucleotide array-CGH for Preimplantation Genetic Diagnosis has been demonstrated in two cases of Robertsonian translocation carriers 45,XY,der(13;14)(q10;q10). Transfer of euploid embryos was performed in both cases and pregnancy was achieved by one of the couples. This is the first time that an oligonucleotide array-CGH approach has been successfully applied to Preimplantation Genetic Diagnosis for balanced chromosome rearrangement carriers. PMID:25415307

  9. Oligonucleotide Arrays vs. Metaphase-Comparative Genomic Hybridisation and BAC Arrays for Single-Cell Analysis: First Applications to Preimplantation Genetic Diagnosis for Robertsonian Translocation Carriers

    PubMed Central

    Ramos, Laia; del Rey, Javier; Daina, Gemma; García-Aragonés, Manel; Armengol, Lluís; Fernandez-Encinas, Alba; Parriego, Mònica; Boada, Montserrat; Martinez-Passarell, Olga; Martorell, Maria Rosa; Casagran, Oriol; Benet, Jordi; Navarro, Joaquima

    2014-01-01

    Comprehensive chromosome analysis techniques such as metaphase-Comparative Genomic Hybridisation (CGH) and array-CGH are available for single-cell analysis. However, while metaphase-CGH and BAC array-CGH have been widely used for Preimplantation Genetic Diagnosis, oligonucleotide array-CGH has not been used in an extensive way. A comparison between oligonucleotide array-CGH and metaphase-CGH has been performed analysing 15 single fibroblasts from aneuploid cell-lines and 18 single blastomeres from human cleavage-stage embryos. Afterwards, oligonucleotide array-CGH and BAC array-CGH were also compared analysing 16 single blastomeres from human cleavage-stage embryos. All three comprehensive analysis techniques provided broadly similar cytogenetic profiles; however, non-identical profiles appeared when extensive aneuploidies were present in a cell. Both array techniques provided an optimised analysis procedure and a higher resolution than metaphase-CGH. Moreover, oligonucleotide array-CGH was able to define extra segmental imbalances in 14.7% of the blastomeres and it better determined the specific unbalanced chromosome regions due to a higher resolution of the technique (≈20 kb). Applicability of oligonucleotide array-CGH for Preimplantation Genetic Diagnosis has been demonstrated in two cases of Robertsonian translocation carriers 45,XY,der(13;14)(q10;q10). Transfer of euploid embryos was performed in both cases and pregnancy was achieved by one of the couples. This is the first time that an oligonucleotide array-CGH approach has been successfully applied to Preimplantation Genetic Diagnosis for balanced chromosome rearrangement carriers. PMID:25415307

  10. Oligonucleotide arrays vs. metaphase-comparative genomic hybridisation and BAC arrays for single-cell analysis: first applications to preimplantation genetic diagnosis for Robertsonian translocation carriers.

    PubMed

    Ramos, Laia; del Rey, Javier; Daina, Gemma; García-Aragonés, Manel; Armengol, Lluís; Fernandez-Encinas, Alba; Parriego, Mònica; Boada, Montserrat; Martinez-Passarell, Olga; Martorell, Maria Rosa; Casagran, Oriol; Benet, Jordi; Navarro, Joaquima

    2014-01-01

    Comprehensive chromosome analysis techniques such as metaphase-Comparative Genomic Hybridisation (CGH) and array-CGH are available for single-cell analysis. However, while metaphase-CGH and BAC array-CGH have been widely used for Preimplantation Genetic Diagnosis, oligonucleotide array-CGH has not been used in an extensive way. A comparison between oligonucleotide array-CGH and metaphase-CGH has been performed analysing 15 single fibroblasts from aneuploid cell-lines and 18 single blastomeres from human cleavage-stage embryos. Afterwards, oligonucleotide array-CGH and BAC array-CGH were also compared analysing 16 single blastomeres from human cleavage-stage embryos. All three comprehensive analysis techniques provided broadly similar cytogenetic profiles; however, non-identical profiles appeared when extensive aneuploidies were present in a cell. Both array techniques provided an optimised analysis procedure and a higher resolution than metaphase-CGH. Moreover, oligonucleotide array-CGH was able to define extra segmental imbalances in 14.7% of the blastomeres and it better determined the specific unbalanced chromosome regions due to a higher resolution of the technique (≈ 20 kb). Applicability of oligonucleotide array-CGH for Preimplantation Genetic Diagnosis has been demonstrated in two cases of Robertsonian translocation carriers 45,XY,der(13;14)(q10;q10). Transfer of euploid embryos was performed in both cases and pregnancy was achieved by one of the couples. This is the first time that an oligonucleotide array-CGH approach has been successfully applied to Preimplantation Genetic Diagnosis for balanced chromosome rearrangement carriers.

  11. Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases

    PubMed Central

    Ye, Lin; Chang, Judy C.; Lin, Chin; Sun, Xiaofang; Yu, Jingwei; Kan, Yuet Wai

    2009-01-01

    The innovation of reprogramming somatic cells to induced pluripotent stem cells provides a possible new approach to treat β-thalassemia and other genetic diseases such as sickle cell anemia. Induced pluripotent stem (iPS) cells can be made from these patients' somatic cells and the mutation in the β-globin gene corrected by gene targeting, and the cells differentiated into hematopoietic cells to be returned to the patient. In this study, we reprogrammed the skin fibroblasts of a patient with homozygous β0 thalassemia into iPS cells, and showed that the iPS cells could be differentiated into hematopoietic cells that synthesized hemoglobin. Prenatal diagnosis and selective abortion have been effective in decreasing the number of β-thalassemia births in some countries that have instituted carrier screening and genetic counseling. To make use of the cells from the amniotic fluid or chorionic villus sampling that are used for prenatal diagnosis, we also showed that these cells could be reprogrammed into iPS cells. This raises the possibility of providing a new option following prenatal diagnosis of a fetus affected by a severe illness. Currently, the parents would choose either to terminate the pregnancy or continue it and take care of the sick child after birth. The cells for prenatal diagnosis can be converted into iPS cells for treatment in the perinatal periods. Early treatment has the advantage of requiring much fewer cells than adult treatment, and can also prevent organ damage in those diseases in which damage can begin in utero or at an early age. PMID:19482945

  12. Prenatal findings and the genetic diagnosis of fetal overgrowth disorders: Simpson-Golabi-Behmel syndrome, Sotos syndrome, and Beckwith-Wiedemann syndrome.

    PubMed

    Chen, Chih-Ping

    2012-06-01

    With the advent of prenatal sonography, fetal overgrowth can be easily detected. Prenatal-onset overgrowth can be secondary to normal variants of familial tall stature, familial rapid maturation, diabetic macrosomia, and congenital nesidioblastosis, or prenatal-onset overgrowth can be primary due to pathological overgrowth disorders. This article provides a comprehensive review of the prenatal findings and the genetic diagnosis of some of the pathological prenatal-onset overgrowth disorders, such as Simpson-Golabi-Behmel syndrome, Sotos syndrome, and Beckwith-Wiedemann syndrome.

  13. Concurrent visual diagnosis and susceptibility profiling of the first line drug against visceral leishmaniasis by plasmonic detection of PCR amplified genetic biomarker.

    PubMed

    Bose, Partha Pratim; Kumar, Prakash; Munagala, Narendar

    2015-12-01

    Visceral form of leishmaniasis (also known as Kala-azar) is a fatal neglected tropical disease affecting 95 countries worldwide. Recently, substantial proportion of resistance related treatment failure cases have been reported against its first line drug, sodium-antimony gluconate (SAG). We report an easy, fast, sensitive and cheap visual diagnosis and SAG susceptibility profiling for this disease based on recently recognized genetic biomarker and gold nanoparticle based plasmonic detection phenomenon. This is a non-gel, non-culture based detection technique, which can be used as simultaneous high throughput detection and SAG-susceptibility profiling in Leishmania endemic resource stringent countries.

  14. Diagnosis of Parkinson’s disease on the basis of clinical–genetic classification: a population-based modelling study

    PubMed Central

    Nalls, Mike A.; McLean, Cory Y.; Rick, Jacqueline; Eberly, Shirley; Hutten, Samantha J.; Gwinn, Katrina; Sutherland, Margaret; Martinez, Maria; Heutink, Peter; Williams, Nigel; Hardy, John; Gasser, Thomas; Brice, Alexis; Price, T. Ryan; Nicolas, Aude; Keller, Margaux F.; Molony, Cliona; Gibbs, J. Raphael; Chen-Plotkin, Alice; Suh, Eunran; Letson, Christopher; Fiandaca, Massimo S.; Mapstone, Mark; Federoff, Howard J.; Noyce, Alastair J; Morris, Huw; Van Deerlin, Vivianna M.; Weintraub, Daniel; Zabetian, Cyrus; Hernandez, Dena G.; Lesage, Suzanne; Mullins, Meghan; Conley, Emily Drabant; Northover, Carrie; Frasier, Mark; Marek, Ken; Day-Williams, Aaron G.; Stone, David J.; Ioannidis, John P. A.; Singleton, Andrew B.

    2015-01-01

    Background Accurate diagnosis and early detection of complex disease has the potential to be of enormous benefit to clinical trialists, patients, and researchers alike. We sought to create a non-invasive, low-cost, and accurate classification model for diagnosing Parkinson’s disease risk to serve as a basis for future disease prediction studies in prospective longitudinal cohorts. Methods We developed a simple disease classifying model within 367 patients with Parkinson’s disease and phenotypically typical imaging data and 165 controls without neurological disease of the Parkinson’s Progression Marker Initiative (PPMI) study. Olfactory function, genetic risk, family history of PD, age and gender were algorithmically selected as significant contributors to our classifying model. This model was developed using the PPMI study then tested in 825 patients with Parkinson’s disease and 261 controls from five independent studies with varying recruitment strategies and designs including the Parkinson’s Disease Biomarkers Program (PDBP), Parkinson’s Associated Risk Study (PARS), 23andMe, Longitudinal and Biomarker Study in PD (LABS-PD), and Morris K. Udall Parkinson’s Disease Research Center of Excellence (Penn-Udall). Findings Our initial model correctly distinguished patients with Parkinson’s disease from controls at an area under the curve (AUC) of 0.923 (95% CI = 0.900 – 0.946) with high sensitivity (0.834, 95% CI = 0.711 – 0.883) and specificity (0.903, 95% CI = 0.824 – 0.946) in PPMI at its optimal AUC threshold (0.655). The model is also well-calibrated with all Hosmer-Lemeshow simulations suggesting that when parsed into random subgroups, the actual data mirrors that of the larger expected data, demonstrating that our model is robust and fits well. Likewise external validation shows excellent classification of PD with AUCs of 0.894 in PDBP, 0.998 in PARS, 0.955 in 23andMe, 0.929 in LABS-PD, and 0.939 in Penn-Udall. Additionally, when our model

  15. [The relationship between hereditary characteristics in the blood (Phi-PO2-Pgd) and susceptibility to stress in swine. A pilot study].

    PubMed

    Oskam, J P; Dings, A; van Haeringen, H

    1989-06-15

    Deaths during transport and the incidence of a poor quality of the meat in pigs were the most important reasons for studying the stress-syndrome (MHS) during the past twenty years. MHS is controlled by an autosomal Hal locus with two alleles N and n. Only pigs of genotype nn are sensitive to halothane and susceptible to stress. As a standard test for use in practice, the halothane test was developed in the Netherlands in 1974 and only this test is used to detect MHS. Heterozygotes can not be detected using this test. Since 1986, additional blood typing was carried out for the systems Phi, Po2 en Pgd in litters including at least one halothane-positive reactor. Blood typing was carried out in 533 pigs of four different lines of breeding company Cofok in Oosterhout and was found to be very successful (using the linkage groups) in identifying the heterozygotes. In 15.5 per cent of the offspring, it could not be stated whether the genotype was HalNN or HalNn. This was due to the fact that in these Nn x Nn matings the two haplotypes of one or both parents were identical. In this population, the haplotype PhiB-Po2S-PgdB was strongly (72-89 per cent) linked to the Haln-allele.

  16. Genetic principles.

    PubMed

    Abuelo, D

    1987-01-01

    The author discusses the basic principles of genetics, including the classification of genetic disorders and a consideration of the rules and mechanisms of inheritance. The most common pitfalls in clinical genetic diagnosis are described, with emphasis on the problem of the negative or misleading family history.

  17. European guidance for the molecular diagnosis of pseudohypoparathyroidism not caused by point genetic variants at GNAS: an EQA study

    PubMed Central

    Garin, Intza; Mantovani, Giovanna; Aguirre, Urko; Barlier, Anne; Brix, Bettina; Elli, Francesca M; Freson, Kathleen; Grybek, Virginie; Izzi, Benedetta; Linglart, Agnès; Perez de Nanclares, Guiomar; Silve, Caroline; Thiele, Susanne; Werner, Ralf

    2015-01-01

    Pseudohypoparathyroidism is a rare endocrine disorder that can be caused by genetic (mainly maternally inherited inactivating point mutations, although intragenic and gross deletions have rarely been reported) or epigenetic alterations at GNAS locus. Clinical and molecular characterization of this disease is not that easy because of phenotypic, biochemical and molecular overlapping features between both subtypes of the disease. The European Consortium for the study of PHP (EuroPHP) designed the present work with the intention of generating the standards of diagnostic clinical molecular (epi)genetic testing in PHP patients. With this aim, DNA samples of eight independent PHP patients carrying GNAS genetic and/or epigenetic defects (three patients with GNAS deletions, two with 20q uniparental disomy and three with a methylation defect of unknown origin) without GNAS point mutations were anonymized and sent to the five participant laboratories for their routine genetic analysis (methylation-specific (MS)-MLPA, pyrosequencing and EpiTYPER) and interpretations. All laboratories were able to detect methylation defects and, after the data analysis, the Consortium compared the results to define technical advantages and disadvantages of different techniques. To conclude, we propose as first-level investigation in PHP patients copy number and methylation analysis by MS-MLPA. Then, in patients with partial methylation defect, the result should be confirmed by single CpG bisulphite-based methods (ie pyrosequencing), whereas in case of a complete methylation defect without detectable deletion, microsatellites or SNP genotyping should be performed to exclude uniparental disomy 20. PMID:25005735

  18. A Family Perspective of the Value of a Diagnosis for Intellectual Disability: Experiences from a Genetic Research Study

    ERIC Educational Resources Information Center

    Statham, Helen; Ponder, Maggie; Richards, Martin; Hallowell, Nina; Raymond, Frances Lucy

    2011-01-01

    Many professionals working with individuals with intellectual disability are unconcerned with why someone has the impairment. Genetic aspects may be viewed as, at best irrelevant, but more often, potentially negative. However, where the intellectual disability may be inherited, there are implications for family members and the individual. The data…

  19. Autism Spectrum Disorders in Genetic Syndromes: Implications for Diagnosis, Intervention and Understanding the Wider Autism Spectrum Disorder Population

    ERIC Educational Resources Information Center

    Moss, J.; Howlin, P.

    2009-01-01

    Background: An emerging literature on behavioural phenotypes has highlighted apparent associations between autism spectrum disorders (ASDs) or ASD-related phenomenology and a number of different genetically determined syndromes. Method: A systematic review of the current literature regarding the association with ASD and ASD characteristics was…

  20. Mediterranean Founder Mutation Database (MFMD): Taking Advantage from Founder Mutations in Genetics Diagnosis, Genetic Diversity and Migration History of the Mediterranean Population.

    PubMed

    Charoute, Hicham; Bakhchane, Amina; Benrahma, Houda; Romdhane, Lilia; Gabi, Khalid; Rouba, Hassan; Fakiri, Malika; Abdelhak, Sonia; Lenaers, Guy; Barakat, Abdelhamid

    2015-11-01

    The Mediterranean basin has been the theater of migration crossroads followed by settlement of several societies and cultures in prehistoric and historical times, with important consequences on genetic and genomic determinisms. Here, we present the Mediterranean Founder Mutation Database (MFMD), established to offer web-based access to founder mutation information in the Mediterranean population. Mutation data were collected from the literature and other online resources and systematically reviewed and assembled into this database. The information provided for each founder mutation includes DNA change, amino-acid change, mutation type and mutation effect, as well as mutation frequency and coalescence time when available. Currently, the database contains 383 founder mutations found in 210 genes related to 219 diseases. We believe that MFMD will help scientists and physicians to design more rapid and less expensive genetic diagnostic tests. Moreover, the coalescence time of founder mutations gives an overview about the migration history of the Mediterranean population. MFMD can be publicly accessed from http://mfmd.pasteur.ma.

  1. Reproductive genetic counselling in non-mosaic 47,XXY patients: implications for preimplantation or prenatal diagnosis: Case report and review.

    PubMed

    Tachdjian, Gérard; Frydman, Nelly; Morichon-Delvallez, Nicole; Dû, Anne Le; Fanchin, Renato; Vekemans, Michel; Frydman, René

    2003-02-01

    With an incidence of approximately 1 in 500 male newborns, the 47,XXY genotype is one the most common sex chromosome anomalies. It is also the most frequent genetic cause of human infertility. Some non-mosaic 47,XXY patients have sperm production which allows infertility treatment to be offered by ICSI. Therefore, the risk of transmitting a chromosome anomaly to the next generation is an important problem in reproductive genetic counselling of these patients. Here, we report on a twin pregnancy where two karyotypically normal neonates 46,XX and 46,XY were born after the use of ICSI in assisted reproduction of a patient with a non-mosaic 47,XXY syndrome. To date, only 38 evolving pregnancies including the present cases, have been reported after ICSI using sperm from non-mosaic 47,XXY patients. Although these data are scarce, they suggest that the risk of chromosome anomaly in the offspring of these patients is low; hence, their reproductive genetic counselling can be reassuring, and management of the pregnancy can proceed with caution.

  2. [Frequencies of red cell enzyme polymorphisms acP, ADA, AK, EsD, 6-PGD, and PGM1 determined by parallel investigations of Turks and Germans living in the Lübeck area (author's transl)].

    PubMed

    Weissmann, J; Oepen, B; Pribilla, O

    1980-01-01

    Gene frequencies for enzyme polymorphisms in the acP, ADA, AK, EsD, 6-PGD, and PGM1 systems were determined by a random sample (n = 281-556-575) Turks living in Lübeck. The results were compared with those of a parallel inquiry on Germans from Lübeck. The following gene frequencies were detected: (table: see text).

  3. Genetic technology: Promises and problems

    NASA Technical Reports Server (NTRS)

    Frankel, M. S.

    1975-01-01

    Issues concerning the use of genetic technology are discussed. Some areas discussed include treating genetic disease, prenatal diagnosis and selective abortion, screening for genetic disease, and genetic counseling. Policy issues stemming from these capabilities are considered.

  4. Analysis of mtDNA variant segregation during early human embryonic development: a tool for successful NARP preimplantation diagnosis

    PubMed Central

    Steffann, J; Frydman, N; Gigarel, N; Burlet, P; Ray, P F; Fanchin, R; Feyereisen, E; Kerbrat, V; Tachdjian, G; Bonnefont, J‐P; Frydman, R; Munnich, A

    2006-01-01

    Background Diseases arising from mitochondrial DNA (mtDNA) mutations are usually serious pleiotropic disorders with maternal inheritance. Owing to the high recurrence risk in the progeny of carrier females, “at‐risk” couples often ask for prenatal diagnosis. However, reliability of such practices remains under debate. Preimplantation diagnosis (PGD), a theoretical alternative to conventional prenatal diagnosis, requires that the mutant load measured in a single cell from an eight cell embryo accurately reflects the overall heteroplasmy of the whole embryo, but this is not known to be the case. Objective To investigate the segregation of an mtDNA length polymorphism in blastomeres of 15 control embryos from four unrelated couples, the NARP mutation in blastomeres of three embryos from a carrier of this mutation. Results Variability of the mtDNA polymorphism heteroplasmy among blastomeres from each embryo was limited, ranging from zero to 19%, with a mean of 7%. PGD for the neurogenic ataxia retinitis pigmentosa (NARP) mtDNA mutation (8993T→G) was therefore carried out in the carrier mother of an affected child. One of three embryos was shown to carry 100% of mutant mtDNA species while the remaining two were mutation‐free. These two embryos were transferred, resulting in a singleton pregnancy with delivery of a healthy child. Conclusions This PGD, the first reported for a mtDNA mutation, illustrates the skewed meiotic segregation of the NARP mtDNA mutation in early human development. However, discrepancies between the segregation patterns of the NARP mutation and the HV2 polymorphism indicate that a particular mtDNA nucleotide variant might differentially influenced the mtDNA segregation, precluding any assumption on feasibility of PGD for other mtDNA mutations. PMID:16155197

  5. Do recent US Supreme Court rulings on patenting of genes and genetic diagnostics affect the practice of genetic screening and diagnosis in prenatal and reproductive care?

    PubMed Central

    Chandrasekharan, Subhashini; McGuire, Amy L.; Van den Veyver, Ignatia B.

