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Sample records for genetic diagnosis pgd

  1. 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

  2. [Preimplantation genetic diagnosis (PGD): the Erasme Hospital experience].

    PubMed

    Gonzalez-Merino, E; Emiliani, S; Pichon, B; Parma, J; Vannin, A S; Delbaere, A; Vassart, G; Abramowicz, M; Englert, Y

    2008-01-01

    The clinical activity of the preimplantation genetic diagnosis (PGD) at Erasme Hospital was carried out since September 1999 for a 47,XYY patient. Up to 31 December 2007, 79 PGD cycles were carried out (45 couples) for either chromosomal structural abnormalities (robertsonian and reciprocal translocations, pericentric inversion, deletion) (n = 41), chromosomal numerical abnormalities (47,XXY, 47,XYY, 45,X/46,XX) (n = 10), aneuploidy screening for recurrent miscarriages or multiple in vitro fertilization failures (n = 10), autosomal recessive diseases (cystic fibrosis and sickle cell anaemia) (n = 12) or X-linked disorders (n = 6). A total of 475 embryos were biopsied for genetic analysis. Unaffected embryos were transferred in 58 cycles, resulting in 22 pregnancies, including fifteen clinical pregnancies. Up to now, 9 babies were born and 3 pregnancies are still ongoing. After a learning curve, our current PGD efficiency shows a total pregnancy rate per transfer of 60.0% and an implantation rate of 28.6%. Each PGD result was confirmed by prenatal or postnatal diagnosis. Our data demonstrate that PGD is a valid technique to allow couples at high risk of transmitting a genetic abnormality to increase their chances of a healthy pregnancy, but considering its complexity, patients must be counselled and selected rigorously. PMID:19202707

  3. Attitudes Toward Pre-implantation Genetic Diagnosis (PGD) for Genetic Disorders Among Potential Users in Malaysia.

    PubMed

    Olesen, Angelina Patrick; Nor, Siti Nurani Mohd; Amin, Latifah

    2016-02-01

    While pre-implantation genetic diagnosis (PGD) is available and legal in Malaysia, there is an ongoing controversy debate about its use. There are few studies available on individuals' attitudes toward PGD, particularly among those who have a genetic disease, or whose children have a genetic disease. To the best of our knowledge, this is, in fact, the first study of its kind in Malaysia. We conducted in-depth interviews, using semi-structured questionnaires, with seven selected potential PGD users regarding their knowledge, attitudes and decisions relating to the use PGD. The criteria for selecting potential PGD users were that they or their children had a genetic disease, and they desired to have another child who would be free of genetic disease. All participants had heard of PGD and five of them were considering its use. The participants' attitudes toward PGD were based on several different considerations that were influenced by various factors. These included: the benefit-risk balance of PGD, personal experiences of having a genetic disease, religious beliefs, personal values and cost. The study's findings suggest that the selected Malaysian participants, as potential PGD users, were supportive but cautious regarding the use of PGD for medical purposes, particularly in relation to others whose experiences were similar. More broadly, the paper highlights the link between the participants' personal experiences and their beliefs regarding the appropriateness, for others, of individual decision-making on PGD, which has not been revealed by previous studies. PMID:25724710

  4. 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

  5. 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. PMID:16206459

  6. 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.

  7. Karyomapping allows preimplantation genetic diagnosis of a de-novo deletion undetectable using conventional PGD technology.

    PubMed

    Giménez, Carles; Sarasa, Jonás; Arjona, César; Vilamajó, Ester; Martínez-Pasarell, Olga; Wheeler, Kenny; Valls, Gemma; Garcia-Guixé, Elena; Wells, Dagan

    2015-12-01

    Preimplantation genetic diagnosis (PGD) was carried out for a couple carrying a de-novo deletion in the TSC2 gene, responsible for tuberous sclerosis. Karyomapping, a method employing genome-wide analysis of single nucleotide polymorphisms (SNP), was used as PGD protocol. Analysis of DNA from the affected parent using karyomapping confirmed the region covered by the deletion and revealed more than 30 SNP located within the affected region. These SNP were subsequently used for embryo diagnosis (deletion revealed by hemizygosity and/or reduced probe intensity). Seven blastocyst embryos underwent trophectoderm biopsy followed by vitrification. Biopsied cells were subjected to comprehensive aneuploidy screening using microarray comparative genomic hybridization (aCGH), with karyomapping for the detection of embryos carrying the mutant TSC2 gene carried out in tandem. Two embryo transfers were performed, the second of which resulted in the birth of a child. This study highlights that karyomapping may be applicable to a subset of de-novo mutations undetectable using standard PGD strategies. Additionally, karyomapping results were in complete concordance with aCGH, both methods revealing the same aneuploidies in the embryos tested. It was concluded that karyomapping may represent a valuable advance in cases of PGD for monogenic diseases. PMID:26507283

  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. PMID:17639853

  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. Reproductive Endocrinologists' Utilization of Genetic Counselors for Oncofertility and Preimplantation Genetic Diagnosis (PGD) Treatment of BRCA1/2 Mutation Carriers.