    2015-01-01

    Thousands of patents have been awarded that claim human gene sequences and their uses, and some have been challenged in court. In a recent high-profile case, Association for Molecular Pathology, et al. vs. Myriad Genetics, Inc., et al., the United States Supreme Court ruled that genes are natural occurring substances and therefore not patentable through “composition of matter” claims. The consequences of this ruling will extend well beyond ending Myriad's monopoly over BRCA testing, and may affect similar monopolies of other commercial laboratories for tests involving other genes. It could also simplify intellectual property issues surrounding genome-wide clinical sequencing, which can generate results for genes covered by intellectual property. Non-invasive prenatal testing (NIPT) for common aneuploidies using cell-free fetal (cff) DNA in maternal blood is currently offered through commercial laboratories and is also the subject of ongoing patent litigation. The recent Supreme Court decision in the Myriad case has already been invoked by a lower district court in NIPT litigation and resulted in invalidation of primary claims in a patent on currently marketed cffDNA-based testing for chromosomal aneuploidies. PMID:24989832

  6. Do recent US Supreme Court rulings on patenting of genes and genetic diagnostics affect the practice of genetic screening and diagnosis in prenatal and reproductive care?

    PubMed

    Chandrasekharan, Subhashini; McGuire, Amy L; Van den Veyver, Ignatia B

    2014-10-01

    Thousands of patents have been awarded that claim human gene sequences and their uses, and some have been challenged in court. In a recent high-profile case, Association for Molecular Pathology, et al. v. Myriad Genetics, Inc., et al., the US Supreme Court ruled that genes are natural occurring substances and therefore not patentable through 'composition of matter' claims. The consequences of this ruling will extend well beyond ending Myriad's monopoly over BRCA testing and may affect similar monopolies of other commercial laboratories for tests involving other genes. It could also simplify intellectual property issues surrounding genome-wide clinical sequencing, which can generate results for genes covered by intellectual property. Non-invasive prenatal testing (NIPT) for common aneuploidies using cell-free fetal (cff) DNA in maternal blood is currently offered through commercial laboratories and is also the subject of ongoing patent litigation. The recent Supreme Court decision in the Myriad case has already been invoked by a lower district court in NIPT litigation and resulted in invalidation of primary claims in a patent on currently marketed cffDNA-based testing for chromosomal aneuploidies.

  7. [Andersen-Tawil syndrome: a review of its clinical and genetic diagnosis with emphasis on cardiac manifestations].

    PubMed

    Márquez, Manlio F; Totomoch-Serra, Armando; Vargas-Alarcón, Gilberto; Cruz-Robles, David; Pellizzon, Oscar A; Cárdenas, Manuel

    2014-01-01

    The Andersen-Tawil syndrome is a cardiac ion channel disease that is inherited in an autosomal dominant way and is classified as type 7 of the congenital long QT syndromes. Affected gene is KCNJ2, which forms the inward rectifier potassium channel designated Kir2.1. This protein is involved in stabilizing the resting membrane potential and controls the duration of the action potential in skeletal muscle and heart. It also participates in the terminal repolarization phase of the action potential in ventricular myocytes and is a major component responsible for the correction in the potassium current during phase 3 of the action potential repolarization. Kir 2.1 channel has a predominant role in skeletal muscle, heart and brain. Alterations in this channel produce flaccid paralysis, arrhythmias, impaired skeletal development primarily in extremities and facial area. In this review we address the disease from the point of view of clinical and molecular diagnosis with emphasis on cardiac manifestations.

  8. Use of high-throughput targeted exome sequencing in genetic diagnosis of Chinese family with congenital cataract

    PubMed Central

    Ma, Ming-Fu; Li, Lian-Bing; Pei, Yun-Qi; Cheng, Zhi

    2016-01-01

    AIM To identify disease-causing mutation in a congenital cataract family using enrichment of targeted genes combined with next-generation sequencing. METHODS A total of 371 known genes related to inherited eye diseases of the proband was selected and captured, followed by high-throughput sequencing. The sequencing data were analyzed by established bioinformatics pipeline. Validation was performed by Sanger sequencing. RESULTS A recurrent heterozygous non-synonymous mutation c.130G>A (p.V44M) in the GJA3 gene was identified in the proband. The result was confirmed by Sanger sequencing. The mutation showed co-segregation with the disease phenotype in the family but was not detected in unaffected controls. CONCLUSION Targeted exome sequencing is a rapid, high-throughput and cost-efficient method for screening known genes and could be applied to the routine gene diagnosis of congenital cataract. PMID:27275416

  9. A comprehensive genetic diagnosis of Chinese muscular dystrophy and congenital myopathy patients by targeted next-generation sequencing.

    PubMed

    Dai, Yi; Wei, Xiaoming; Zhao, Yanhuan; Ren, Haitao; Lan, Zhangzhang; Yang, Yun; Chen, Lin; Cui, Liying

    2015-08-01

    Muscular dystrophies and congenital myopathies are a large group of heterogeneous inherited muscle disorders. The spectrum of muscular dystrophies and congenital myopathies extends to more than 50 diseases today, even excluding the common forms Duchenne Muscular Dystrophy, Myotonic Dystrophy and Facioscapulohumeral Dystrophy. Unfortunately, even by critical clinical evaluation and muscle pathology, diagnosis is still difficult. To potentially remediate this difficulty, we applied a microarray-based targeted next-generation sequencing (NGS) technology to diagnose these patients. There were 55 consecutive unrelated patients who underwent the test, 36 of which (65%) were found to have a causative mutation. Our result shows the accuracy and efficiency of next-generation sequencing in clinical circumstances and reflects the features and relative distribution of inherited myopathies in the Chinese population.

  10. [Current Status of Genetic Diagnosis of Charcot-Marie-Tooth Disease: Variety of the Disease-causing Genes].

    PubMed

    Hashiguchi, Akihiro; Higuchi, Yujiro; Takashima, Hiroshi

    2016-01-01

    At least 40 genes have been associated with Charcot-Marie-Tooth disease (CMT) and the related inherited neuropathies. Genetic studies have revealed the following factors as causes of inherited neuropathies: myelin components, transcription factors for myelination, myelin maintenance systems, differentiation factors of the peripheral nerve, neurofilaments, protein transfer systems, mitochondrial proteins, DNA repair, RNA/protein synthesis, ion channels, and aminoacyl-tRNA synthetases. Since 2007, we have tried to screen for mutations in CMT patients using microarrays or next generation sequencers. As a result, the detection rate of gene mutations has improved to about 25%. In this study, we applied target resequencing to 72 genes. From the negative examples, we identified the cases based on clinical course, family history, and electrophysiological findings, and then performed exome analysis. We then tried to identify novel causative genes by analyzing the enormous data obtained from our exome analysis.

  11. A truncated hMSH2 transcript occurs as a common variant in the population: implications for genetic diagnosis.

    PubMed

    Xia, L; Shen, W; Ritacca, F; Mitri, A; Madlensky, L; Berk, T; Cohen, Z; Gallinger, S; Bapat, B

    1996-05-15

    Germline mutations of the hMSH2 gene are responsible for many cases of hereditary nonpolyposis colorectal cancer. While screening for hMSH2 gene mutations in hereditary nonpolyposis colorectal cancer kindreds, we observed that a previously reported germline mutation is in fact a common, alternatively spliced variant in the population. Using RT-PCR and the protein truncation test, the hMSH2 exon 13 deletion variant was found in more than 90% of individuals. The exon 13 deletion transcript was only present in lymphocyte RNA, no abnormalities were detected in genomic DNA flanking exon 13, and the deletion transcript is apparently not translated. These findings highlight further that caution should be exercised in providing genetic risk assessment on the basis of currently used germline mutation detection strategies. PMID:8625301

  12. IFI27 Is a Useful Genetic Marker for Diagnosis of Immunoglobulin A Nephropathy and Membranous Nephropathy Using Peripheral Blood

    PubMed Central

    Muso, Eri; Yamamoto, Ryohei; Shinzawa, Maki; Iwasaki, Yukako; Iwatani, Hirotsugu; Nakanishi, Takeshi; Isaka, Yoshitaka; Nojima, Hiroshi

    2016-01-01

    Diagnosis of chronic glomerulonephritis (CGN) depends primarily on renal biopsy, which is expensive and requires hospitalization, creating a demand for noninvasive diagnostic method for this disease. We used DNA microarray analysis to search for genes whose expression levels in peripheral blood mononuclear cells (PBMCs) could distinguish between patients with CGN and healthy volunteers (HVs). We selected immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) as typical forms of CGN. The mRNA level of the gene encoding interferon (IFN)-alpha-inducible protein 27, IFI27, which is preferentially expressed in podocytes of glomeruli, was lower in PBMCs of IgAN and MN patients than in those of HVs. This result was confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Moreover, qRT-PCR analysis revealed that the IFI27 mRNA level was reduced in PBMCs of patients with other types of chronic glomerulonephritis. IFI27 immunohistochemical staining of biopsied specimens also confirmed reduced expression of IFI27 protein in IgAN and MN patients. Based on these results, we propose that IFI27 could serve as a noninvasive diagnostic marker for CGNs using peripheral blood. PMID:27100186

  13. IFI27 Is a Useful Genetic Marker for Diagnosis of Immunoglobulin A Nephropathy and Membranous Nephropathy Using Peripheral Blood.

    PubMed

    Nagasawa, Yasuyuki; Okuzaki, Daisuke; Muso, Eri; Yamamoto, Ryohei; Shinzawa, Maki; Iwasaki, Yukako; Iwatani, Hirotsugu; Nakanishi, Takeshi; Isaka, Yoshitaka; Nojima, Hiroshi

    2016-01-01

    Diagnosis of chronic glomerulonephritis (CGN) depends primarily on renal biopsy, which is expensive and requires hospitalization, creating a demand for noninvasive diagnostic method for this disease. We used DNA microarray analysis to search for genes whose expression levels in peripheral blood mononuclear cells (PBMCs) could distinguish between patients with CGN and healthy volunteers (HVs). We selected immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) as typical forms of CGN. The mRNA level of the gene encoding interferon (IFN)-alpha-inducible protein 27, IFI27, which is preferentially expressed in podocytes of glomeruli, was lower in PBMCs of IgAN and MN patients than in those of HVs. This result was confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Moreover, qRT-PCR analysis revealed that the IFI27 mRNA level was reduced in PBMCs of patients with other types of chronic glomerulonephritis. IFI27 immunohistochemical staining of biopsied specimens also confirmed reduced expression of IFI27 protein in IgAN and MN patients. Based on these results, we propose that IFI27 could serve as a noninvasive diagnostic marker for CGNs using peripheral blood. PMID:27100186

  14. Predictive testing and existential absurdity: resonances between experiences around genetic diagnosis and the philosophy of Albert Camus.

    PubMed

    Porz, Rouven; Widdershoven, Guy

    2011-07-01

    Predictive genetic testing may confront those affected with difficult life situations that they have not experienced before. These life situations may be interpreted as 'absurd'. In this paper we present a case study of a predictive test situation, showing the perspective of a woman going through the process of deciding for or against taking the test, and struggling with feelings of alienation. To interpret her experiences, we refer to the concept of absurdity, developed by the French Philosopher Albert Camus. Camus' writings on absurdity appear to resonate with patients' stories when they talk about their body and experiences of illness. In this paper we draw on Camus' philosophical essay 'The Myth of Sisyphus' (1942), and compare the absurd experiences of Sisyphus with the interviewee's story. This comparison opens up a field of ethical reflection. We demonstrate that Camus' concept of absurdity offers a new and promising approach to understanding the fragility of patients' situations, especially in the field of predictive testing. We show that people affected might find new meaning through narratives that help them to reconstruct the absurd without totally overcoming it. In conclusion, we will draw out some normative consequences of our narrative approach.

  15. Clinical evaluation, biochemistry and genetic polymorphism analysis for the diagnosis of lactose intolerance in a population from northeastern Brazil

    PubMed Central

    Ponte, Paulo Roberto Lins; de Medeiros, Pedro Henrique Quintela Soares; Havt, Alexandre; Caetano, Joselany Afio; Cid, David A C; de Moura Gondim Prata, Mara; Soares, Alberto Melo; Guerrant, Richard L; Mychaleckyj, Josyf; Lima, Aldo Ângelo Moreira

    2016-01-01

    OBJECTIVE: This work aimed to evaluate and correlate symptoms, biochemical blood test results and single nucleotide polymorphisms for lactose intolerance diagnosis. METHOD: A cross-sectional study was conducted in Fortaleza, Ceará, Brazil, with a total of 119 patients, 54 of whom were lactose intolerant. Clinical evaluation and biochemical blood tests were conducted after lactose ingestion and blood samples were collected for genotyping evaluation. In particular, the single nucleotide polymorphisms C>T-13910 and G>A-22018 were analyzed by restriction fragment length polymorphism/polymerase chain reaction and validated by DNA sequencing. RESULTS: Lactose-intolerant patients presented with more symptoms of flatulence (81.4%), bloating (68.5%), borborygmus (59.3%) and diarrhea (46.3%) compared with non-lactose-intolerant patients (p<0.05). We observed a significant association between the presence of the alleles T-13910 and A-22018 and the lactose-tolerant phenotype (p<0.05). After evaluation of the biochemical blood test results for lactose, we found that the most effective cutoff for glucose levels obtained for lactose malabsorbers was <15 mg/dL, presenting an area under the receiver operating characteristic curve greater than 80.3%, with satisfactory values for sensitivity and specificity. CONCLUSIONS: These data corroborate the association of these single nucleotide polymorphisms (C>T-13910 and G>A-22018) with lactose tolerance in this population and suggest clinical management for patients with lactose intolerance that considers single nucleotide polymorphism detection and a change in the biochemical blood test cutoff from <25 mg/dL to <15 mg/dL. PMID:26934237

  16. Attitudes of women of advanced maternal age undergoing invasive prenatal diagnosis and the impact of genetic counselling.

    PubMed

    Godino, Lea; Pompilii, Eva; D'Anna, Federica; Morselli-Labate, Antonio M; Nardi, Elena; Seri, Marco; Rizzo, Nicola; Pilu, Gianluigi; Turchetti, Daniela

    2016-03-01

    Despite the increasing availability and effectiveness of non-invasive screening for foetal aneuploidies, most women of advanced maternal age (AMA) still opt for invasive tests. A retrospective cross-sectional survey was performed on women of AMA undergoing prenatal invasive procedures, in order to explore their motivations and the outcome of preliminary genetic counselling according to the approach (individual or group) adopted. Of 687 eligible women, 221 (32.2%) participated: 117 had received individual counselling, while 104 had attended group sessions. The two groups did not differ by socio-demographic features. The commonest reported reason to undergo invasive tests was AMA itself (67.4%), while only 10.4% of women mentioned the opportunity of making informed choices. The majority perceived as clear and helpful the information received at counselling, and only 12.7% had doubts left that, however, often concerned non-pertinent issues. The impact of counselling on risk perception and decisions was limited: a minority stated their perceived risk of foetal abnormalities had either increased (6.8%) or reduced (3.6%), and only one eventually declined invasive test. The 52.6% of women expressed a preference toward individual counselling, which also had a stronger impact on perceived risk reduction (P=0.003). Nevertheless, group counselling had a more favourable impact on both clarity of understanding and helpfulness (P=0.0497 and P=0.035, respectively). The idea that AMA represents an absolute indication for invasive tests appears deeply rooted; promotion of non-invasive techniques may require extensive educational efforts targeted to both the general population and health professionals.

  17. Genetic diagnosis of autosomal dominant polycystic kidney disease by targeted capture and next-generation sequencing: utility and limitations.

    PubMed

    Qi, Xiao-Ping; Du, Zhen-Fang; Ma, Ju-Ming; Chen, Xiao-Ling; Zhang, Qing; Fei, Jun; Wei, Xiao-Ming; Chen, Dong; Ke, Hai-Ping; Liu, Xuan-Zhu; Li, Feng; Chen, Zhen-Guang; Su, Zheng; Jin, Hang-Yang; Liu, Wen-Ting; Zhao, Yan; Jiang, Hu-Ling; Lan, Zhang-Zhang; Li, Peng-Fei; Fang, Ming-Yan; Dong, Wei; Zhang, Xian-Ning

    2013-03-01

    Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, and duplication sequences of PKD1. Recently, targeted resequencing by pooling long-range polymerase chain reaction (LR-PCR) amplicons has been used in the identification of mutations in ADPKD. Despite its high sensitivity, specificity and accuracy, LR-PCR is still complicated. We performed whole-exome sequencing on two unrelated typical Chinese ADPKD probands and evaluated the effectiveness of this approach compared with Sanger sequencing. Meanwhile, we performed targeted gene and next-generation sequencing (targeted DNA-HiSeq) on 8 individuals (1 patient from one family, 5 patients and 2 normal individuals from another family). Both whole-exome sequencing and targeted DNA-HiSeq confirmed c.11364delC (p.H3788QfsX37) within the unduplicated region of PKD1 in one proband; in the other family, targeted DNA-HiSeq identified a small insertion, c.401_402insG (p.V134VfsX79), in PKD2. These methods do not overcome the screening complexity of homology. However, the true positives of variants confirmed by targeted gene and next-generation sequencing were 69.4%, 50% and 100% without a false positive in the whole coding region and the duplicated and unduplicated regions, which indicated that the screening accuracy of PKD1 and PKD2 can be largely improved by using a greater sequencing depth and elaborate design of the capture probe.

  18. Utility of immunohistochemical investigation of SDHB and molecular genetic analysis of SDH genes in the differential diagnosis of mesenchymal tumors of GIT.

    PubMed

    Dubova, M; Sedivcova, M; Michal, M; Kokoskova, B; Ryska, A; Smid, D; Daum, O

    2015-02-01

    Loss of expression of beta subunit of succinate dehydrogenase (SDHB) was proved to be present in a subgroup of KIT/PDGFRA wt gastrointestinal stromal tumors (GISTs). To evaluate possible diagnostic utility of SDHB immunohistochemistry in the differential diagnostics of mesenchymal tumors of gastrointestinal tract (GIT), 11 cases of KIT/PDGFRA wt GISTs, 12 gastric schwannomas (GSs), 20 solitary fibrous tumors (SFTs), 4 leiomyomas (LMs), 16 leiomyosarcomas (LMSs), 5 synovial sarcomas (SSs), 3 endometrioid stromal sarcomas (ESSs), and 1 ileal inflammatory myofibroblastic tumor (IMT) were investigated for SDHB immunoexpression together with molecular genetic analysis of genes encoding succinate dehydrogenase (SDH). Three recent cases of KIT/PDGFRA mutant GISTs were used as controls. Among the 11 KIT/PDGFRA wt GISTs, 6 expressed SDHB, 1 of them harboring a sequence change of SDHD. All SDHB-negative cases were SDHB-D wt. In 1 of the control GIST cases molecular genetic analysis revealed an SDHD sequence change in addition to a mutation in KIT exon 11. No SFT was truly SDHB-negative, but in 2 of them the staining was impossible to analyze. Furthermore, 1 SFT carried an SDHB and another 1 SDHD sequence change. All GSs, LMs, LMSs, SSs, ESSs, and IMT were SDHB-positive or non-analyzable, and SDHB-D wt. Additional factors may play a role in regulating expression of SDHB. Furthermore, SDHB immunohistochemistry alone may be misleading in excluding tumors other than GIST (especially SFT) in the differential diagnosis of KIT/PDGFRA wt mesenchymal tumors of GIT.

  19. Absence of family history and phenotype-genotype correlation in pediatric Brugada syndrome: more burden to bear in clinical and genetic diagnosis.

    PubMed

    Daimi, Houria; Khelil, Amel Haj; Ben Hamda, Khaldoun; Aranega, Amelia; Chibani, Jemni B E; Franco, Diego

    2015-06-01

    Brugada syndrome (BrS) is an autosomal-dominant genetic cardiac disorder caused in 18-30 % of the cases by SCN5A gene mutations and manifested by an atypical right bundle block pattern with ST segment elevation and T wave inversion in the right precordial leads. The syndrome is usually detected after puberty. The identification of BrS in pediatric patients is thus a rare occurrence, and most of the reported cases are unmasked after febrile episodes. Usually, having a family history of sudden death represents the first reason to perform an ECG in febrile children. However, this practice makes the sporadic cases of cardiac disease and specially the asymptomatic ones excluded from this diagnosis. Here, we report a sporadic case of a 2-month-old male patient presented with vaccination-related fever and ventricular tachycardia associated with short breathing, palpitation and cold sweating. ECG changes were consistent with type 1 BrS. SCN5A gene analysis of the proband and his family revealed a set of mutations and polymorphisms differentially distributed among family members, however, without any clear genotype-phenotype correlation. Based on our findings, we think that genetic testing should be pursued as a routine practice in symptomatic and asymptomatic pediatric cases of BrS, with or without family history of sudden cardiac death. Similarly, our study suggests that pediatrician should be encouraged to perform an ECG profiling in suspicious febrile children and quickly manage fever since it is the most important factor unmasking BrS in children.

  20. WHAT ROLE SHOULD PUBLIC OPINION PLAY IN ETHICO-LEGAL DECISION MAKING? THE EXAMPLE OF SELECTING SEX FOR NON-MEDICAL REASONS USING PREIMPLANTATION GENETIC DIAGNOSIS.

    PubMed

    Fovargue, Sara; Bennett, Rebecca

    2016-01-01

    In this article, we consider the prohibition on the use of preimplantation genetic diagnosis to select an embryo on the basis of its sex for non -: medical reasons. We use this as a case study to explore the role that public consultations have and should play in ethico-legal decision-making. Until the Human Fertilisation and Embryology Act 1990 was amended by the Human Fertilisation and Embryology Act 2008, non-medical sex selection of an embryo was not statutorily regulated, but it was the policy of the Human Fertilisation and Embryology Authority that such selection should not occur. However, since 2009, it has been a criminal offence to select an embryo on the basis of its sex for non-medical reasons. We consider the reasons given for this change and explore the role that 'public opinion' had in the decision-making process. On the face of it, asking the public what they think seems reasonable, fair and democratic, and those who are not in favour of public consultations being accorded great weight in matters of policy may appear out of touch and as wanting to impose their moral views on the public at large. But there are problems with doing so, especially when seeking to regulate ethically controversial issues. We discuss whether regulation should be influenced by public opinion obtained via 'public consultations', and utilise sex selection for non-medical reasons as an example of how (apparently) public opinion was used to support the criminalisation of this practice.

  1. Importance of Genetic Diversity Assessment in Crop Plants and Its Recent Advances: An Overview of Its Analytical Perspectives

    PubMed Central

    Govindaraj, M.; Vetriventhan, M.; Srinivasan, M.

    2015-01-01

    The importance of plant genetic diversity (PGD) is now being recognized as a specific area since exploding population with urbanization and decreasing cultivable lands are the critical factors contributing to food insecurity in developing world. Agricultural scientists realized that PGD can be captured and stored in the form of plant genetic resources (PGR) such as gene bank, DNA library, and so forth, in the biorepository which preserve genetic material for long period. However, conserved PGR must be utilized for crop improvement in order to meet future global challenges in relation to food and nutritional security. This paper comprehensively reviews four important areas; (i) the significance of plant genetic diversity (PGD) and PGR especially on agriculturally important crops (mostly field crops); (ii) risk associated with narrowing the genetic base of current commercial cultivars and climate change; (iii) analysis of existing PGD analytical methods in pregenomic and genomic era; and (iv) modern tools available for PGD analysis in postgenomic era. This discussion benefits the plant scientist community in order to use the new methods and technology for better and rapid assessment, for utilization of germplasm from gene banks to their applied breeding programs. With the advent of new biotechnological techniques, this process of genetic manipulation is now being accelerated and carried out with more precision (neglecting environmental effects) and fast-track manner than the classical breeding techniques. It is also to note that gene banks look into several issues in order to improve levels of germplasm distribution and its utilization, duplication of plant identity, and access to database, for prebreeding activities. Since plant breeding research and cultivar development are integral components of improving food production, therefore, availability of and access to diverse genetic sources will ensure that the global food production network becomes more sustainable

  2. Importance of genetic diversity assessment in crop plants and its recent advances: an overview of its analytical perspectives.

    PubMed

    Govindaraj, M; Vetriventhan, M; Srinivasan, M

    2015-01-01

    The importance of plant genetic diversity (PGD) is now being recognized as a specific area since exploding population with urbanization and decreasing cultivable lands are the critical factors contributing to food insecurity in developing world. Agricultural scientists realized that PGD can be captured and stored in the form of plant genetic resources (PGR) such as gene bank, DNA library, and so forth, in the biorepository which preserve genetic material for long period. However, conserved PGR must be utilized for crop improvement in order to meet future global challenges in relation to food and nutritional security. This paper comprehensively reviews four important areas; (i) the significance of plant genetic diversity (PGD) and PGR especially on agriculturally important crops (mostly field crops); (ii) risk associated with narrowing the genetic base of current commercial cultivars and climate change; (iii) analysis of existing PGD analytical methods in pregenomic and genomic era; and (iv) modern tools available for PGD analysis in postgenomic era. This discussion benefits the plant scientist community in order to use the new methods and technology for better and rapid assessment, for utilization of germplasm from gene banks to their applied breeding programs. With the advent of new biotechnological techniques, this process of genetic manipulation is now being accelerated and carried out with more precision (neglecting environmental effects) and fast-track manner than the classical breeding techniques. It is also to note that gene banks look into several issues in order to improve levels of germplasm distribution and its utilization, duplication of plant identity, and access to database, for prebreeding activities. Since plant breeding research and cultivar development are integral components of improving food production, therefore, availability of and access to diverse genetic sources will ensure that the global food production network becomes more sustainable

  3. Frontotemporal Dementia: Genetics

    MedlinePlus

    ... Calendar of Events Fundraising Events Conferences Press Releases Genetics of FTD After receiving a diagnosis of FTD ... that recent advances in science have brought the genetics of FTD into much better focus. In 2012, ...

  4. Genetic engineering, medicine and medical genetics.

    PubMed

    Motulsky, A G

    1984-01-01

    The impact of DNA technology in the near future will be on the manufacture of biologic agents and reagents that will lead to improved therapy and diagnosis. The use of DNA technology for prenatal and preclinical diagnosis in genetic diseases is likely to affect management of genetic diseases considerably. New and old questions regarding selective abortion and the psychosocial impact of early diagnosis of late appearing diseases and of genetic susceptibilities are being raised. Somatic therapy with isolated genes to treat disease has not been achieved. True germinal genetic engineering is far off for humans but may find applications in animal agriculture.

  5. Genetics Home Reference: sporadic hemiplegic migraine

    MedlinePlus

    ... Diagnosis & Management These resources address the diagnosis or management of sporadic hemiplegic migraine: Genetic Testing Registry: Migraine, sporadic hemiplegic Journal of the American Medical Association Patient Page: Migraine ...

  6. Macrophages programmed by apoptotic cells inhibit epithelial-mesenchymal transition in lung alveolar epithelial cells via PGE2, PGD2, and HGF

    PubMed Central

    Yoon, Young-So; Lee, Ye-Ji; Choi, Youn-Hee; Park, Young Mi; Kang, Jihee Lee

    2016-01-01

    Apoptotic cell clearance results in the release of growth factors and the action of signaling molecules involved in tissue homeostasis maintenance. Here, we investigated whether and how macrophages programmed by apoptotic cells inhibit the TGF-β1-induced Epithelial-mesenchymal transition (EMT) process in lung alveolar epithelial cells. Treatment with conditioned medium derived from macrophages exposed to apoptotic cells, but not viable or necrotic cells, inhibited TGF-β1-induced EMT, including loss of E-cadherin, synthesis of N-cadherin and α-smooth muscle actin, and induction of EMT-activating transcription factors, such as Snail1/2, Zeb1/2, and Twist1. Exposure of macrophages to cyclooxygenase (COX-2) inhibitors (NS-398 and COX-2 siRNA) or RhoA/Rho kinase inhibitors (Y-27632 and RhoA siRNA) and LA-4 cells to antagonists of prostaglandin E2 (PGE2) receptor (EP4 [AH-23848]), PGD2 receptors (DP1 [BW-A868C] and DP2 [BAY-u3405]), or the hepatocyte growth factor (HGF) receptor c-Met (PHA-665752), reversed EMT inhibition by the conditioned medium. Additionally, we found that apoptotic cell instillation inhibited bleomycin-mediated EMT in primary mouse alveolar type II epithelial cells in vivo. Our data suggest a new model for epithelial cell homeostasis, by which the anti-EMT programming of macrophages by apoptotic cells may control the progressive fibrotic reaction via the production of potent paracrine EMT inhibitors. PMID:26875548

  7. The H-bond network surrounding the pyranopterins modulates redox cooperativity in the molybdenum-bisPGD cofactor in arsenite oxidase.

    PubMed

    Duval, Simon; Santini, Joanne M; Lemaire, David; Chaspoul, Florence; Russell, Michael J; Grimaldi, Stephane; Nitschke, Wolfgang; Schoepp-Cothenet, Barbara

    2016-09-01

    While the molybdenum cofactor in the majority of bisPGD enzymes goes through two consecutive 1-electron redox transitions, previous protein-film voltammetric results indicated the possibility of cooperative (n=2) redox behavior in the bioenergetic enzyme arsenite oxidase (Aio). Combining equilibrium redox titrations, optical and EPR spectroscopies on concentrated samples obtained via heterologous expression, we unambiguously confirm this claim and quantify Aio's redox cooperativity. The stability constant, Ks, of the Mo(V) semi-reduced intermediate is found to be lower than 10(-3). Site-directed mutagenesis of residues in the vicinity of the Mo-cofactor demonstrates that the degree of redox cooperativity is sensitive to H-bonding interactions between the pyranopterin moieties and amino acid residues. Remarkably, in particular replacing the Gln-726 residue by Gly results in stabilization of (low-temperature) EPR-observable Mo(V) with KS=4. As evidenced by comparison of room temperature optical and low temperature EPR titrations, the degree of stabilization is temperature-dependent. This highlights the importance of room-temperature redox characterizations for correctly interpreting catalytic properties in this group of enzymes. Geochemical and phylogenetic data strongly indicate that molybdenum played an essential biocatalytic roles in early life. Molybdenum's redox versatility and in particular the ability to show cooperative (n=2) redox behavior provide a rationale for its paramount catalytic importance throughout the evolutionary history of life. Implications of the H-bonding network modulating Molybdenum's redox properties on details of a putative inorganic metabolism at life's origin are discussed.

  8. Macrophages programmed by apoptotic cells inhibit epithelial-mesenchymal transition in lung alveolar epithelial cells via PGE2, PGD2, and HGF.

    PubMed

    Yoon, Young-So; Lee, Ye-Ji; Choi, Youn-Hee; Park, Young Mi; Kang, Jihee Lee

    2016-01-01

    Apoptotic cell clearance results in the release of growth factors and the action of signaling molecules involved in tissue homeostasis maintenance. Here, we investigated whether and how macrophages programmed by apoptotic cells inhibit the TGF-β1-induced Epithelial-mesenchymal transition (EMT) process in lung alveolar epithelial cells. Treatment with conditioned medium derived from macrophages exposed to apoptotic cells, but not viable or necrotic cells, inhibited TGF-β1-induced EMT, including loss of E-cadherin, synthesis of N-cadherin and α-smooth muscle actin, and induction of EMT-activating transcription factors, such as Snail1/2, Zeb1/2, and Twist1. Exposure of macrophages to cyclooxygenase (COX-2) inhibitors (NS-398 and COX-2 siRNA) or RhoA/Rho kinase inhibitors (Y-27632 and RhoA siRNA) and LA-4 cells to antagonists of prostaglandin E2 (PGE2) receptor (EP4 [AH-23848]), PGD2 receptors (DP1 [BW-A868C] and DP2 [BAY-u3405]), or the hepatocyte growth factor (HGF) receptor c-Met (PHA-665752), reversed EMT inhibition by the conditioned medium. Additionally, we found that apoptotic cell instillation inhibited bleomycin-mediated EMT in primary mouse alveolar type II epithelial cells in vivo. Our data suggest a new model for epithelial cell homeostasis, by which the anti-EMT programming of macrophages by apoptotic cells may control the progressive fibrotic reaction via the production of potent paracrine EMT inhibitors. PMID:26875548

  9. Genetics Home Reference: Paget disease of bone

    MedlinePlus

    ... genetic cause of classic Paget disease of bone , accounting for 10 to 50 percent of cases that ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  10. Prostaglandin (PG)D2 and 15-deoxy-Δ12,14-PGJ2, but not PGE2, Mediate Shear-Induced Chondrocyte Apoptosis via Protein Kinase A-dependent Regulation of Polo-like Kinases

    PubMed Central

    Zhu, Fei; Wang, Pu; Kontrogianni-Konstantopoulos, Aikaterini; Konstantopoulos, Konstantinos

    2010-01-01

    Excessive mechanical loading of cartilage producing hydrostatic stress, tensile strain and fluid flow leads to chondrocyte apoptosis and osteoarthritis. High fluid flow induces cyclooxygenase-2 (COX-2) expression in sheared chondrocytes, which suppresses their antioxidant capacity and contributes to apoptosis. The pivotal role of COX-2 in shear-induced chondrocyte apoptosis and the conflicting literature data on the roles of prostaglandin (PG)E2, PGD2 and its metabolite 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) in chondrocyte apoptosis prompted us to investigate which COX-2-derived PG is involved in this process. We show that exogenously added PGD2 and 15d-PGJ2, but not PGE2, diminish the viability of human T/C-28a2 chondrocytes under static conditions. In agreement with these observations, knockdown of L-PGD synthase (L-PGDS) abolishes shear-induced chondrocyte apoptosis. Using cDNA microarrays in conjunction with clustering algorithms, we propose a novel signaling pathway by which high fluid shear mediates COX-2/L-PGDS-dependent chondrocyte apoptosis, which is validated by molecular interventions. We demonstrate that L-PGDS controls the downregulation of Protein Kinase A (PKA), which in turn regulates Polo-like kinase1 (Plk1) and Plk3. Plks target p53, which controls the transcription of p53 effectors (TP53INPs, FAS and Bax) involved in chondrocyte apoptosis. Reconstructing the signaling network regulating chondrocyte apoptosis may provide insights to optimize conditions for culturing artificial cartilage in bioreactors and for developing therapeutic strategies for arthritic disorders. PMID:20150912

  11. Complement-coated antibody-transfer (CCAT); serum IgA1 antibodies intercept and transport C4 and C3 fragments and preserve IgG1 deployment (PGD).

    PubMed

    Boackle, Robert J; Nguyen, Quang L; Leite, Renata S; Yang, Xiaofeng; Vesely, Jana

    2006-02-01

    In periodontal disease, IgG1 and IgA1 antibodies produced in situ deposit on antigens in the affected tissues. Thus, there is an interest in the effect of co-deposited IgA1 antibodies on complement activation by IgG1-immune complexes. In the present study, we first analyzed the effect of IgA1-immune complexes on complement using human IgA1 antibodies to dansyl (with dansylated human serum albumin serving as the immobilized antigen). It was observed that these IgA1-immune complexes when incubated for prolonged times with 33% human serum as a source of complement received C4b and C3b deposition. As C4b and C3b deposited on the IgA1 antibodies and on the antigenic surface, the complement-coated IgA1 antibodies departed. These fluid-phase complement-coated IgA1 antibodies were transferred to antigen-coated microtiter-ELISA plates, where they became bound to the antigens. Thus, the complement-coated IgA1 antibodies retained their antigen-binding function, especially as a proportion of their covalently bound C3b progressively degraded to iC3b and C3d. Genetically engineered carbohydrate-deficient mutant human IgA1 antibodies were used to assess the role of carbohydrate in accepting the C4b and C3b depositions, and these studies indicated that the carbohydrate on the Fc-region of IgA1 played a positive role. Another interesting finding generated by this study was that when IgA1 was co-deposited with IgG1 antibodies, and serum complement was added, the IgG1 antibodies tended to remain on the antigenic surface. The co-deposited IgA1 antibodies not only controlled (reduced) the rate of the consumption of the first component of complement (C1) and of classical complement pathway activation by IgG1-immune complexes (and therein reduced the rate of complement-mediated dissolution of the IgG1-immune complexes), but also the co-deposited IgA1 antibodies simultaneously intercepted/accepted C4b and C3b, then departed, as complement began to cover the antigenic surfaces. The process

  12. The Future of Prenatal Diagnosis and Screening

    PubMed Central

    Pergament, Eugene

    2014-01-01

    The future of prenatal diagnosis and screening lies in developing clinical approaches and laboratory technologies applicable to genetic analyses and therapeutic interventions during embryonic development. PMID:26237604

  13. Genetics Home Reference: Fraser syndrome

    MedlinePlus

    ... FRAS1 gene mutations are the most common cause, accounting for about half of cases of Fraser syndrome . ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  14. Genetics Home Reference: multiminicore disease

    MedlinePlus

    ... are less common than the classic form, together accounting for about 25 percent of all cases. The ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  15. Genetics Home Reference: hereditary angioedema

    MedlinePlus

    ... 000 people. Type I is the most common, accounting for 85 percent of cases. Type II occurs ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  16. Genetics Home Reference: Sotos syndrome

    MedlinePlus

    ... gene are the primary cause of Sotos syndrome , accounting for up to 90 percent of cases. Other ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  17. Genetics Home Reference: Cushing disease

    MedlinePlus

    ... condition is known as pseudo-Cushing syndrome. Not accounting for increases in cortisol due to prescription drugs, ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  18. [Genetic structure of the Iranian-speaking population of Azerbaijan from data on frequencies of immunologic and biochemical gene markers].

    PubMed

    Asadova, P Sh; Shneĭder, Iu V; Shil'nikova, I N; Zhukova, O V

    2003-11-01

    The data on the genetic studies of Iranian-speaking populations from Azerbaijan (Talyshs and Tats) are presented. In these populations gene frequency distributions for the immunological (AB0, MN, Rhesus-D, -C, -E, P, Lewis, and Kell-Chellano) and biochemical (HP, GC, C'3, TF, 6PGD, GLO1, ESD, ACP1, and PGM1) gene markers were determined. Comparison of the genetic structure of the populations examined with the other Iranian-speaking populations (Persians and Kurds from Iran, Ossetins and Tajiks) and Azerbaijanis showed that Iranian-speaking populations from Azerbaijan were more close to Azerbaijanis, than to Iranian-speaking populations inhabiting other world regions. PMID:14714471

  19. Genetic diversity of allozymes in turnip (Brassica rapa L. var. rapa) from the Nordic area.

    PubMed

    Persson, K; Fält, A S; von Bothmer, R

    2001-01-01

    Genetic diversity and relationships based on isozymes were studied in 31 accessions of turnip (Brassica rapa L. var. rapa). The material included varieties, elite stocks, landraces and older turnip of slash-and-burn type from the Nordic area. A total of 9 isozyme loci and 26 alleles were studied. The isozyme systems were ACO, DIA, GPI, GOT, PGM, PGD and SKD. The level of heterozygosity was reduced in the landraces, but it was high for the variety group 'Ostersundom'. Turnip has a higher genetic variation than other crops within B. rapa and than in other species with the same breeding system. The genetic diversity showed that 18.7% of the genetic variation was within the accessions, and the total H tau value was 0.358. Gpi-I and Pgd-I showed the lowest variation compared with the other loci. The cluster analysis revealed five clusters, with one main cluster including 25 of the 31 accessions. The dendrogram indicated that the variety group 'Ostersundom' clustered together whereas the variety group 'Bortfelder' was associated with country of origin. The landraces were spread in different clusters. The 'slash-and-burn' type of turnip belonged to two groups.

  20. Genetic diversity of allozymes in turnip (Brassica rapa L. var. rapa) from the Nordic area.

    PubMed

    Persson, K; Fält, A S; von Bothmer, R

    2001-01-01

    Genetic diversity and relationships based on isozymes were studied in 31 accessions of turnip (Brassica rapa L. var. rapa). The material included varieties, elite stocks, landraces and older turnip of slash-and-burn type from the Nordic area. A total of 9 isozyme loci and 26 alleles were studied. The isozyme systems were ACO, DIA, GPI, GOT, PGM, PGD and SKD. The level of heterozygosity was reduced in the landraces, but it was high for the variety group 'Ostersundom'. Turnip has a higher genetic variation than other crops within B. rapa and than in other species with the same breeding system. The genetic diversity showed that 18.7% of the genetic variation was within the accessions, and the total H tau value was 0.358. Gpi-I and Pgd-I showed the lowest variation compared with the other loci. The cluster analysis revealed five clusters, with one main cluster including 25 of the 31 accessions. The dendrogram indicated that the variety group 'Ostersundom' clustered together whereas the variety group 'Bortfelder' was associated with country of origin. The landraces were spread in different clusters. The 'slash-and-burn' type of turnip belonged to two groups. PMID:11525064

  1. Basic genetics for dermatologists.

    PubMed

    Kumaran, Muthu Sendhil; De, Dipankar

    2013-01-01

    During the past few decades, advances in the field of molecular genetics have enriched us in understanding the pathogenesis of diseases, their identification, and appropriate therapeutic interventions. In the last 20 years, genetic basis of more than 350 monogenic skin diseases have been elucidated and is counting. The widespread use of molecular genetics as a tool in diagnosis is not practiced routinely due to genetic heterogenicity, limited access and low sensitivity. In this review, we have presented the very basics of genetics so as to enable dermatologists to have working understanding of medical genetics.

  2. Molecular systematics and diagnosis.

    PubMed

    Thompson, R C A; Zarlenga, D S; La Rosa, G; Pozio, E; Rosenthal, B; Bandi, C; Mortarino, M; Casiraghi, M; Genchi, C; Gasser, R B; Hu, M; Chilton, N B; Matthews, J B; Hodgkinson, J E

    2004-10-28

    This collection of articles provides an account of six presentations delivered at the 19th International Conference of the World Association for the Advancement of Veterinary Parasitology(WAAVP) (held in New Orleans, Louisiana, USA, from 10 to 14 August 2003) in a symposium session on Molecular Systematics and Diagnosis, organised and chaired by R.B. Gasser and D.S. Zarlenga. The focus was on recent advances in molecular tools for specific and genotypic identification,diagnosis, systematics and population genetics, with special emphasis on investigations of parasitic nematodes and protists.

  3. Ethical issues in genetics.

    PubMed

    Shannon, T A

    1999-03-01

    The first section of the Notes on Moral Theology reviews ethical issues in genetics through the lenses of privacy-confidentiality; risk-benefit analysis in relation to prenatal diagnosis and gene therapy; and freedom-determinism/human dignity in the context of cloning. The author provides an overview of developments in genetics and highlights thematic issues common to these developments.

  4. Population genetic study among the Orange Asli (Semai Senoi) of Malaysia: Malayan aborigines.

    PubMed

    Saha, N; Mak, J W; Tay, J S; Liu, Y; Tan, J A; Low, P S; Singh, M

    1995-02-01

    A population genetic study was undertaken to provide gene frequency data on the additional blood genetic markers in the Semai and to estimate the genetic relations between the Semai and their neighboring and linguistically related populations by genetic distance and principal components analyses. Altogether 10 polymorphic and 7 monomorphic blood genetic markers (plasma proteins and red cell enzymes) were studied in a group of 349 Senoi Semai from 11 aboriginal settlements (villages) in the Pahang State of western Malaysia. Both the red cell glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (PGD) loci reveal the presence of polymorphic frequencies of a nondeficient slow allele at the G6PD locus and a fast allele at the PGD locus. The Semai are characterized by high prevalences of ahaptoglobinemia and G6PD deficiency, high frequencies of HP*1, HB*E, RH*R1, ACP*C, GLO1*1, PGM1*2+, and GC*1F and corresponding low frequencies of ABO*A, HbCoSp, HB*B0, TF*D, CHI, and GC*2. Genetic distance analyses by both cluster and principal components models were performed between the Semai and 14 other populations (Malay; Javanese; Khmer; Veddah; Tamils of Malaysia, Sri Lanka, and India; Sinhalese; Oraon; Toda and Irula of India; Chinese; Japanese; Koreans) on the basis of 30 alleles at 7 polymorphic loci. A more detailed analysis using 53 alleles at 13 polymorphic loci with 10 populations was carried out. Both analyses give genetic evidence of a close relationship between the Semai and the Khmer of Cambodia. Furthermore, the Semai are more closely related to the Javanese than to their close neighbors--the Malay, Chinese, and Tamil Indians. There is no evidence for close genetic relationship between the Semai and the Veddah or other Indian tribes. The evidence fits well with the linguistic relationship of the Semai with the Mon-Khmer branch of the Austro-Asiatic language family.

  5. Genetic Characterisation of Plasmodium falciparum Isolates with Deletion of the pfhrp2 and/or pfhrp3 Genes in Colombia: The Amazon Region, a Challenge for Malaria Diagnosis and Control.

    PubMed

    Dorado, Erika Jimena; Okoth, Sheila Akinyi; Montenegro, Lidia Madeline; Diaz, Gustavo; Barnwell, John W; Udhayakumar, Venkatachalam; Murillo Solano, Claribel

    2016-01-01

    Most Plasmodium falciparum-detecting rapid diagnostic tests (RDTs) target histidine-rich protein 2 (PfHRP2). However, P. falciparum isolates with deletion of the pfhrp2 gene and its homolog gene, pfhrp3, have been detected. We carried out an extensive investigation on 365 P. falciparum dried blood samples collected from seven P. falciparum endemic sites in Colombia between 2003 and 2012 to genetically characterise and geographically map pfhrp2- and/or pfhrp3-negative P. falciparum parasites in the country. We found a high proportion of pfhrp2-negative parasites only in Amazonas (15/39; 38.5%), and these parasites were also pfhrp3-negative. These parasites were collected between 2008 and 2009 in Amazonas, while pfhrp3-negative parasites (157/365, 43%) were found in all the sites and from each of the sample collection years evaluated (2003 to 2012). We also found that all pfhrp2- and/or pfhrp3-negative parasites were also negative for one or both flanking genes. Six sub-population clusters were established with 93.3% (14/15) of the pfhrp2-negative parasites grouped in the same cluster and sharing the same haplotype. This haplotype corresponded with the genetic lineage BV1, a multidrug resistant strain that caused two outbreaks reported in Peru between 2010 and 2013. We found this BV1 lineage in the Colombian Amazon as early as 2006. Two new clonal lineages were identified in these parasites from Colombia: the genetic lineages EV1 and F. PfHRP2 sequence analysis revealed high genetic diversity at the amino acid level, with 17 unique sequences identified among 53 PfHRP2 sequences analysed. The use of PfHRP2-based RDTs is not recommended in Amazonas because of the high proportion of parasites with pfhrp2 deletion (38.5%), and implementation of new strategies for malaria diagnosis and control in Amazonas must be prioritised. Moreover, studies to monitor and genetically characterise pfhrp2-negative P. falciparum parasites in the Americas are warranted, given the extensive

  6. Genetic Characterisation of Plasmodium falciparum Isolates with Deletion of the pfhrp2 and/or pfhrp3 Genes in Colombia: The Amazon Region, a Challenge for Malaria Diagnosis and Control.

    PubMed

    Dorado, Erika Jimena; Okoth, Sheila Akinyi; Montenegro, Lidia Madeline; Diaz, Gustavo; Barnwell, John W; Udhayakumar, Venkatachalam; Murillo Solano, Claribel

    2016-01-01

    Most Plasmodium falciparum-detecting rapid diagnostic tests (RDTs) target histidine-rich protein 2 (PfHRP2). However, P. falciparum isolates with deletion of the pfhrp2 gene and its homolog gene, pfhrp3, have been detected. We carried out an extensive investigation on 365 P. falciparum dried blood samples collected from seven P. falciparum endemic sites in Colombia between 2003 and 2012 to genetically characterise and geographically map pfhrp2- and/or pfhrp3-negative P. falciparum parasites in the country. We found a high proportion of pfhrp2-negative parasites only in Amazonas (15/39; 38.5%), and these parasites were also pfhrp3-negative. These parasites were collected between 2008 and 2009 in Amazonas, while pfhrp3-negative parasites (157/365, 43%) were found in all the sites and from each of the sample collection years evaluated (2003 to 2012). We also found that all pfhrp2- and/or pfhrp3-negative parasites were also negative for one or both flanking genes. Six sub-population clusters were established with 93.3% (14/15) of the pfhrp2-negative parasites grouped in the same cluster and sharing the same haplotype. This haplotype corresponded with the genetic lineage BV1, a multidrug resistant strain that caused two outbreaks reported in Peru between 2010 and 2013. We found this BV1 lineage in the Colombian Amazon as early as 2006. Two new clonal lineages were identified in these parasites from Colombia: the genetic lineages EV1 and F. PfHRP2 sequence analysis revealed high genetic diversity at the amino acid level, with 17 unique sequences identified among 53 PfHRP2 sequences analysed. The use of PfHRP2-based RDTs is not recommended in Amazonas because of the high proportion of parasites with pfhrp2 deletion (38.5%), and implementation of new strategies for malaria diagnosis and control in Amazonas must be prioritised. Moreover, studies to monitor and genetically characterise pfhrp2-negative P. falciparum parasites in the Americas are warranted, given the extensive

  7. Genetic Characterisation of Plasmodium falciparum Isolates with Deletion of the pfhrp2 and/or pfhrp3 Genes in Colombia: The Amazon Region, a Challenge for Malaria Diagnosis and Control

    PubMed Central

    Dorado, Erika Jimena; Okoth, Sheila Akinyi; Montenegro, Lidia Madeline; Diaz, Gustavo; Barnwell, John W.; Udhayakumar, Venkatachalam; Murillo Solano, Claribel

    2016-01-01

    Most Plasmodium falciparum-detecting rapid diagnostic tests (RDTs) target histidine-rich protein 2 (PfHRP2). However, P. falciparum isolates with deletion of the pfhrp2 gene and its homolog gene, pfhrp3, have been detected. We carried out an extensive investigation on 365 P. falciparum dried blood samples collected from seven P. falciparum endemic sites in Colombia between 2003 and 2012 to genetically characterise and geographically map pfhrp2- and/or pfhrp3-negative P. falciparum parasites in the country. We found a high proportion of pfhrp2-negative parasites only in Amazonas (15/39; 38.5%), and these parasites were also pfhrp3-negative. These parasites were collected between 2008 and 2009 in Amazonas, while pfhrp3-negative parasites (157/365, 43%) were found in all the sites and from each of the sample collection years evaluated (2003 to 2012). We also found that all pfhrp2- and/or pfhrp3-negative parasites were also negative for one or both flanking genes. Six sub-population clusters were established with 93.3% (14/15) of the pfhrp2-negative parasites grouped in the same cluster and sharing the same haplotype. This haplotype corresponded with the genetic lineage BV1, a multidrug resistant strain that caused two outbreaks reported in Peru between 2010 and 2013. We found this BV1 lineage in the Colombian Amazon as early as 2006. Two new clonal lineages were identified in these parasites from Colombia: the genetic lineages EV1 and F. PfHRP2 sequence analysis revealed high genetic diversity at the amino acid level, with 17 unique sequences identified among 53 PfHRP2 sequences analysed. The use of PfHRP2-based RDTs is not recommended in Amazonas because of the high proportion of parasites with pfhrp2 deletion (38.5%), and implementation of new strategies for malaria diagnosis and control in Amazonas must be prioritised. Moreover, studies to monitor and genetically characterise pfhrp2-negative P. falciparum parasites in the Americas are warranted, given the extensive

  8. Clinical Genetic Testing in Epilepsy

    PubMed Central

    2015-01-01

    New technologies for mutation detection in the human genome have greatly increased our understanding of epilepsy genetics. Application of genomic technologies in the clinical setting allows for more efficient genetic diagnosis in some patients; therefore, it is important to understand the types of tests available and the types of mutations that can be detected. Making a genetic diagnosis improves overall patient care by enhancing prognosis and recurrence risk counseling and informing treatment decisions. PMID:26316867

  9. Genetic Stroke Syndromes

    PubMed Central

    Barrett, Kevin M.; Meschia, James F.

    2014-01-01

    Purpose of Review: This review describes the clinical and radiographic features, genetic determinants, and treatment options for the most well-characterized monogenic disorders associated with stroke. Recent Findings: Stroke is a phenotype of many clinically important inherited disorders. Recognition of the clinical manifestations of genetic disorders associated with stroke is important for accurate diagnosis and prognosis. Genetic studies have led to the discovery of specific mutations associated with the clinical phenotypes of many inherited stroke syndromes. Summary: Several inherited causes of stroke have established and effective therapies, further underscoring the importance of timely diagnosis. PMID:24699489

  10. Genetic alteration and mutation profiling of circulating cell-free tumor DNA (cfDNA) for diagnosis and targeted therapy of gastrointestinal stromal tumors.

    PubMed

    Yan, Weixin; Zhang, Aiguo; Powell, Michael J

    2016-07-21

    Gastrointestinal stromal tumors (GISTs) have been recognized as a biologically distinctive type of tumor, different from smooth muscle and neural tumors of the gastrointestinal tract. The identification of genetic aberrations in proto-oncogenes that drive the growth of GISTs is critical for improving the efficacy of cancer therapy by matching targeted drugs to specific mutations. Research into the oncogenic mechanisms of GISTs has found that these tumors frequently contain activating gene mutations in either platelet-derived growth factor receptor A (PDGFRA) or a receptor tyrosine protein associated with a mast cell growth factor receptor encoded by the KIT gene. Mutant cancer subpopulations have the potential to disrupt durable patient responses to molecularly targeted therapy for GISTs, yet the prevalence and size of subpopulations remain largely unexplored. Detection of the cancer subpopulations that harbor low-frequency mutant alleles of target proto-oncogenes through the use of molecular genetic methods, such as polymerase chain reaction (PCR) target amplification technology, is hampered by the high abundance of wild-type alleles, which limit the sensitivity of detection of these minor mutant alleles. This is especially true in the case of mutant tumor DNA derived "driver" and "drug-resistant" alleles that are present in the circulating cell-free tumor DNA (cfDNA) in the peripheral blood circulation of GIST patients. So-called "liquid biopsy" allows for the dynamic monitoring of the patients' tumor status during treatment using minimally invasive sampling. New methodologies, such as a technology that employs a xenonucleic acid (XNA) clamping probe to block the PCR amplification of wild-type templates, have allowed improved molecular detection of these low-frequency alleles both in tissue biopsy samples and in cfDNA. These new methodologies could be widely applied for minimally invasive molecular testing in the therapeutic management of GISTs.

  11. Prenatal Diagnosis of Congenital Adrenal Hyperplasia.

    PubMed

    Yau, Mabel; Khattab, Ahmed; New, Maria I

    2016-06-01

    Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is a monogenic disorder of adrenal steroidogenesis. To prevent genital ambiguity, in girls, prenatal dexamethasone treatment is administered early in the first trimester. Prenatal genetic diagnosis of CAH and fetal sex determination identify affected female fetuses at risk for genital virilization. Advancements in prenatal diagnosis are owing to improved understanding of the genetic basis of CAH and improved technology. Cloning of the CYP21A2 gene ushered in molecular genetic analysis as the current standard of care. Noninvasive prenatal diagnosis allows for targeted treatment and avoids unnecessary treatment of males and unaffected females. PMID:27241964

  12. Association between Genetic Variation in the Oxytocin Receptor Gene and Emotional Withdrawal, but not between Oxytocin Pathway Genes and Diagnosis in Psychotic Disorders

    PubMed Central

    Haram, Marit; Tesli, Martin; Bettella, Francesco; Djurovic, Srdjan; Andreassen, Ole Andreas; Melle, Ingrid

    2015-01-01

    Social dysfunction is common in patients with psychotic disorders. Oxytocin is a neuropeptide with a central role in social behavior. This study aims to explore the relationship between oxytocin pathway genes and symptoms related to social dysfunction in patients with psychotic disorders. We performed association analyses between four oxytocin pathway genes (OXT, OXTR, AVP, and CD38) and four areas of social behavior-related psychopathology as measured by Positive and Negative Syndrome Scale. For this purpose, we used both a polygenic risk score (PGRS) and single OXTR candidate single nucleotide polymorphism previously reported in the literature (rs53576, rs237902, and rs2254298). A total of 734 subjects with DSM-IV psychotic spectrum disorders and 420 healthy controls were included. Oxytocin pathway PGRSs were calculated based on the independent Psychiatric Genomics Consortium study sample. There was a significant association between symptom of Emotional Withdrawal and the previously reported OXTR risk allele A in rs53576. No significant associations between oxytocin pathway gene variants and a diagnosis of psychotic disorder were found. Our findings indicate that while oxytocin pathway genes do not appear to contribute to the susceptibility to psychotic disorders, variations in the OXTR gene might play a role in the development of impaired social behavior. PMID:25667571

  13. Current diagnosis of temporomandibular pathologies.

    PubMed

    Learreta, Jorge A; Matos, Jane L F; Matos, Marcelo Freire; Durst, Andreas C

    2009-04-01

    The current scientific knowledge of TMJ pathologies points to the importance of etiological research and the need for differential diagnosis using the most modem technological resources. Those include MRI, computed tomography, serologic studies, genetic mapping, and bioelectronic instruments which allow clinicians to study, understand, and measure respectively, the structural changes of soft and hard tissues, infections, genetic susceptibility for autoimmune diseases, and stomatognathic function. The purpose of this article is an overview of the current knowledge and related tools for the diagnosis of TMJ pathologies.

  14. The genetics of cancer survivorship.

    PubMed

    Allan, James M

    2008-04-01

    Constitutional (hereditary) genetic variation and somatic genetic alterations acquired during transformation to the neoplastic phenotype are both critical determinants of cancer outcome, and can ultimately have a significant effect on cancer survivorship. This article discusses the role of constitutional and somatic genetics in determining outcome and survivorship following a diagnosis of cancer using illustrative examples primarily from the hematologic malignancies. PMID:18395149

  15. Genetics Home Reference: Sézary syndrome

    MedlinePlus

    ... of cutaneous T-cell lymphoma after mycosis fungoides , accounting for approximately 3 to 5 percent of cases ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  16. Genetics Home Reference: critical congenital heart disease

    MedlinePlus

    ... are the most common type of birth defect, accounting for more than 30 percent of all infant ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  17. Genetics Home Reference: Treacher Collins syndrome

    MedlinePlus

    ... are the most common cause of the disorder, accounting for 81 to 93 percent of all cases. ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  18. Genetics Home Reference: familial isolated pituitary adenoma

    MedlinePlus

    ... 1,000 people. FIPA, though, is quite rare, accounting for approximately 2 percent of pituitary adenomas. More ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  19. Genetic risk, risk perception, and decision making

    SciTech Connect

    Evers-Kiebooms, G.; Cassiman, J.J.; VanDenBerghe, H.; D'Ydewalle, G. )

    1987-01-01

    This book covers the proceedings of a conference held by March of Dimes Birth Defects Foundation. Topics presented include: Diagnosis of Genetic disease by linkage analysis and DNA diagnosis of autosomal dominant and recessive diseases.

  20. Delayed diagnosis of Pendred syndrome.

    PubMed

    Smith, Natalie; U-King-Im, Jean-Marie; Karalliedde, Janaka

    2016-01-01

    We describe a case of a delayed diagnosis of Pendred syndrome. The patient had a history of hearing loss from childhood and presented to the endocrine clinic when aged 32 with an enlarging goitre. The characteristic Mondini deformity was noted on auditory canal MRI scan. Genetic tests confirmed the diagnosis. Pendred syndrome is an autosomal recessive disorder, characterised by congenital sensorineural hearing loss, goitre and impaired iodide organification and can present at any age. We highlight to the general physician the classical features of this syndrome that would aid early diagnosis. PMID:27620717

  1. A handheld flow genetic analysis system (FGAS): towards rapid, sensitive, quantitative and multiplex molecular diagnosis at the point-of-care level.

    PubMed

    Shu, Bowen; Zhang, Chunsun; Xing, Da

    2015-06-21

    A handheld flow genetic analysis system (FGAS) is proposed for rapid, sensitive, multiplex and real-time quantification of nucleic acids at the point-of-care (POC) level. The FGAS includes a helical thermal-gradient microreactor and a microflow actuator, as well as control circuitry for temperature, fluid and power management, and smartphone fluorescence imaging. All of these features are integrated into a field-portable and easy-to-use molecular diagnostic platform powered by lithium batteries. Due to the unique design of the microreactor, not only steady temperatures for denaturation and annealing/extension but also a linear thermal gradient for spatial high-resolution melting can be achieved through simply maintaining a single heater at constant temperature. The smartphone fluorescence imaging system has a wide field of view that captures all PCR channels of the microreactor in a single snapshot without the need for any mechanical scanning. By these designs, the FGAS enables real-time monitoring of the temporal and spatial fluorescence signatures of amplicons during continuous-flow amplification. On the current FGAS, visual detection of as little as 10 copies per μL of genomic DNA of Salmonella enterica was achieved in 15 min, with real-time quantitative detection of the DNA over 6 orders of magnitude concentration from 10(6) to 10(1) copies per μL also completed in 7.5-15 min. In addition, multiple pathogenic DNA targets could be simultaneously discriminated with direct bar-chart readout or multiplex spatial melting in serial flow. We anticipate that the FGAS has great potential to become a next-generation gene analyzer for POC molecular diagnostics. PMID:25953325

  2. Differences in the diagnostic value of various criteria of negative T waves for hypertrophic cardiomyopathy based on a molecular genetic diagnosis.

    PubMed

    Konno, Tetsuo; Fujino, Noboru; Hayashi, Kenshi; Uchiyama, Katsuharu; Masuta, Eiichi; Katoh, Hiromasa; Sakamoto, Yuichiro; Tsubokawa, Toshinari; Ino, Hidekazu; Yamagishi, Masakazu

    2007-06-01

    Differences in the diagnostic value of a variety of definitions of negative T waves for HCM (hypertrophic cardiomyopathy) have not yet been clarified, resulting in a number of definitions being applied in previous studies. The aim of the present study was to determine the most accurate diagnostic definition of negative T waves for HCM in genotyped populations. Electrocardiographic and echocardiographic findings were analysed in 161 genotyped subjects (97 carriers and 64 non-carriers). We applied three different criteria that have been used in previous studies: Criterion 1, negative T wave >10 mm in depth in any leads; Criterion 2, negative T wave >3 mm in depth in at least two leads; and Criterion 3, negative T wave >1 mm in depth in at least two leads. Of the three criteria, Criterion 3 had the highest sensitivity (43% compared with 5 and 26% in Criterion 1 and Criterion 2 respectively; P<0.0001) and retained a specificity of 95%, resulting in the highest accuracy. In comparison with abnormal Q waves, negative T waves for Criterion 3 had a lower sensitivity in detecting carriers without LVH (left ventricular hypertrophy) (12.9% for negative T waves compared with 22.6% for abnormal Q waves). On the other hand, in detecting carriers with LVH, the sensitivity of negative T waves increased in a stepwise direction with the increasing extent of LVH (P<0.001), whereas there was less association between the sensitivity of abnormal Q waves and the extent of LVH. In conclusion, Criterion 3 for negative T waves may be the most accurate definition of HCM based on genetic diagnoses. Negative T waves may show different diagnostic value according to the different criteria and phenotypes in genotyped populations with HCM.

  3. Embryo genome profiling by single-cell sequencing for successful preimplantation genetic diagnosis in a family harboring COL4A1 c.1537G>A; p.G513S mutation

    PubMed Central

    Patel, Nayana H.; Bhadarka, Harsha K.; Patel, Kruti B.; Vaniawala, Salil N.; Acharya, Arpan; Mukhopadhyaya, Pratap N.; Sodagar, Nilofar R.

    2016-01-01

    CONTEXT: Genetic profiling of embryos (also known as preimplantation genetic diagnosis) before implantation has dramatically enhanced the success quotient of in vitro fertilization (IVF) in recent times. The technology helps in avoiding selective pregnancy termination since the baby is likely to be free of the disease under consideration. AIM: Screening of embryos free from c.1537G>A; p.G513S mutation within the COL4A1 gene for which the father was known in before be in heterozygous condition. SUBJECTS AND METHODS: Processing of trophectoderm biopsies was done from twelve embryos for c.1537G>A; p.G513S mutation within the COL4A1 gene. DNA extracted from isolated cells were subjected to whole genome amplification using an isothermal amplification and strand displacement technology. Oligonucleotide primers bracketing the mutation were synthesized and used to amplify 162 base pairs (bp) polymerase chain reaction amplicons originating from each embryo which were subsequently sequenced to detect the presence or absence of the single base polymorphism. RESULTS: Three out of 12 embryos interrogated in this study were found to be normal while 9 were found to harbor the mutation in heterozygous condition. Implantation of one of the normal embryos following by chorionic villus sampling at 11th week of pregnancy indicated that the baby was free from c.1537G>A; p.G513S mutation within the COL4A1 gene. CONCLUSIONS: Single-cell sequencing is a helpful tool for preimplantation embryo profiling. This is the first report from India describing the birth of a normal child through IVF procedure where a potential pathogenic COL4A1 allele was avoided using this technology. PMID:27803589

  4. [Diagnosis of inherited thrombocytopenia].

    PubMed

    Baccini, V; Alessi, M C

    2016-02-01

    Inherited thrombocytopenias are rare, heterogenous and probably under-diagnosed because often classified as autoimmune thrombocytopenia. About 20 genes were described responsible for these thrombocytopenias. Precise diagnosis is necessary because the prognosis is different and some of them can evolve into hemopathies. First of all, it is important to gather a body of evidence to orientate towards an inherited cause: presence of the thrombocytopenia since childhood and of other family cases is a strong argument. Secondly, it is difficult to target the genetic investigations that settle the precise diagnosis. Genetic variants responsible for inherited thrombocytopenias affect different stage during megakaryocytopoiesis and cause thrombocytopenias with distinct characteristics. Presence of extra-hematological features, platelets' size measurement and evaluation of bone marrow megakaryocyte morphology when it is possible allow a primary orientation. We propose a diagnostic approach considering extra-hematological features, mode of inheritance, morphology, molecular and functional platelets' studies and bone marrow megakaryocyte morphology in order to better target genetic study. Nevertheless, despite this approach, some inherited thrombocytopenias remain still unexplained and could benefit from new methods of new generation sequencing in the future. PMID:26617290

  5. [Hereditary hearing loss: genetic counselling].

    PubMed

    Cabanillas Farpón, Rubén; Cadiñanos Bañales, Juan

    2012-01-01

    The aim of this review is to provide an updated overview of hereditary hearing loss, with special attention to the etiological diagnosis of sensorineural hearing loss, the genes most frequently mutated in our environment, the techniques available for their analysis and the clinical implications of genetic diagnosis. More than 60% of childhood sensorineural hearing loss is genetic. In adults, the percentage of hereditary hearing loss is unknown. Genetic testing is the highest yielding test for evaluating patients with sensorineural hearing loss. The process of genetic counselling is intended to inform patients and their families of the medical, psychological and familial implications of genetic diseases, as well as the risks, benefits and limitations of genetic testing. The implementation of any genetic analysis must be always preceded by an appropriate genetic counselling process.

  6. Fault diagnosis

    NASA Technical Reports Server (NTRS)

    Abbott, Kathy

    1990-01-01

    The objective of the research in this area of fault management is to develop and implement a decision aiding concept for diagnosing faults, especially faults which are difficult for pilots to identify, and to develop methods for presenting the diagnosis information to the flight crew in a timely and comprehensible manner. The requirements for the diagnosis concept were identified by interviewing pilots, analyzing actual incident and accident cases, and examining psychology literature on how humans perform diagnosis. The diagnosis decision aiding concept developed based on those requirements takes abnormal sensor readings as input, as identified by a fault monitor. Based on these abnormal sensor readings, the diagnosis concept identifies the cause or source of the fault and all components affected by the fault. This concept was implemented for diagnosis of aircraft propulsion and hydraulic subsystems in a computer program called Draphys (Diagnostic Reasoning About Physical Systems). Draphys is unique in two important ways. First, it uses models of both functional and physical relationships in the subsystems. Using both models enables the diagnostic reasoning to identify the fault propagation as the faulted system continues to operate, and to diagnose physical damage. Draphys also reasons about behavior of the faulted system over time, to eliminate possibilities as more information becomes available, and to update the system status as more components are affected by the fault. The crew interface research is examining display issues associated with presenting diagnosis information to the flight crew. One study examined issues for presenting system status information. One lesson learned from that study was that pilots found fault situations to be more complex if they involved multiple subsystems. Another was pilots could identify the faulted systems more quickly if the system status was presented in pictorial or text format. Another study is currently under way to

  7. [Cryptorchidism: diagnosis and treatment].

    PubMed

    Longui, Carlos Alberto

    2005-02-01

    Cryptorchidism corresponds to the extra-scrotal position of the testis, and can be found in 3% of the term newborns and 0.5 to 1.0% of adults. It is usually an isolated clinical feature, but in around 10% of the cases can be associated to hypothalamic-pituitary dysfunction and genetic or embryonic disorders. The presence of additional genital abnormalities, such as hypospadia or micropenis, increases the probability of the diagnosis of an intersex condition. Detailed description of the testicular anatomic position is essential to adequate diagnosis, treatment and prognostic evaluation. The diagnosis of cryptorchidism is made by clinical examination. The complementary exams, such as image analysis, add limited information on the diagnosis. Gonadotropins and testicular hormones measurement can be useful if the hypothalamic-pituitary-gonadal axis is activated, as observed during the first 6 months of life or during puberty. Clinical treatment is indicated in patients with retained testis or in severely retractile testis. In these cases, human chorionic gonadotropin is employed at a dose of 50 IU/kg/week for 6 consecutive weeks. Clinical treatment cannot be used in cases of confirmed inguinal hernia, varicocele or spermatic cord cysts. Surgical correction is indicated after failure of clinical treatment or for ectopic testes. The long-term prognosis of cryptorchidism seems to be related to the precocity of the therapy. Therefore, recognition and treatment of cryptorchid testes should be done during the first 2 years of life, potentially improving the risks of infertility and gonadal neoplasia.

  8. Human prenatal diagnosis

    SciTech Connect

    Filkins, K.; Russo, J.F.

    1985-01-01

    Advances in the field of prenatal diagnosis have been rapid during the past decade. Moreover, liberal use of birth control methods and restriction of family size have placed greater emphasis on optimum outcome of each pregnancy. There are many prenatal diagnostic techniques of proven value; the risks, including false negatives and false positives, are known. With the rapid proliferation of new and experimental techniques, many disorders are potential diagnosable or even treatable; however, risk factors are unknown and issues relating to quality control have not been resolved. These problems are readily appreciated in the dramatic new techniques involving recombinant DNA, chorion villus sampling, and fetal surgery. Unfortunately, clinicians may not appreciate the difficulties that may also be encountered in the more mundane prenatal diagnostic tests such as ultrasonography or enzymatic testing. The aim of this volume is to clarify and rationalize certain aspects of diagnosis, genetic counseling, and intervention. New and experimental techniques are presented in the light of current knowledge.

  9. Pediatric genetic disorders of lens.

    PubMed

    Nihalani, Bharti R

    2014-12-01

    Pediatric genetic disorders of lens include various cataractous and non-cataractous anomalies. The purpose of this review is to help determine the genetic cause based on the lens appearance, ocular and systemic associations. Children with bilateral cataracts require a comprehensive history, ophthalmic and systemic examination to guide further genetic evaluation. With advancements in genetics, it is possible to determine the genetic mutations and assess phenotype genotype correlation in different lens disorders. The genetic diagnosis helps the families to better understand the disorder and develop realistic expectations as to the course of their child's disorder. PMID:27625879

  10. Pediatric genetic disorders of lens

    PubMed Central

    Nihalani, Bharti R.

    2014-01-01

    Pediatric genetic disorders of lens include various cataractous and non-cataractous anomalies. The purpose of this review is to help determine the genetic cause based on the lens appearance, ocular and systemic associations. Children with bilateral cataracts require a comprehensive history, ophthalmic and systemic examination to guide further genetic evaluation. With advancements in genetics, it is possible to determine the genetic mutations and assess phenotype genotype correlation in different lens disorders. The genetic diagnosis helps the families to better understand the disorder and develop realistic expectations as to the course of their child's disorder.

  11. The genetics of the epilepsies.

    PubMed

    El Achkar, Christelle M; Olson, Heather E; Poduri, Annapurna; Pearl, Phillip L

    2015-07-01

    While genetic causes of epilepsy have been hypothesized from the time of Hippocrates, the advent of new genetic technologies has played a tremendous role in elucidating a growing number of specific genetic causes for the epilepsies. This progress has contributed vastly to our recognition of the epilepsies as a diverse group of disorders, the genetic mechanisms of which are heterogeneous. Genotype-phenotype correlation, however, is not always clear. Nonetheless, the developments in genetic diagnosis raise the promise of a future of personalized medicine. Multiple genetic tests are now available, but there is no one test for all possible genetic mutations, and the balance between cost and benefit must be weighed. A genetic diagnosis, however, can provide valuable information regarding comorbidities, prognosis, and even treatment, as well as allow for genetic counseling. In this review, we will discuss the genetic mechanisms of the epilepsies as well as the specifics of particular genetic epilepsy syndromes. We will include an overview of the available genetic testing methods, the application of clinical knowledge into the selection of genetic testing, genotype-phenotype correlations of epileptic disorders, and therapeutic advances as well as a discussion of the importance of genetic counseling. PMID:26008807

  12. Genetics Home Reference: vibratory urticaria

    MedlinePlus

    ... hand clapping, running, a bumpy ride in a vehicle, or other repetitive stimulation. Headaches, fatigue, faintness, blurry ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources from MedlinePlus offer information about the ...

  13. Molecular diagnosis of 65 families with mucopolysaccharidosis type II (Hunter syndrome) characterized by 16 novel mutations in the IDS gene: Genetic, pathological, and structural studies on iduronate-2-sulfatase.

    PubMed

    Kosuga, Motomichi; Mashima, Ryuichi; Hirakiyama, Asami; Fuji, Naoko; Kumagai, Tadayuki; Seo, Joo-Hyun; Nikaido, Mari; Saito, Seiji; Ohno, Kazuki; Sakuraba, Hitoshi; Okuyama, Torayuki

    2016-07-01

    Mucopolysaccharidosis type II (MPS II: also called as Hunter syndrome) is an X-linked recessive lysosomal storage disorder characterized by the accumulation of extracellular glycosaminoglycans due to the deficiency of the enzyme iduronate-2-sulfatase (IDS). Previous observations suggested that MPS II can be classified into two distinct disease subtypes: (1) severe type of MPS II involves a decline in the cognitive ability of a patient and (2) attenuated type of MPS II exhibits no such intellectual phenotype. To determine whether such disease subtypes of MPS II could be explained by genetic diagnosis, we analyzed mutations in the IDS gene of 65 patients suffering from MPS II among the Japanese population who were diagnosed with both the accumulation of urinary glycosaminoglycans and a decrease in their IDS enzyme activity between 2004 and 2014. Among the specimens examined, we identified the following mutations: 33 missense, 8 nonsense, 7 frameshift, 4 intronic changes affecting splicing, 8 recombinations involving IDS-IDS2, and 7 other mutations including 4 large deletions. Consistent with the previous data, the results of our study showed that most of the attenuated phenotype was derived from the missense mutations of the IDS gene, whereas mutations associated with a large structural alteration including recombination, splicing, frameshift, and nonsense mutations were linked to the severe phenotype of MPS II. Furthermore, we conducted a homology modeling study of IDS P120R and N534I mutant as representatives of the causative mutation of the severe and attenuated type of MPS II, respectively. We found that the substitution of P120R of the IDS enzyme was predicted to deform the α-helix generated by I119-F123, leading to the major structural alteration of the wild-type IDS enzyme. In sharp contrast, the effect of the structural alteration of N534I was marginal; thus, this mutation was pathogenically predicted to be associated with the attenuated type of MPS II

  14. Fanconi Anemia and its Diagnosis

    PubMed Central

    Auerbach, Arleen D.

    2009-01-01

    Fanconi anemia (FA) is a genetically and phenotypically heterogeneous recessive disorder characterized by diverse congenital malformations, progressive pancytopenia, and predisposition to both hematologic malignancies and solid tumors. Congenital anomalies vary from patient to patient and may affect skeletal morphogenesis as well as any of the major organ systems. Although this highly variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, laboratory study of chromosomal breakage induced by diepoxybutane (DEB) or other crosslinking agents provides a unique cellular marker for the diagnosis of the disorder either prenatally or postnatally. Diagnosis based on abnormal response to DNA crosslinking agents can be used to identify the pre-anemia patient as well as patients with aplastic anemia or leukemia who may or may not have the physical stigmata associated with the syndrome. This overview will present our present knowledge regarding the varied phenotypic manifestations of FA and procedures for diagnosis based upon abnormal DNA damage responses. PMID:19622403

  15. Genetic testing in hyperlipidemia.

    PubMed

    Bilen, Ozlem; Pokharel, Yashashwi; Ballantyne, Christie M

    2015-05-01

    Hereditary dyslipidemias are often underdiagnosed and undertreated, yet with significant health implications, most importantly causing preventable premature cardiovascular diseases. The commonly used clinical criteria to diagnose hereditary lipid disorders are specific but are not very sensitive. Genetic testing may be of value in making accurate diagnosis and improving cascade screening of family members, and potentially, in risk assessment and choice of therapy. This review focuses on using genetic testing in the clinical setting for lipid disorders, particularly familial hypercholesterolemia.

  16. Genetic Testing in Hyperlipidemia.

    PubMed

    Bilen, Ozlem; Pokharel, Yashashwi; Ballantyne, Christie M

    2016-03-01

    Hereditary dyslipidemias are often underdiagnosed and undertreated, yet with significant health implications, most importantly causing preventable premature cardiovascular diseases. The commonly used clinical criteria to diagnose hereditary lipid disorders are specific but are not very sensitive. Genetic testing may be of value in making accurate diagnosis and improving cascade screening of family members, and potentially, in risk assessment and choice of therapy. This review focuses on using genetic testing in the clinical setting for lipid disorders, particularly familial hypercholesterolemia.

  17. Morphological and molecular description of Tenuisentis niloticus (Meyer, 1932) (Acanthocephala: Tenuisentidae) from Heterotis niloticus (Cuvier) (Actinopterygii: Arapaimidae), in Burkina Faso, with emendation of the family diagnosis and notes on new features, cryptic genetic diversity and histopathology.

    PubMed

    Amin, Omar M; Evans, R Paul; Boungou, Magloire; Heckmann, Richard

    2016-02-01

    Specimens described as Rhadinorhynchus niloticus Meyer, 1932 (Rhadinorhynchidae) from two male specimens collected from Heterotis niloticus (Cuvier) in the Egyptian Nile were later redescribed in the genus Tenuisentis Van Cleave, 1936 (Tenuisentidae) based on 12 specimens collected from the same host species in the White Nile. That redescription basically distinguished the two genera based on five traits but did not actually provide a formal description. His account left out information about cerebral ganglion, lemnisci, some reproductive structures, eggs, proboscis hook dissymmetry and roots, size of trunk and a few other structures. We provide (i) the first complete description of this species enhanced by SEM, molecular, and histo-pathological studies; (ii) expand the existing descriptions; (iii) correct questionable accounts advanced by Van Cleave on the cement gland and the hypodermal giant nuclei; and (iv) add descriptions of new features such as the para-receptacle structure which we also report from Paratenuisentis Bullock & Samuel, 1975, the only other genus in Tenuisentidae Van Cleave, 1936. The subsequent description of a few more specimens from the same host collected in Mali was more informative yet incomplete and at variance with our specimens from Burkina Faso. Genetic divergence and phylogenetic analyses of mitochondrial (cytochrome oxidase c subunit I; COI) and nuclear (18S ribosomal RNA) gene relationships uncovered a cryptic species complex containing two lineages. Based on our studies, the family diagnosis is emended. The acanthocephalan causes damage to the host intestine as depicted in histopathological sections. The invading worm can extend from the mucosal layer to the muscularis externa of the host with subsequent tissue necrosis, villi compression, haemorrhaging and blood loss. PMID:26790681

  18. Morphological and molecular description of Tenuisentis niloticus (Meyer, 1932) (Acanthocephala: Tenuisentidae) from Heterotis niloticus (Cuvier) (Actinopterygii: Arapaimidae), in Burkina Faso, with emendation of the family diagnosis and notes on new features, cryptic genetic diversity and histopathology.

    PubMed

    Amin, Omar M; Evans, R Paul; Boungou, Magloire; Heckmann, Richard

    2016-02-01

    Specimens described as Rhadinorhynchus niloticus Meyer, 1932 (Rhadinorhynchidae) from two male specimens collected from Heterotis niloticus (Cuvier) in the Egyptian Nile were later redescribed in the genus Tenuisentis Van Cleave, 1936 (Tenuisentidae) based on 12 specimens collected from the same host species in the White Nile. That redescription basically distinguished the two genera based on five traits but did not actually provide a formal description. His account left out information about cerebral ganglion, lemnisci, some reproductive structures, eggs, proboscis hook dissymmetry and roots, size of trunk and a few other structures. We provide (i) the first complete description of this species enhanced by SEM, molecular, and histo-pathological studies; (ii) expand the existing descriptions; (iii) correct questionable accounts advanced by Van Cleave on the cement gland and the hypodermal giant nuclei; and (iv) add descriptions of new features such as the para-receptacle structure which we also report from Paratenuisentis Bullock & Samuel, 1975, the only other genus in Tenuisentidae Van Cleave, 1936. The subsequent description of a few more specimens from the same host collected in Mali was more informative yet incomplete and at variance with our specimens from Burkina Faso. Genetic divergence and phylogenetic analyses of mitochondrial (cytochrome oxidase c subunit I; COI) and nuclear (18S ribosomal RNA) gene relationships uncovered a cryptic species complex containing two lineages. Based on our studies, the family diagnosis is emended. The acanthocephalan causes damage to the host intestine as depicted in histopathological sections. The invading worm can extend from the mucosal layer to the muscularis externa of the host with subsequent tissue necrosis, villi compression, haemorrhaging and blood loss.

  19. Modern diagnosis and management of the porphyrias.

    PubMed

    Sassa, Shigeru

    2006-11-01

    Recent advances in the molecular understanding of the porphyrias now offer specific diagnosis and precise definition of the types of genetic mutations involved in the disease. Molecular diagnostic testing is powerful and very useful in kindred evaluation and genetic counselling when a disease-responsible mutation has been identified in the family. It is also the only way to properly screen asymptomatic gene carriers, facilitating correct treatment and appropriate genetic counselling of family members at risk. However, it should be noted that DNA-based testing is for the diagnosis of the gene carrier status, but not for the diagnosis of clinical syndrome or severity of the disease, e.g. an acute attack. For the diagnosis of clinically expressed porphyrias, a logical stepwise approach including the analysis of porphyrins and their precursors should not be underestimated, as it is still very useful, and is often the best from the cost-effective point of view.

  20. Melanoma Diagnosis

    NASA Astrophysics Data System (ADS)

    Horsch, Alexander

    The chapter deals with the diagnosis of the malignant melanoma of the skin. This aggressive type of cancer with steadily growing incidence in white populations can hundred percent be cured if it is detected in an early stage. Imaging techniques, in particular dermoscopy, have contributed significantly to improvement of diagnostic accuracy in clinical settings, achieving sensitivities for melanoma experts of beyond 95% at specificities of 90% and more. Automatic computer analysis of dermoscopy images has, in preliminary studies, achieved classification rates comparable to those of experts. However, the diagnosis of melanoma requires a lot of training and experience, and at the time being, average numbers of lesions excised per histology-proven melanoma are around 30, a number which clearly is too high. Further improvements in computer dermoscopy systems and their competent use in clinical settings certainly have the potential to support efforts of improving this situation. In the chapter, medical basics, current state of melanoma diagnosis, image analysis methods, commercial dermoscopy systems, evaluation of systems, and methods and future directions are presented.

  1. Obtaining genetic testing in pediatric epilepsy.

    PubMed

    Ream, Margie A; Patel, Anup D

    2015-10-01

    The steps from patient evaluation to genetic diagnosis remain complicated. We discuss some of the genetic testing methods available along with their general advantages and disadvantages. We briefly review common pediatric epilepsy syndromes with strong genetic association and provide a potentially useful algorithm for genetic testing in drug-resistant epilepsy. We performed an extensive literature review of available information as it pertains to genetic testing and genetics in pediatric epilepsy. If a genetic disorder is suspected as the cause of epilepsy, based on drug resistance, family history, or clinical phenotype, timely diagnosis may reduce overall cost, limit the diagnostic odyssey that can bring much anxiety to families, improve prognostic accuracy, and lead to targeted therapy. Interpretation of complicated results should be performed only in collaboration with geneticists and genetic counselors, unless the ordering neurologist has a strong background in and understanding of genetics. Genetic testing can play an important role in the care provided to patients with epilepsy.

  2. Wavelets meet genetic imaging

    NASA Astrophysics Data System (ADS)

    Wang, Yu-Ping

    2005-08-01

    Genetic image analysis is an interdisciplinary area, which combines microscope image processing techniques with the use of biochemical probes for the detection of genetic aberrations responsible for cancers and genetic diseases. Recent years have witnessed parallel and significant progress in both image processing and genetics. On one hand, revolutionary multiscale wavelet techniques have been developed in signal processing and applied mathematics in the last decade, providing sophisticated tools for genetic image analysis. On the other hand, reaping the fruit of genome sequencing, high resolution genetic probes have been developed to facilitate accurate detection of subtle and cryptic genetic aberrations. In the meantime, however, they bring about computational challenges for image analysis. In this paper, we review the fruitful interaction between wavelets and genetic imaging. We show how wavelets offer a perfect tool to address a variety of chromosome image analysis problems. In fact, the same word "subband" has been used in the nomenclature of cytogenetics to describe the multiresolution banding structure of the chromosome, even before its appearance in the wavelet literature. The application of wavelets to chromosome analysis holds great promise in addressing several computational challenges in genetics. A variety of real world examples such as the chromosome image enhancement, compression, registration and classification will be demonstrated. These examples are drawn from fluorescence in situ hybridization (FISH) and microarray (gene chip) imaging experiments, which indicate the impact of wavelets on the diagnosis, treatments and prognosis of cancers and genetic diseases.

  3. Genetic autonomic disorders.

    PubMed

    Axelrod, Felicia B

    2013-03-01

    Genetic disorders affecting the autonomic nervous system can result in abnormal development of the nervous system or they can be caused by neurotransmitter imbalance, an ion-channel disturbance or by storage of deleterious material. The symptoms indicating autonomic dysfunction, however, will depend upon whether the genetic lesion has disrupted peripheral or central autonomic centers or both. Because the autonomic nervous system is pervasive and affects every organ system in the body, autonomic dysfunction will result in impaired homeostasis and symptoms will vary. The possibility of genetic confirmation by molecular testing for specific diagnosis is increasing but treatments tend to remain only supportive and directed toward particular symptoms. PMID:23465768

  4. Genetics of Male Infertility.

    PubMed

    Neto, Filipe Tenorio Lira; Bach, Phil Vu; Najari, Bobby Baback; Li, Philip Shihua; Goldstein, Marc

    2016-10-01

    While 7 % of the men are infertile, currently, a genetic etiology is identified in less than 25 % of those men, and 30 % of the infertile men lack a definitive diagnosis, falling in the "idiopathic infertility" category. Advances in genetics and epigenetics have led to several proposed mechanisms for male infertility. These advances may result in new diagnostic tools, treatment approaches, and better counseling with regard to treatment options and prognosis. In this review, we focus on clinical aspects of male infertility and the role of genetics in elucidating etiologies and the potential of treatments. PMID:27502429

  5. Diagnosis and prevention of thalassemia.

    PubMed

    Ip, Ho-Wan; So, Chi-Chiu

    2013-11-01

    Thalassemia is the most common monogenic inherited disease worldwide and it affects most countries to various extents. This review summarizes the current approaches to phenotypic and genotypic diagnosis of thalassemia in clinical practice. Prevention strategies that encompass carrier screening, genetic counseling and prenatal diagnosis are discussed. The importance of public education and an awareness of a changing perception regarding this group of diseases are emphasized. It also addresses the impact of the rapidly increasing knowledge in disease severity modification by hemoglobin F (Hb F).

  6. [Genetics and genetic counseling].

    PubMed

    Izzi, Claudia; Liut, Francesca; Dallera, Nadia; Mazza, Cinzia; Magistroni, Riccardo; Savoldi, Gianfranco; Scolari, Francesco

    2016-01-01

    Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent genetic disease, characterized by progressive development of bilateral renal cysts. Two causative genes have been identified: PKD1 and PKD2. ADPKD phenotype is highly variable. Typically, ADPKD is an adult onset disease. However, occasionally, ADPKD manifests as very early onset disease. The phenotypic variability of ADPKD can be explained at three genetic levels: genic, allelic and gene modifier effects. Recent advances in molecular screening for PKD gene mutations and the introduction of the new next generation sequencing (NGS)- based genotyping approach have generated considerable improvement regarding the knowledge of genetic basis of ADPKD. The purpose of this article is to provide a comprehensive review of the genetics of ADPKD, focusing on new insights in genotype-phenotype correlation and exploring novel clinical approach to genetic testing. Evaluation of these new genetic information requires a multidisciplinary approach involving a nephrologist and a clinical geneticist. PMID:27067213

  7. Molecular Diagnosis of Cystic Fibrosis.

    PubMed

    Deignan, Joshua L; Grody, Wayne W

    2016-01-01

    This unit describes a recommended approach to identifying causal genetic variants in an individual suspected of having cystic fibrosis. An introduction to the genetics and clinical presentation of cystic fibrosis is initially presented, followed by a description of the two main strategies used in the molecular diagnosis of cystic fibrosis: (1) an initial targeted variant panel used to detect only the most common cystic fibrosis-causing variants in the CFTR gene, and (2) sequencing of the entire coding region of the CFTR gene to detect additional rare causal CFTR variants. Finally, the unit concludes with a discussion regarding the analytic and clinical validity of these approaches.

  8. [Genetic information and future medicine].

    PubMed

    Sakurai, Akihiro

    2012-11-01

    Rapid technological advances in genetic analysis have revealed the genetic background of various diseases. Elucidation of the genes responsible for a disease enables better clinical management of the disease and helps to develop targeted drugs. Also, early diagnosis and management of at-risk family members can be made by identification of a genetic disease in the proband. On the other hand, genetic issues often cause psychological distress to the family. To perform genetic testing appropriately and to protect patients and family members from any harm, guidelines for genetic testing were released from the alliance of Japanese genetics-related academic societies in 2003. As genetic testing is becoming incorporated into clinical practice more broadly, the guideline was revised and released by the Japanese Society of Medical Sciences in 2011. All medical professionals in Japan are expected to follow this guideline.

  9. Medical genetics

    SciTech Connect

    Nora, J.J.; Fraser, F.C.

    1989-01-01

    This book presents a discussion of medical genetics for the practitioner treating or counseling patients with genetic disease. It includes a discussion of the relationship of heredity and diseases, the chromosomal basis for heredity, gene frequencies, and genetics of development and maldevelopment. The authors also focus on teratology, somatic cell genetics, genetics and cancer, genetics of behavior.

  10. Genetics of monoamine neurotransmitter disorders

    PubMed Central

    2015-01-01

    The monoamine neurotransmitter disorders are a heterogeneous group of inherited neurological disorders involving defects in the metabolism of dopamine, norepinephrine, epinephrine and serotonin. The inheritance of these disorders is mostly autosomal recessive. The neurological symptoms are primarily attributable to cerebral deficiency of dopamine, serotonin or both. The clinical presentations were highly variable and substantial overlaps exist. Evidently, laboratory investigations are crucial for accurate diagnosis. Measurement of neurotransmitter metabolites in cerebral spinal fluid (CSF) is the key to delineate the metabolic defects. Adjuvant investigations including plasma phenylalanine, urine pterins, urine 3-O-methyldopa (3-OMD) and serum prolactin are also helpful to establish the diagnosis. Genetic analyses are pivotally important to confirm the diagnosis which allows specific treatments, proper genetic counselling, prognosis prediction, assessment of recurrent risk in the family as well as prenatal diagnosis. Early diagnosis with appropriate treatment is associated with remarkable response and favourable clinical outcome in several disorders in this group. PMID:26835371

  11. The value of cardiac genetic testing.

    PubMed

    Ingles, Jodie; Semsarian, Christopher

    2014-08-01

    Genetic testing is an important and necessary aspect of the management of families with cardiac genetic conditions. Commercial genetic tests are available for most cardiac genetic diseases, and increasing uptake amongst patients has contributed to a vastly improved knowledge of the genetic basis of these diseases. The incredible advances in genetic technologies have translated to faster, more comprehensive, and inexpensive commercial genetic tests and has completely changed the landscape of commercial genetic testing in recent years. While there are enormous challenges, mostly relating to interpretation of variants, the value of a genetic diagnosis should not be underestimated. In almost all cases, the single greatest utility is for the predictive genetic testing of family members. This review will describe the value of cardiac genetic testing in the current climate of rapid genetic advancements.

  12. Molecular diagnosis of intrahepatic cholangiocarcinoma

    PubMed Central

    Haga, Hiroaki; Patel, Tushar

    2015-01-01

    Intrahepatic cholangiocarcinomas (iCCA) are primary intrahepatic malignancies originating from biliary epithelia. While both hepatocellular cancer and iCCA can present as mass lesions within the liver, these cancers are distinct in their morphology, etiology, pathology, natural history and response to therapy. There is a need for accurate and sensitive molecular markers for the diagnosis of iCCA. Recent advances in elucidating molecular and genetic characteristics of iCCA offer the potential of molecular-based diagnosis of iCCA. Specific genetic mutations of IDH1/2, BAP1, p53, and KRAS, FGFR gene fusions and alterations in microRNA have all been described in iCCA. Although there are no accurate serum or biliary biomarkers currently available for diagnosis of iCCA, several potential candidates have been identified. Knowledge of specific genetic or molecular abnormalities offers potential for individualized approaches for the treatment of patients with iCCA in the future. PMID:25267595

  13. Ethical questions raised by human genetics. A personal contribution to the preparation of a legal instrument of the Council of Europe on human genetics (part I).

    PubMed

    Sebatier, S

    1998-01-01

    (1) Classification of so-called "genetic" diseases. (1.1) Diseases linked to chromosomal abnormalities. (1.2) Monogenic diseases. (1.3) Polygenic and multifactorial diseases. (1.4) Mitochondrial diseases. (1.5) Diseases involving infectious agents. (2) Genetic screening and diagnoses. (2.1) Community screening and genetics. (2.2) Prenuptial genetic diagnosis. (2.3) Pre-ICSI diagnosis. (2.4) Pre-implantation diagnosis. (2.5) Prenatal diagnosis. (2.6) Neonatal diagnosis. (3) Access to screening and diagnosis results.

  14. Genetics in the art and art in genetics.

    PubMed

    Bukvic, Nenad; Elling, John W

    2015-01-15

    "Healing is best accomplished when art and science are conjoined, when body and spirit are probed together", says Bernard Lown, in his book "The Lost Art of Healing". Art has long been a witness to disease either through diseases which affected artists or diseases afflicting objects of their art. In particular, artists have often portrayed genetic disorders and malformations in their work. Sometimes genetic disorders have mystical significance; other times simply have intrinsic interest. Recognizing genetic disorders is also an art form. From the very beginning of my work as a Medical Geneticist I have composed personal "algorithms" to piece together evidence of genetics syndromes and diseases from the observable signs and symptoms. In this paper we apply some 'gestalt' Genetic Syndrome Diagnostic algorithms to virtual patients found in some art masterpieces. In some the diagnosis is clear and in others the artists' depiction only supports a speculative differential diagnosis.

  15. Genetics in the art and art in genetics.

    PubMed

    Bukvic, Nenad; Elling, John W

    2015-01-15

    "Healing is best accomplished when art and science are conjoined, when body and spirit are probed together", says Bernard Lown, in his book "The Lost Art of Healing". Art has long been a witness to disease either through diseases which affected artists or diseases afflicting objects of their art. In particular, artists have often portrayed genetic disorders and malformations in their work. Sometimes genetic disorders have mystical significance; other times simply have intrinsic interest. Recognizing genetic disorders is also an art form. From the very beginning of my work as a Medical Geneticist I have composed personal "algorithms" to piece together evidence of genetics syndromes and diseases from the observable signs and symptoms. In this paper we apply some 'gestalt' Genetic Syndrome Diagnostic algorithms to virtual patients found in some art masterpieces. In some the diagnosis is clear and in others the artists' depiction only supports a speculative differential diagnosis. PMID:25089030

  16. Using PGD to reduce surgical infection risk.

    PubMed

    Archyangelio, Annesha; Shakhon, Amritpal

    Patients with spinal injuries are at increased risk of surgical site infection due to increased numbers of comorbidities and prolonged surgical procedures. This article describes the impact of a patient group direction that was used in a pre-operative assessment clinic to provide Staphylococcus aureus decolonisation to patients with a spinal injury who required prophylaxis. A post-implementation audit revealed that, in the main, staff and patients adhered to the direction, and infection rates were reduced.

  17. Genetics Home Reference: limb-girdle muscular dystrophy

    MedlinePlus

    ... most common form of limb-girdle muscular dystrophy , accounting for about 30 percent of cases. Dysferlinopathy, also ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  18. Diagnosis of Sarcoidosis.

    PubMed

    Wessendorf, Thomas E; Bonella, Francesco; Costabel, Ulrich

    2015-08-01

    The diagnosis of sarcoidosis, a systemic granulomatous disease, is based on a compatible clinical-radiological picture and the histological evidence of noncaseating granulomas. Other diseases mimicking sarcoidosis, mostly infections and other granulomatoses, have to be excluded. There is no single test for sarcoidosis, and the presence of granulomas alone does not establish the diagnosis. Symptoms of sarcoidosis are not specific and can be markedly different according to organ involvement and disease course. Respiratory symptoms and fatigue are the most common symptoms at any stage of disease. Histological confirmation is not needed for Löfgren's or Heerfordt's syndrome and asymptomatic bihilar lymphadenopathy. The radiological staging system is still based on chest radiography, and computed tomography is not mandatory for routine follow-up. (18)F-fluorodeoxyglucose positron emission tomography may be of value in special cases. For assessment of lung involvement and follow-up, pulmonary function tests are necessary with vital capacity being the most important single parameter and diffusion capacity the most sensitive. Bronchoscopy with biopsy is the most common procedure for detection of granulomas, when there is no easier biopsy site like skin or peripheral lymph nodes. Endobronchial ultrasonography-guided transbronchial needle aspiration has replaced mediastinoscopy for evaluation of mediastinal and hilar lymph nodes with a high diagnostic yield. Despite numerous studies, no single biomarker can be reliably used for correct diagnosis or exclusion of sarcoidosis. Genetic testing, despite promising advances, has still not been included in routine care for sarcoidosis patients. The long-term prognosis of sarcoidosis depends on the different organ manifestations: Cardiac or central nervous involvement, together with respiratory complications, is critical. A multidisciplinary approach is necessary for comprehensive care of the sarcoidosis patient.

  19. [Genetics of neuropathies].

    PubMed

    Gess, B; Schirmacher, A; Young, P

    2013-02-01

    Hereditary neuropathies belong to the most common neurogenetic disorders. They appear mostly as sensory and motor neuropathies but there are also pure sensory, pure motor as well as sensory and autonomic hereditary neuropathies. In clinical practice, knowledge of hereditary neuropathies is important in order to recognize them among polyneuropathies and achieve a successful genetic diagnosis. The molecular genetics of hereditary neuropathies are very heterogeneous with currently more than 40 known disease-causing genes. The 4 most common genes account for almost 90% of the genetically diagnosed hereditary neuropathies. In this review article we provide an overview of the currently known genes and propose a rational genetic work-up protocol of the most common genes.

  20. Genetics for the ophthalmologist.

    PubMed

    Sadagopan, Karthikeyan A; Capasso, Jenina; Levin, Alex V

    2012-09-01

    The eye has played a major role in human genomics including gene therapy. It is the fourth most common organ system after integument (skin, hair and nails), nervous system, and musculoskeletal system to be involved in genetic disorders. The eye is involved in single gene disorders and those caused by multifactorial etiology. Retinoblastoma was the first human cancer gene to be cloned. Leber hereditary optic neuropathy was the first mitochondrial disorder described. X-Linked red-green color deficiency was the first X-linked disorder described. The eye, unlike any other body organ, allows directly visualization of genetic phenomena such as skewed X-inactivation in the fundus of a female carrier of ocular albinism. Basic concepts of genetics and their application to clinical ophthalmological practice are important not only in making a precise diagnosis and appropriate referral, but also in management and genetic counseling. PMID:23439654

  1. [Protective management for genetic information].

    PubMed

    Niikawa, Norio

    2005-03-01

    With advances in genomic and genetic medicine, genomic information is being used for the management of disorders. In addition, personalized medicine will be in practice in the near future. Because genetic information, i.e., disease diagnosis, gene mutations, and/or nucleotide sequences, remains unchanged through an individual's life, there are important issues for discussion, such as informed consent at sampling, protection of an individual's genetic information from any social discrimination, handling of samples, and genetic counseling. In this review, how to protect and manage the genetic information at researching and at medical practice, together with several bioethical guidelines regarding such issues, are described. A triangle system in which sample donators, directing physicians/researchers and genetic counselors participate, to manage genetic information appropriately, is also proposed.

  2. Genetic polymorphism of blood groups and erythrocytes enzymes in population groups of the Republic of Macedonia.

    PubMed

    Efremovska, Lj; Schmidt, H D; Scheil, H G; Gjorgjevic, D; Nikoloska Dadic, E

    2007-12-01

    This study presents the results of an examination of 3 blood-group systems (ABO, Rhesus, and P1) and erythrocyte enzymes (ADA, AK, ALADH, PGD, SAHH, PGM1, PGM3, GPT, GOT, ACP, UMPK, ESD and GLO) in populations that reside in R. Macedonia. Four population samples from the Republic of Macedonia (129 Macedonians from Skopje, 98 Albanians from Skopje, 95 Aromanians from Krusevo, 102 Aromanians from Stip) were included in the study. A comparison of the obtained results with data from literature on other Balkan populations has been made. The results of the comparison of the studied alleles indicate relatively small genetic distances among the studied populations. The obtained dendrograms indicate a larger homogeneity in the large Balkan populations, and a manifest trend of separating the Aromanian population of the Stip region. A larger separation is characteristic in the Greek population of Thrace.

  3. Genetic algorithms

    NASA Technical Reports Server (NTRS)

    Wang, Lui; Bayer, Steven E.

    1991-01-01

    Genetic algorithms are mathematical, highly parallel, adaptive search procedures (i.e., problem solving methods) based loosely on the processes of natural genetics and Darwinian survival of the fittest. Basic genetic algorithms concepts are introduced, genetic algorithm applications are introduced, and results are presented from a project to develop a software tool that will enable the widespread use of genetic algorithm technology.

  4. Genetic counseling services and development of training programs in Malaysia.

    PubMed

    Lee, Juliana Mei-Har; Thong, Meow-Keong

    2013-12-01

    Genetic counseling service is urgently required in developing countries. In Malaysia, the first medical genetic service was introduced in 1994 at one of the main teaching hospitals in Kuala Lumpur. Two decades later, the medical genetic services have improved with the availability of genetic counseling, genetic testing and diagnosis, for both paediatric conditions and adult-onset inherited conditions, at four main centers of medical genetic services in Malaysia. Prenatal diagnosis services and assisted reproductive technologies are available at tertiary centres and private medical facilities. Positive developments include governmental recognition of Clinical Genetics as a subspecialty, increased funding for genetics services, development of medical ethics guidelines, and establishment of support groups. However, the country lacked qualified genetic counselors. Proposals were presented to policy-makers to develop genetic counseling courses. Challenges encountered included limited resources and public awareness, ethical dilemmas such as religious and social issues and inadequate genetic health professionals especially genetic counselors.

  5. Diagnosis and treatment planning.

    PubMed

    Fagan, D A

    1986-09-01

    It must be emphasized that any examination of a supposedly healthy patient must be thorough and careful, for the early detection of disease demands that minute and inconspicuous deviations from the normal be evaluated carefully. The detection of disease occurs during the examination procedure, and from a practical point of view, it appears that clinicians employ at least the following three types of examination, depending upon circumstances: the comprehensive examination; the screening examination; and the emergency or limited examination. Although the latter two types represent a justifiable compromise with respect to the comprehensive examination in light of limitations of time or resources, the general inaccessibility of the patient in veterinary practice suggests that one should make the most of the opportunity for examination when it presents itself. A complete, thorough examination is not, by definition, a time-consuming and expensive procedure, particularly if there is no disease present. Exam-related expense is more a function of a differential diagnostic effort once clinical abnormality is detected, and then it is certainly justified. The term "diagnosis" originates from a Greek word meaning to distinguish or to discern. For the clinician, it refers to the process of identification of a disease by investigating, in all their manifestations, the signs and symptoms presented by the patient. The word diagnosis describes not just a "disease identified," but the process by which the identification is made. The procedure for making a diagnosis includes the following four primary steps: Collection of the facts. Analysis of the data for relative importance. Correlation between synthesized data and descriptive features of suspected diseases. Selection of the disease that best explains the collected facts and apparent disturbed physiologic processes of the patient. The process of diagnosis usually results in the naming of a disease. It is well to remember that a

  6. New Genetics

    MedlinePlus

    ... human genome, behavioral genetics, pharmacogenetics, drug resistance, biofilms, computer modeling. » more Chapter 5: 21st-Century Genetics Covers systems biology, GFP, genetic testing, privacy concerns, DNA forensics, ...

  7. Genetic Counseling

    MedlinePlus

    Genetic counseling provides information and support to people who have, or may be at risk for, genetic disorders. A ... meets with you to discuss genetic risks. The counseling may be for yourself or a family member. ...

  8. Genetic Counseling

    MedlinePlus

    ... Articles Genetic Counseling Information For... Media Policy Makers Genetic Counseling Language: English Español (Spanish) Recommend on Facebook ... informed decisions about testing and treatment. Reasons for Genetic Counseling There are many reasons that people go ...

  9. Diagnosis of automotive fuel cell power generators

    NASA Astrophysics Data System (ADS)

    Hissel, D.; Péra, M. C.; Kauffmann, J. M.

    Most of car manufacturers around the world have launched important research programs on the integration of fuel cell (FC) power generators into cars. Despite the first achievements, fuel cell systems are still badly known, particularly when talking about fault diagnosis and predictive maintenance. This paper proposes a first step in this way by introducing a simple but also efficient diagnosis-oriented model of a proton exchange membrane fuel cell (PEMFC). The considered diagnosis model is here a fuzzy one and is tuned thanks to genetic algorithms.

  10. The genetics of dilated cardiomyopathy

    PubMed Central

    Dellefave, Lisa; McNally, Elizabeth M.

    2010-01-01

    Purpose of review More than forty different individual genes have been implicated in the inheritance of dilated cardiomyopathy. For a subset of these genes, mutations can lead to a spectrum of cardiomyopathy that extends to hypertrophic cardiomyopathy and left ventricular noncompaction. In nearly all cases, there is an increased risk of arrhythmias. With some genetic mutations, extracardiac manifestations are likely to be present. The precise genetic etiology can usually not be discerned from the cardiac and/or extracardiac manifestations and requires molecular genetic diagnosis for prognostic determination and cardiac care. Recent findings Newer technologies are influencing genetic testing, especially cardiomyopathy genetic testing, where an increased number of genes are now routinely being tested simultaneously. While this approach to testing multiple genes is increasing the diagnostic yield, the analysis of multiple genes in one test is also resulting in a large amount of genetic information of unclear significance. Summary Genetic testing is highly useful in the care of patients and families, since it guides diagnosis, influences care and aids in prognosis. However, the large amount of benign human genetic variation may complicate genetic results, and often requires a skilled team to accurately interpret the findings. PMID:20186049

  11. Reproductive decisions after fetal genetic counselling.

    PubMed

    Pergament, Eugene; Pergament, Deborah

    2012-10-01

    A broad range of testing modalities for fetal genetic disease has been established. These include carrier screening for single-gene mutations, first-trimester and second-trimester screening for chromosome abnormalities and open neural-tube defects, prenatal diagnosis by means of chorionic villus sampling and amniocentesis, and preimplantation genetic diagnosis. Reproductive decisions before and after fetal genetic counselling represent the culmination of a dynamic interaction between prospective parents, obstetrician and genetic counsellor. The decision to undergo genetic testing before and after genetic counselling is influenced by a host of interrelated factors, including patient-partner and family relationships, patient-physician communication, societal mores, religious beliefs, and the media. Because of the complexity of personal and societal factors involved, it is not surprising that genetic counselling concerning reproductive decision-making must be individualised. A limited number of principles, guidelines and standards apply when counselling about testing for fetal genetic disease. These principles are that genetic counselling should be non-directive and unbiased and that parental decisions should be supported regardless of the reproductive choice. A critical responsibility of the obstetrician and genetic counsellor is to provide accurate and objective information about the implications, advantages, disadvantages and consequences of any genetic testing applied to prospective parents and their fetuses. These principles and responsibilities will be tested as newer technologies, such as array comparative genome hybridisation, non-invasive prenatal diagnosis and sequencing of the entire genome are introduced into the field of reproductive genetics and become routine practice.

  12. Pediatric genetic ocular tumors

    PubMed Central

    Rouhani, Behnaz; Ramasubramanian, Aparna

    2014-01-01

    Pediatric genetic ocular tumors include malignancies like retinoblastoma and phakomatosis like neurofibromatosis, tuberous sclerosis, von Hippel-Lindau syndrome, and nevoid basal cell carcinoma syndrome. It is important to screen for ocular tumors both for visual prognosis and also for systemic implications. The phakomatosis comprise of multitude of benign tumors that are aysmptomatic but their detection can aid in the diagnosis of the syndrome. Retinoblastoma is the most common malignant intraocular tumor in childhood and with current treatment modalities, the survival is more than 95%. It is transmitted as an autosomal dominant fashion and hence the offsprings of all patients with the germline retinoblastoma need to be screened from birth. This review discusses the various pediatric genetic ocular tumors discussing the clinical manifestation, diagnosis and treatment.

  13. Pediatric genetic ocular tumors.

    PubMed

    Rouhani, Behnaz; Ramasubramanian, Aparna

    2014-12-01

    Pediatric genetic ocular tumors include malignancies like retinoblastoma and phakomatosis like neurofibromatosis, tuberous sclerosis, von Hippel-Lindau syndrome, and nevoid basal cell carcinoma syndrome. It is important to screen for ocular tumors both for visual prognosis and also for systemic implications. The phakomatosis comprise of multitude of benign tumors that are aysmptomatic but their detection can aid in the diagnosis of the syndrome. Retinoblastoma is the most common malignant intraocular tumor in childhood and with current treatment modalities, the survival is more than 95%. It is transmitted as an autosomal dominant fashion and hence the offsprings of all patients with the germline retinoblastoma need to be screened from birth. This review discusses the various pediatric genetic ocular tumors discussing the clinical manifestation, diagnosis and treatment. PMID:27625882

  14. Prevention is the Best Therapy: The Geneticist's Approach.

    PubMed

    Altarescu, Gheona

    2016-06-01

    Abstract During the last two decades prenatal genetic screening and diagnosis has become the cornerstone of medical care for family planning to prevent genetic disease. Carrier screening programs for genetic disorders that are prevalent in various populations identify couples and pregnancies at risk of having an affected child. These couples can proceed with a choice of invasive prenatal diagnosis tests of the fetus (chorionic villous sampling and amniocentesis), or non-invasive prenatal testing of free fetal DNA circulation in the maternal blood which has emerged within the last few years and is currently available for fetal sexing for X Linked disorders. Despite the advances in prenatal diagnosis, couples found to have a fetus affected with a genetic disorder may need to face the dilemma of pregnancy termination. Preimplantation genetic diagnosis (PGD) is an alternative to preempt risk of having a child affected with a life-altering genetic disorder. This technique allows biopsy and genetic diagnosis of embryos obtained from in vitro fertilization by analysis of the genetic material from one or a few embryonic cells. Only unaffected embryos are returned to the mother to establish the pregnancy. We present our experience using PGD for four Lysosomal storage disorders: Tay Sachs, Gaucher type 1, Hunter and Fabry disease with some of the couples being carriers of more than one genetic disorder. PGD is applicable to most disorders for which the gene and the familial mutation are known and should be presented to couples as an alternative to invasive prenatal testing.

  15. Prevention is the Best Therapy: The Geneticist's Approach.

    PubMed

    Altarescu, Gheona

    2016-06-01

    Abstract During the last two decades prenatal genetic screening and diagnosis has become the cornerstone of medical care for family planning to prevent genetic disease. Carrier screening programs for genetic disorders that are prevalent in various populations identify couples and pregnancies at risk of having an affected child. These couples can proceed with a choice of invasive prenatal diagnosis tests of the fetus (chorionic villous sampling and amniocentesis), or non-invasive prenatal testing of free fetal DNA circulation in the maternal blood which has emerged within the last few years and is currently available for fetal sexing for X Linked disorders. Despite the advances in prenatal diagnosis, couples found to have a fetus affected with a genetic disorder may need to face the dilemma of pregnancy termination. Preimplantation genetic diagnosis (PGD) is an alternative to preempt risk of having a child affected with a life-altering genetic disorder. This technique allows biopsy and genetic diagnosis of embryos obtained from in vitro fertilization by analysis of the genetic material from one or a few embryonic cells. Only unaffected embryos are returned to the mother to establish the pregnancy. We present our experience using PGD for four Lysosomal storage disorders: Tay Sachs, Gaucher type 1, Hunter and Fabry disease with some of the couples being carriers of more than one genetic disorder. PGD is applicable to most disorders for which the gene and the familial mutation are known and should be presented to couples as an alternative to invasive prenatal testing. PMID:27491212

  16. Experimental studies on some genetic effects of marine pollution

    NASA Astrophysics Data System (ADS)

    Battaglia, B.; Bisol, P. M.; Rodinò, E.

    1980-03-01

    Following the results of a series of investigations carried out to estimate the degree of marine pollution by utilizing certain marine filter feeders, such as the blue mussel Mytilus galloprovincialis, research has been planned to detect possible genetic effects of pollutants, with special attention to those acting at the population level. The possible selective role of pollutants has been studied both in natural ( Mytilus) and in experimental ( Tisbe holothuriae) populations by utilizing some electrophoretically-detected gene-enzyme systems as genetic markers. For some of the seven polymorphic loci studied in Mytilus (AP, LAP, 6-PGD, IDHs, IDHm, PGI, PGM) significant changes in gene frequencies have been detected which can be related to the degree of pollution in the sampling areas. In the more polluted areas these changes were accompanied by a decrease in the frequency of heterozygotes. Similar changes in gene frequencies also occurred in laboratory populations of the copepod Tisbe, reared under various experimental conditions. In particular, certain alleles of two loci, PGI-1 and AP-1, exhibited an increase in frequency, especially in populations cultured at various levels of oil pollution. This trend appeared more significant for the locus PGI. The fact that equilibria are reached and that the less favoured alleles are nevertheless maintained in the populations, even at extremely low frequencies, suggests the balanced nature of these enzyme polymorphisms. The significance of the above findings is briefly discussed.

  17. [Genetics of sudden unexplained death].

    PubMed

    Campuzano, Oscar; Allegue, Catarina; Brugada, Ramon

    2014-03-20

    Sudden unexplained death is defined by death without a conclusive diagnosis after autopsy and it is responsible for a large percentage of sudden deaths. The progressive interaction between genetics and forensics in post-mortem studies has identified inheritable alterations responsible for pathologies associated with arrhythmic sudden death. The genetic diagnosis of the deceased enables the undertaking of preventive measures in family members, many of them asymptomatic but at risk. The implications of this multidisciplinary translational medical approach are complex, requiring the dedication of a specialized team.

  18. [Genetics of sudden unexplained death].

    PubMed

    Campuzano, Oscar; Allegue, Catarina; Brugada, Ramon

    2014-03-20

    Sudden unexplained death is defined by death without a conclusive diagnosis after autopsy and it is responsible for a large percentage of sudden deaths. The progressive interaction between genetics and forensics in post-mortem studies has identified inheritable alterations responsible for pathologies associated with arrhythmic sudden death. The genetic diagnosis of the deceased enables the undertaking of preventive measures in family members, many of them asymptomatic but at risk. The implications of this multidisciplinary translational medical approach are complex, requiring the dedication of a specialized team. PMID:24018251

  19. Human herpesvirus infections: Pathogenesis, diagnosis, and treatment

    SciTech Connect

    Lopez, C.; Roizman, B.

    1986-01-01

    This book contains 24 selections. Some of the titles are: Molecular Biology of Latent HSV-1; Molecular Genetics of Antiviral Chemotherapy of Herpes Viruses; Molecular Basis of Foscarnet Action; Use of Vaccinia Virus as a Vector for Expression of Herpesvirus Genes; and Diagnosis of Herpesvirus with Monoclonal Antibodies.

  20. Diagnosis of arsenicosis.

    PubMed

    Saha, Kshitish Chandra

    2003-01-01

    Arsenicosis is chronic subclinical or clinical toxicity due to high level of arsenic in body. Diagnosis of arsenicosis was derived by chronological establishment of facts: (a) arsenic as the cause of malady, (b) drinking water (tubewell water) as the vehicle of arsenic, (c) soil as the source of arsenic, (d) mechanism of leaching of arsenic from soil, and (e) cause of prevalence in particular areas of the country. Arsenicosis has been classified by the author into 4 stages, 7 grades and 20 subgrades. Stage I is pre-clinical or grade 0. While clinical features were not found at this stage, high level of arsenic metabolites was observed in urine. As disease progressed to stable phase of grade 0, high level of arsenic was also found in nails, hair, and skin scales. Stage II or clinical stage is divided into 4 grades, (1) Melanosis, (2) Spotted keratosis in palms/soles, (3) Diffuse keratosis in palms/soles, and (4) Dorsal keratosis. Clinical complications are grouped in stage III and grade 5. Malignancy is considered in stage IV and grade 6. There is a concern of both underdiagnosis and overdiagnosis. Therefore, cases of arsenicosis should be cautiously evaluated. Melanosis was the earliest cutaneous sign of clinical arsenicosis. Mild cases of melanosis could only be revealed by a thorough comparison with normal palms. Similarly mild cases of keratosis might not be visible and could only be revealed by careful palpation of palms and soles. Combination of melanosis and keratosis in adults indicated clinical diagnosis of arsenical dermatosis (ASD) that should be confirmed by showing high arsenic concentration in body tissues e.g., nails, hair, skin scales. Isolated melanosis or keratosis in newborn or children below 2 years almost negated the diagnosis of arsenicosis. Genetic melanosis or keratosis is often present since birth. Isolated melanosis or keratosis in adults should be differentiated from non-arsenical dermatosis and proven by absence of high arsenic level in

  1. Genetic Technologies and Ethics

    PubMed Central

    Ardekani, Ali M.

    2009-01-01

    In the past decade, the human genome has been completely sequenced and the knowledge from it has begun to influence the fields of biological and social sciences in fundamental ways. Identification of about 25000 genes in the human genome is expected to create great benefits in diagnosis and treatment of diseases in the coming years. However, Genetic technologies have also created many interesting and difficult ethical issues which can affect the human societies now and in the future. Application of genetic technologies in the areas of stem cells, cloning, gene therapy, genetic manipulation, gene selection, sex selection and preimplantation diagnosis has created a great potential for the human race to influence and change human life on earth as we know it today. Therefore, it is important for leaders of societies in the modern world to pay attention to the advances in genetic technologies and prepare themselves and those institutions under their command to face the challenges which these new technologies induce in the areas of ethics, law and social policies. PMID:23908725

  2. Genetics in Osteoarthritis

    PubMed Central

    Fernández-Moreno, Mercedes; Rego, Ignacio; Carreira-Garcia, Vanessa; Blanco, Francisco J

    2008-01-01

    Osteoarthritis is a degenerative articular disease with complex pathogeny because diverse factors interact causing a process of deterioration of the cartilage. Despite the multifactorial nature of this pathology, from the 50’s it´s known that certain forms of osteoarthritis are related to a strong genetic component. The genetic bases of this disease do not follow the typical patterns of mendelian inheritance and probably they are related to alterations in multiple genes. The identification of a high number of candidate genes to confer susceptibility to the development of the osteoarthritis shows the complex nature of this disease. At the moment, the genetic mechanisms of this disease are not known, however, which seems clear is that expression levels of several genes are altered, and that the inheritance will become a substantial factor in future considerations of diagnosis and treatment of the osteoarthritis. PMID:19516961

  3. Recommendations for the diagnosis and management of Turner syndrome.

    PubMed

    Saenger, P; Wikland, K A; Conway, G S; Davenport, M; Gravholt, C H; Hintz, R; Hovatta, O; Hultcrantz, M; Landin-Wilhelmsen, K; Lin, A; Lippe, B; Pasquino, A M; Ranke, M B; Rosenfeld, R; Silberbach, M

    2001-07-01

    Comprehensive recommendations on the diagnosis of Turner syndrome (TS) and the care of affected individuals were published in 1994. In the light of recent advances in diagnosis and treatment of TS, an international multidisciplinary workshop was convened in March 2000, in Naples, Italy, in conjunction with the Fifth International Symposium on Turner Syndrome to update these recommendations. The present paper details the outcome from this workshop. The genetics and diagnosis of the syndrome are described, and practical treatment guidelines are presented.

  4. Genetic testing and blood biomarkers in paediatric pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.

    PubMed

    Pattathu, Joseph; Gorenflo, Matthias; Hilgendorff, Anne; Koskenvuo, Juha W; Apitz, Christian; Hansmann, Georg; Alastalo, Tero-Pekka

    2016-05-01

    Childhood-onset pulmonary arterial hypertension (PAH) is considered complex and multifactorial, with relatively poor estimates of the natural history of the disease. Strategies allowing earlier detection, establishment of disease aetiology together with more accurate and sensitive biomarkers could enable better estimates of prognosis and individualise therapeutic strategies. Evidence is accumulating that genetic defects play an important role in the pathogenesis of idiopathic and hereditary forms of PAH. Altogether nine genes have been reported so far to be associated with childhood onset PAH suggesting that comprehensive multigene diagnostics can be useful in the assessment. Identification of disease-causing mutations allows estimates of prognosis and forms the most effective way for risk stratification in the family. In addition to genetic determinants the analysis of blood biomarkers are increasingly used in clinical practice to evaluate disease severity and treatment responses. As in genetic diagnostics, a multiplex approach can be helpful, as a single biomarker for PAH is unlikely to meet all requirements. This consensus statement reviews the current evidence for the use of genetic diagnostics and use of blood biomarkers in the assessment of paediatric patients with PAH. PMID:27053696

  5. Genetic testing and blood biomarkers in paediatric pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.

    PubMed

    Pattathu, Joseph; Gorenflo, Matthias; Hilgendorff, Anne; Koskenvuo, Juha W; Apitz, Christian; Hansmann, Georg; Alastalo, Tero-Pekka

    2016-05-01

    Childhood-onset pulmonary arterial hypertension (PAH) is considered complex and multifactorial, with relatively poor estimates of the natural history of the disease. Strategies allowing earlier detection, establishment of disease aetiology together with more accurate and sensitive biomarkers could enable better estimates of prognosis and individualise therapeutic strategies. Evidence is accumulating that genetic defects play an important role in the pathogenesis of idiopathic and hereditary forms of PAH. Altogether nine genes have been reported so far to be associated with childhood onset PAH suggesting that comprehensive multigene diagnostics can be useful in the assessment. Identification of disease-causing mutations allows estimates of prognosis and forms the most effective way for risk stratification in the family. In addition to genetic determinants the analysis of blood biomarkers are increasingly used in clinical practice to evaluate disease severity and treatment responses. As in genetic diagnostics, a multiplex approach can be helpful, as a single biomarker for PAH is unlikely to meet all requirements. This consensus statement reviews the current evidence for the use of genetic diagnostics and use of blood biomarkers in the assessment of paediatric patients with PAH.

  6. Ethical issues in the diagnosis and management of fetal disorders.

    PubMed

    Chadwick, Ruth; Childs, Richardo

    2012-10-01

    The ethics of diagnosis and management of fetal genetic disorders are particularly controversial because of the contested status of the fetus and perceptions of genetics. An additional complicating factor is the potential conflict between mother and fetus. Ethical issues in diagnosis include the nature and purpose of the diagnosis itself, and management of the information. Management of the disorder includes issues of termination as an option, and the emerging field of fetal gene therapy with associated issues of somatic versus germ-line interventions. PMID:22901734

  7. [The Human Genome Project, genetic viability and genetic epidemiology].

    PubMed

    Hagymási, Krisztina; Tulassay, Zsolt

    2005-12-18

    The goal of the Human Genome Project to elucidate the complete sequence of the human genome has been achieved. The aims of the "post-genome" era are explaining the genetic information, characterisation of functional elements encoded in the human genome and mapping the human genetic variability as well. Two unrelated human beings also share 99.9% of their genomic sequence. The difference of 0.1% is the result of genetic polymorphisms: single nucleotide polymorphisms, repetitive sequences and insertion/deletion. The genetic differences, coupled with environmental exposures will determine the phenotypic variation we observe in health or disease. The disease-causing genetic variants can be identified by linkage analysis or association studies. The knowledge of human genome and application of multiple biomarkers will improve our ability to identify individuals at risk, so that preventive interventions can be applied, earlier diagnosis can be made and treatment can be optimized.

  8. Fetal cardiac anomalies and genetic syndromes.

    PubMed

    Pajkrt, Eva; Weisz, Boaz; Firth, Helen V; Chitty, Lyn S

    2004-12-30

    Cardiac anomalies may occur in isolation or can be part of a genetic syndrome. In this article, we describe some of the genetic syndromes commonly associated with cardiac anomalies where there are other sonographic features that may aid accurate prenatal diagnosis.

  9. The Psychosocial Impact of Genetic Disease.

    ERIC Educational Resources Information Center

    Costello, Audrey

    1988-01-01

    Genetic diseases in children present difficulties to the children themselves and to their families. This article reviews the features of genetic disease, stresses surrounding diagnosis, difficulties associated with each developmental stage, other sources of psychosocial stress on the family (e.g., finances, hospitalization, placement decisions),…

  10. Family Assessment and Genetic Counseling.

    ERIC Educational Resources Information Center

    Carpenter, Pat; And Others

    Presented are two papers from a panel discussion on prenatal diagnosis and genetic counseling with families. D. Blackston (director of the Developmental Evaluation Clinic, Decatur, Georgia) points out that a concise family history, pregnancy and birth data, developmental history, careful physical examination, and appropriate laboratory studies are…

  11. Genetic Mapping

    MedlinePlus

    ... Genetic Education Resources for Teachers Genomic Careers National DNA Day Online Education Kit Online Genetics Education Resources ... prevalent. Using various laboratory techniques, the scientists isolate DNA from these samples and examine it for unique ...

  12. Genetic Disorders

    MedlinePlus

    ... This can cause a medical condition called a genetic disorder. You can inherit a gene mutation from ... during your lifetime. There are three types of genetic disorders: Single-gene disorders, where a mutation affects ...

  13. Genetic modification and genetic determinism

    PubMed Central

    Resnik, David B; Vorhaus, Daniel B

    2006-01-01

    In this article we examine four objections to the genetic modification of human beings: the freedom argument, the giftedness argument, the authenticity argument, and the uniqueness argument. We then demonstrate that each of these arguments against genetic modification assumes a strong version of genetic determinism. Since these strong deterministic assumptions are false, the arguments against genetic modification, which assume and depend upon these assumptions, are therefore unsound. Serious discussion of the morality of genetic modification, and the development of sound science policy, should be driven by arguments that address the actual consequences of genetic modification for individuals and society, not by ones propped up by false or misleading biological assumptions. PMID:16800884

  14. Genetics of man, 2nd ed

    SciTech Connect

    Fraser, F.C.; Nora, J.J.

    1986-01-01

    New information in this book centers on DNA technology and its clinical application, progress in pre-natal diagnosis, teratogenic syndromes, immunogenetics, and cancer genetics. Normal and abnormal human genetic variations are detailed, along with methods of assessing their genetic components. The book then explains the ways in which this information is applicable to genetic counseling, the management of hereditary disease, and other social and ethical issues. Incorporating basic genetic principles, this referenced text is augmented by a glossary, illustrations and photographs, and an appendix of Chromosome Band Nomenclature.

  15. Imaging Genetics

    ERIC Educational Resources Information Center

    Munoz, Karen E.; Hyde, Luke W.; Hariri, Ahmad R.

    2009-01-01

    Imaging genetics is an experimental strategy that integrates molecular genetics and neuroimaging technology to examine biological mechanisms that mediate differences in behavior and the risks for psychiatric disorder. The basic principles in imaging genetics and the development of the field are discussed.

  16. Genetic Testing

    MedlinePlus

    ... genetic tests for several reasons. These include Finding genetic diseases in unborn babies Finding out if people carry a gene for a disease and might pass it on to their children Screening embryos for disease Testing for genetic diseases in adults before they cause ...

  17. Pubic "Crab" Lice Diagnosis

    MedlinePlus

    ... Treatment FAQs Malathion FAQs Epidemiology & Risk Factors Disease Biology Diagnosis Treatment Prevention & Control Resources for Health Professionals ... Frequently Asked Questions (FAQs) Epidemiology & Risk Factors Disease Biology Diagnosis Treatment Prevention & Control Resources for Health Professionals ...

  18. Head Lice: Diagnosis

    MedlinePlus

    ... Treatment FAQs Malathion FAQs Epidemiology & Risk Factors Disease Biology Diagnosis Treatment Prevention & Control Resources for Health Professionals ... Frequently Asked Questions (FAQs) Epidemiology & Risk Factors Disease Biology Diagnosis Treatment Prevention & Control Resources for Health Professionals ...

  19. Body Lice Diagnosis

    MedlinePlus

    ... Treatment FAQs Malathion FAQs Epidemiology & Risk Factors Disease Biology Diagnosis Treatment Prevention & Control Resources for Health Professionals ... Frequently Asked Questions (FAQs) Epidemiology & Risk Factors Disease Biology Diagnosis Treatment Prevention & Control Resources for Health Professionals ...

  20. Prenatal diagnosis of achondrogenesis.

    PubMed

    Golbus, M S; Hall, B D; Filly, R A; Poskanzer, L B

    1977-09-01

    Severe rhizomelic and mesomelic dwarfism was demonstrated in a 20-week gestation fetus by amniography. A systematic progressive approach to prenatal diagnosis in the absence of a definitive diagnosis and the use of contrast radiography is discussed. PMID:894421

  1. Bell's Palsy Diagnosis

    MedlinePlus

    ... Stories Español Eye Health / Eye Health A-Z Bell's Palsy Sections What Is Bell's Palsy? Bell's Palsy Symptoms ... Bell's Palsy? Bell's Palsy Diagnosis Bell's Palsy Treatment Bell's Palsy Diagnosis Reviewed by: Philip R Rizzuto, MD FACS ...

  2. Genetic study of the tribal populations of Andhra Pradesh, south India.

    PubMed

    Papiha, S S; Singh, B N; Lanchbury, J S; Mastana, S S; Rao, Y S

    1997-04-01

    Regional variation in the genetic constitution and genetic differentiation of three tribal populations (Koya, Lambadi, and Chenchu) of Andhra Pradesh, South India, was examined from the data of 27 polymorphic loci (9 blood groups, 13 red cell enzymes, and 5 serum proteins). Significant heterogeneity was observed among the three tribal groups at several loci (ABO, RH, P, ADA, PGM, ACP, ESD, PGD, GPT, HP, C3, and BF). Pairwise comparisons also showed significant genetic differences between the Koya and the Chenchu at seven loci, between the Koya and the Lambadi at nine loci, and between the Chenchu and the Lambadi at seven loci. Gene differentiation among the three tribes was sufficient to allow an overall excess of heterozygosity. The FIS estimates of each tribe showed positive values, but a great number of alleles showed negative FIS values, supporting varying degrees of gene flow and admixture with neighboring populations. The genetic differentiation and affinity of 14 tribal populations of Andhra Pradesh were further examined using published and unpublished data on 11 polymorphic genetic systems. Despite the genetic distinctions between two Chenchu samples and Koya and Koya-related tribes (Koya Dora and Konda Dora), geographic proximity seems to be an important determinant of affinity of the tribal populations of Andhra Pradesh. The extent of genetic diversity is high compared with previous reports from this state. No evidence from the present data indicates that selection had any appreciable effect on local differentiation, but the present analysis suggests that differences are more likely to be maintained by genetic drift, admixture, and inbreeding.

  3. Exostoses, enchondromatosis and metachondromatosis; diagnosis and management.

    PubMed

    McFarlane, John; Knight, Tim; Sinha, Anubha; Cole, Trevor; Kiely, Nigel; Freeman, Rob

    2016-03-01

    We describe a 5 years old girl who presented to the multidisciplinary skeletal dysplasia clinic following excision of two bony lumps from her fingers. Based on clinical examination, radiolographs and histological results an initial diagnosis of hereditary multiple exostosis (HME) was made. Four years later she developed further lumps which had the radiological appearance of enchondromas. The appearance of both exostoses and enchondromas suggested a possible diagnosis of metachondromatosis. Genetic testing revealed a splice site mutation at the end of exon 11 on the PTPN11 gene, confirming the diagnosis of metachondromatosis. While both single or multiple exostoses and enchondromas occur relatively commonly on their own, the appearance of multiple exostoses and enchondromas together is rare and should raise the differential diagnosis of metachondromatosis. Making this diagnosis is important as the lesions in metachondromatosis may spontaneously resolve and therefore surgical intervention is often unnecessary. We discuss the diagnostic findings, genetic causes, treatment and prognosis of this rare condition of which less than thirty cases have previously been reported. PMID:26984661

  4. Macromelanosomes in the early diagnosis of neurofibromatosis.

    PubMed

    Slater, C; Hayes, M; Saxe, N; Temple-Camp, C; Beighton, P

    1986-08-01

    Skin biopsies of café-au-lait macules from 34 patients with a clinical diagnosis of classical neurofibromatosis were examined histologically and ultrastructurally to determine the presence or absence of macromelanosomes in the epidermal melanocytes and keratinocytes. Sixteen of the 34 patients had macromelanosomes. The presence of macromelanosomes varied with age and ethnic background; they were detected in nine of 12 Whites, six of 10 persons of mixed ancestry, and one of two Blacks. In these populations skin biopsy is useful in early diagnosis of neurofibromatosis. However, none of 10 persons of Indian stock had macromelanosomes. Their total absence in this group may be indicative of genetic heterogeneity.

  5. Postpartal nursing diagnosis.

    PubMed

    Gorrie, T M

    1986-01-01

    The responsibility of nurses for postpartal patients has changed greatly in the past few years. No longer is it adequate to assess and manage only those physical problems that occur during the hospital stay. Today, potential psychosocial problems and consequences of parental knowledge deficit are part of nursing's domain of diagnosis and management. A review of the purpose of nursing diagnosis is important. Clarifying the difference between medical diagnosis and nursing diagnosis is also essential if one is to be comfortable with the process. Careful scrutiny of the unique needs of new parents will form the basis for formulating meaningful postpartal nursing diagnosis.

  6. Genomics in pediatric endocrinology-genetic disorders and new techniques.

    PubMed

    Tenore, Alfred; Driul, Daniela

    2011-10-01

    In the last few years, there have been remarkable advances in the development of new and more sophisticated genetic techniques. These have allowed a better understanding of the molecular mechanisms of genetically determined pediatric endocrine disorders and are paving the way for a radical change in diagnosis and treatment. This article introduces some of these concepts and some of the genetic techniques being used.

  7. Pediatric Cholestatic Disorders: Approach to Pathologic Diagnosis.

    PubMed

    Morotti, Raffaella A; Jain, Dhanpat

    2013-06-01

    This article addresses select liver diseases that are commonly seen in the pediatric group and pose diagnostic challenges in practice. The key genetic/molecular abnormalities, clinical features, histopathologic findings, diagnostic modalities, differential diagnoses, and possible pitfalls in diagnosis are discussed in detail. Although recent advances in understanding the pathophysiology of bile synthesis and transport along with advances in molecular genetics have allowed a better characterization of many of these liver diseases, significant overlap in the histopathologic features of many of these disorders still leads to diagnostic challenges for the pathologist.

  8. Diagnosis and management of hereditary hemochromatosis.

    PubMed

    Salgia, Reena J; Brown, Kimberly

    2015-02-01

    Hereditary hemochromatosis is a rare genetic disorder that can have significant clinical consequences. Hemochromatosis is associated with iron overload, and can initially be recognized through laboratory testing for serum ferritin and transferrin saturation. Genetic testing for the HFE mutation can be performed in patients with elevated iron indices and a suspicion for hemochromatosis or liver disease. The main pathway resulting in iron overload is through altered hepcidin levels. Treatment of patients with the clinical phenotype of hereditary hemochromatosis is commonly through phlebotomy for removal of excess iron stores. This article highlights the current information and data regarding the diagnosis and management of hemochromatosis.

  9. Genetic screening: marvel or menace?

    PubMed

    Rowley, P T

    1984-07-13

    Genetic screening is a systematic search in the population for persons of certain genotypes. The usual purpose is to detect persons who themselves or whose offspring are at risk for genetic diseases or genetically determined susceptibilities to environmental agents. Is genetic screening a marvel about to free us from the scourge of genetic disease or a menace about to invade our privacy and determine who may reproduce? There are three different types of genetic screening. Newborn screening identifies serious genetic disease at birth, permitting prompt treatment to prevent mental and physical retardation. Fetal screening and prenatal diagnosis identify genetic disease in the fetus permitting selective termination of pregnancy and the opportunity to have children free of defects detectable in utero. Carrier screening identifies individuals heterozygous for a gene for a serious recessive disease who may be at risk for affected offspring. The challenge to society is to provide (by way of cost-effective programs) expert services, including genetic counseling and follow-up, to all who may benefit, to ensure confidentiality and freedom of choice, and to avoid misunderstanding and stigmatization. It is recommended that the objective of screening programs should be to maximize the options available to families at risk rather than to reduce the incidence of genetic diseases. Whenever possible, the providers of these services should be the providers of primary health care. Urgently needed are a greater awareness of avoidable genetic diseases on the part of primary care providers and efforts to familiarize the public with the basic concepts of human genetics through the public school system.

  10. Genetic screening: marvel or menace?

    PubMed

    Rowley, P T

    1984-07-13

    Genetic screening is a systematic search in the population for persons of certain genotypes. The usual purpose is to detect persons who themselves or whose offspring are at risk for genetic diseases or genetically determined susceptibilities to environmental agents. Is genetic screening a marvel about to free us from the scourge of genetic disease or a menace about to invade our privacy and determine who may reproduce? There are three different types of genetic screening. Newborn screening identifies serious genetic disease at birth, permitting prompt treatment to prevent mental and physical retardation. Fetal screening and prenatal diagnosis identify genetic disease in the fetus permitting selective termination of pregnancy and the opportunity to have children free of defects detectable in utero. Carrier screening identifies individuals heterozygous for a gene for a serious recessive disease who may be at risk for affected offspring. The challenge to society is to provide (by way of cost-effective programs) expert services, including genetic counseling and follow-up, to all who may benefit, to ensure confidentiality and freedom of choice, and to avoid misunderstanding and stigmatization. It is recommended that the objective of screening programs should be to maximize the options available to families at risk rather than to reduce the incidence of genetic diseases. Whenever possible, the providers of these services should be the providers of primary health care. Urgently needed are a greater awareness of avoidable genetic diseases on the part of primary care providers and efforts to familiarize the public with the basic concepts of human genetics through the public school system. PMID:6729472

  11. Genetic pediatric retinal diseases

    PubMed Central

    Say, Emil Anthony T.

    2014-01-01

    Hereditary pediatric retinal diseases are a diverse group of disorders with pathologies affecting different cellular structures or retinal development. Many can mimic typical pediatric retinal disease such as retinopathy of prematurity, vitreous hemorrhage, retinal detachment and cystoid macular edema. Multisystem involvement is frequently seen in hereditary pediatric retinal disease. A thorough history coupled with a good physical examination can oftentimes lead the ophthalmologist or pediatrician to the correct genetic test and correct diagnosis. In some instances, evaluation of parents or siblings may be required to determine familial involvement when the history is inconclusive or insufficient and clinical suspicion is high.

  12. Genetic pediatric retinal diseases.

    PubMed

    Say, Emil Anthony T

    2014-12-01

    Hereditary pediatric retinal diseases are a diverse group of disorders with pathologies affecting different cellular structures or retinal development. Many can mimic typical pediatric retinal disease such as retinopathy of prematurity, vitreous hemorrhage, retinal detachment and cystoid macular edema. Multisystem involvement is frequently seen in hereditary pediatric retinal disease. A thorough history coupled with a good physical examination can oftentimes lead the ophthalmologist or pediatrician to the correct genetic test and correct diagnosis. In some instances, evaluation of parents or siblings may be required to determine familial involvement when the history is inconclusive or insufficient and clinical suspicion is high. PMID:27625880

  13. Advances in human genetics

    SciTech Connect

    Harris, H.; Hirschhorn, K.

    1993-01-01

    This book has five chapters covering peroxisomal diseases, X-linked immunodeficiencies, genetic mutations affecting human lipoproteins and their receptors and enzymes, genetic aspects of cancer, and Gaucher disease. The chapter on peroxisomes covers their discovery, structure, functions, disorders, etc. The chapter on X-linked immunodeficiencies discusses such diseases as agammaglobulinemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, animal models, linkage analysis, etc. Apolipoprotein formation, synthesis, gene regulation, proteins, etc. are the main focus of chapter 3. The chapter on cancer covers such topics as oncogene mapping and the molecular characterization of some recessive oncogenes. Gaucher disease is covered from its diagnosis, classification, and prevention, to its organ system involvement and molecular biology.

  14. Genetic barcodes

    DOEpatents

    Weier, Heinz -Ulrich G

    2015-08-04

    Herein are described multicolor FISH probe sets termed "genetic barcodes" targeting several cancer or disease-related loci to assess gene rearrangements and copy number changes in tumor cells. Two, three or more different fluorophores are used to detect the genetic barcode sections thus permitting unique labeling and multilocus analysis in individual cell nuclei. Gene specific barcodes can be generated and combined to provide both numerical and structural genetic information for these and other pertinent disease associated genes.

  15. Paleopopulation genetics.

    PubMed

    Wall, Jeffrey D; Slatkin, Montgomery

    2012-01-01

    Paleopopulation genetics is a new field that focuses on the population genetics of extinct groups and ancestral populations (i.e., populations ancestral to extant groups). With recent advances in DNA sequencing technologies, we now have unprecedented ability to directly assay genetic variation from fossils. This allows us to address issues, such as past population structure, changes in population size, and evolutionary relationships between taxa, at a much greater resolution than can traditional population genetics studies. In this review, we discuss recent developments in this emerging field as well as prospects for the future. PMID:22994357

  16. Mitochondrial disorders: Challenges in diagnosis & treatment

    PubMed Central

    Khan, Nahid Akhtar; Govindaraj, Periyasamy; Meena, Angamuthu Kannan; Thangaraj, Kumarasamy

    2015-01-01

    Mitochondrial dysfunctions are known to be responsible for a number of heterogenous clinical presentations with multi-systemic involvement. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these disorders. Despite significant progress made in the field of mitochondrial medicine during the last two decades, the molecular mechanisms underlying these disorders are not fully understood. Since the identification of first mitochondrial DNA (mtDNA) mutation in 1988, there has been an exponential rise in the identification of mtDNA and nuclear DNA mutations that are responsible for mitochondrial dysfunction and disease. Genetic complexity together with ever widening clinical spectrum associated with mitochondrial dysfunction poses a major challenge in diagnosis and treatment. Effective therapy has remained elusive till date and is mostly efficient in relieving symptoms. In this review, we discuss the important clinical and genetic features of mitochondrials disorders with special emphasis on diagnosis and treatment. PMID:25857492

  17. [Genetic diagnostic testing in inherited retinal dystrophies].

    PubMed

    Kohl, S; Biskup, S

    2013-03-01

    Inherited retinal dystrophies are clinically and genetically highly heterogeneous. They can be divided according to the clinical phenotype and course of the disease, as well as the underlying mode of inheritance. Isolated retinal dystrophies (i.e., retinitis pigmentosa, Leber's congenital amaurosis, cone and cone-rod dystrophy, macular dystrophy, achromatopsia, congenital stationary nightblindness) and syndromal forms (i.e., Usher syndrome, Bardet-Biedl syndrome) can be differentiated. To date almost 180 genes and thousands of distinct mutations have been identified that are responsible for the different forms of these blinding illnesses. Until recently, there was no adequate diagnostic genetic testing available. With the development of the next generation sequencing technologies, a comprehensive genetic screening analysis for all known genes for inherited retinal dystrophies has been established at reasonable costs and in appropriate turn-around times. Depending on the primary clinical diagnosis and the presumed mode of inheritance, different diagnostic panels can be chosen for genetic testing. Statistics show that in 55-80 % of the cases the genetic defect of the inherited retinal dystrophy can be identified with this approach, depending on the initial clinical diagnosis. The aim of any genetic diagnostics is to define the genetic cause of a given illness within the affected patient and family and thereby i) confirm the clinical diagnosis, ii) provide targeted genetic testing in family members, iii) enable therapeutic intervention, iv) give a prognosis on disease course and progression and v) in the long run provide the basis for novel therapeutic approaches and personalised medicine.

  18. [Insights about uncertainty in genetic counseling].

    PubMed

    Huicochea-Montiel, Juan Carlos; Cárdenas-Conejo, Alan; Cervantes-Díaz, María Teresa; Araujo-Solís, María Antonieta de Jesús

    2015-01-01

    Genetic counseling is an information process to help people in the understanding and adaptation to the medical, psychological and family implications of the genetic contribution in diseases. This counseling encompasses all sorts of patients. This represents a challenge in the daily work of the medical geneticist, because giving information in a meaningful way to the patient and his family implies an emotional and psychological burden. Generally we can see two outcomes in the medical practice of genetics, which converge after a diagnosis process: 1) we can face the inability to reach a diagnostic conclusion or 2) we can establish or confirm a diagnosis with certainty, which is the main piece in the genetic counseling. However, in all the situations the uncertainty is a fact, since in the case of those individuals who come in for genetic counseling before symptoms appear or those in prenatal cases, the absence of clinical manifestations and the impossibility to change the course of events lead to the appearance of helplessness and despair. In those cases without diagnostic conclusion, this situation represents a reason for uncertainty, and even in those patients with a diagnosis, certain factors can modify the circumstances in which genetic counseling occurs, such as unpredictability or lack of control. Therefore, it is important to consider the management of uncertainty as an inherent part throughout the process of care in medical genetics. The teaching of medical genetics should also consider the inclusion of topics related to this circumstance.

  19. Genetics of alcoholism.

    PubMed

    Edenberg, Howard J; Foroud, Tatiana

    2014-01-01

    Multiple lines of evidence strongly indicate that genetic factors contribute to the risk for alcohol use disorders (AUD). There is substantial heterogeneity in AUD, which complicates studies seeking to identify specific genetic factors. To identify these genetic effects, several different alcohol-related phenotypes have been analyzed, including diagnosis and quantitative measures related to AUDs. Study designs have used candidate gene analyses, genetic linkage studies, genomewide association studies (GWAS), and analyses of rare variants. Two genes that encode enzymes of alcohol metabolism have the strongest effect on AUD: aldehyde dehydrogenase 2 and alcohol dehydrogenase 1B each has strongly protective variants that reduce risk, with odds ratios approximately 0.2-0.4. A number of other genes important in AUD have been identified and replicated, including GABRA2 and alcohol dehydrogenases 1B and 4. GWAS have identified additional candidates. Rare variants are likely also to play a role; studies of these are just beginning. A multifaceted approach to gene identification, targeting both rare and common variations and assembling much larger datasets for meta-analyses, is critical for identifying the key genes and pathways important in AUD.

  20. Celiac Disease: Diagnosis.

    PubMed

    Byrne, Greg; Feighery, Conleth F

    2015-01-01

    Historically the diagnosis of celiac disease has relied upon clinical, serological, and histological evidence. In recent years the use of sensitive serological methods has meant an increase in the diagnosis of celiac disease. The heterogeneous nature of the disorder presents a challenge in the study and diagnosis of the disease with patients varying from subclinical or latent disease to patients with overt symptoms. Furthermore the related gluten-sensitive disease dermatitis herpetiformis, while distinct in some respects, shares clinical and serological features with celiac disease. Here we summarize current best practice for the diagnosis of celiac disease and briefly discuss newer approaches. The advent of next-generation assays for diagnosis and newer clinical protocols may result in more sensitive screening and ultimately the possible replacement of the intestinal biopsy as the gold standard for celiac disease diagnosis.