    PubMed

    Goetsch, Allison L; Wicklund, Catherine; Clayman, Marla L; Woodruff, Teresa K

    2016-06-01

    Genetic counselors believe fertility preservation and preimplantation genetic diagnosis (PGD) discussions to be a part of their role when counseling BRCA1/2 mutation-positive patients. This study is the first to explore reproductive endocrinologists' (REI) practices and attitudes regarding involvement of genetic counselors in the care of BRCA1/2 mutation carriers seeking fertility preservation and PGD. A survey was mailed to 1000 REIs from Reproductive Endocrinology & Infertility (SREI), an American Society for Reproductive Medicine (ASRM) affiliate group. A 14.5 % response rate was achieved; data was analyzed using SPSS software. The majority of participating REIs were found to recommend genetic counseling to cancer patients considering fertility preservation (82 %) and consult with a genetic counselor regarding PGD for hereditary cancer syndromes (92 %). Additionally, REIs consult genetic counselors regarding PGD patient counseling (88 %), genetic testing (78 %), and general genetics questions (66 %). Two areas genetic counselors may further aid REIs are: elicitation of family history, which is useful to determine fertility preservation and PGD intervention timing (32 % of REIs utilize a cancer family history to determine intervention timing); and, interpretation of variants of uncertain significance (VOUS) as cancer panel genetic testing becomes more common (36 % of REIs are unfamiliar with VOUS). Given our findings, the Oncofertility Consortium® created an online resource for genetic counselors focused on fertility preservation education and communication strategies. PMID:26567039

  11. 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. PMID:25803702

  12. Developmental neuropsychological assessment of 4- to 5-year-old children born following Preimplantation Genetic Diagnosis (PGD): A pilot study.

    PubMed

    Sacks, Gilat Chaya; Altarescu, Gheona; Guedalia, Judith; Varshaver, Irit; Gilboa, Tal; Levy-Lahad, Ephrat; Eldar-Geva, Talia

    2016-01-01

    The purpose of this pilot study was to evaluate developmental neuropsychological profiles of 4- to 5-year-old children born after Preimplantation Genetic Diagnosis (PGD). Twenty-seven participants received a neurological examination and a battery of neuropsychological assessments including Wechsler Preschool & Primary Scale of Intelligence - Third Edition (WPPSI-III; cognitive development), Preschool Language Scale, Fourth Edition (PLS-4; language development), Wide Range Assessment of Visual Motor Abilities (visual motor abilities), Childhood Autism Rating Scales II (a screening test for autistic spectrum disorders), and the Miles ABC Test (ocular dominance). Parental questionnaires included the Behavior Rating Inventory of Executive Function Preschool Version (BRIEF-P; executive function), Child Behavior Checklist (CBCL) and the Carey Temperament Scales Behavioral Style Questionnaire (socioemotional development and temperament), and the Vineland Adaptive Behavior Scales, Interview Edition, Second Edition (general adaptive behavior). Subjects' tests results were compared to each test's norms. Children born after PGD demonstrated scores within the normal or above-normal ranges for all developmental outcomes (mean ± SD): WPPSI-III-VIQ 107.4 ± 14.4 (p = .013), PLS-4-Total 113.2 ± 12.4, p < .001), CBCL-Total 41.1 ± 8.6 (p < .001), BRIEF-P-Global Executive Composite 44.8 ± 9.5 (p = .009). Twelve (44%) of the PGD children had a significant difference between their VIQ and PIQ scores (compared to 27% in the general population). One subject was found to show possible signs of autistic spectrum disorder, although a family history of autism was noted. In conclusion, in this pilot study, children assessed at age 4-5 years and conceived after PGD displayed developmental neuropsychological outcomes within normal limits as compared to their chronologic peers. A larger study is needed to evaluate and follow the neuropsychological development of children born after PGD. PMID:25774437

  13. Addressing the idiosyncratic needs of Orthodox Jewish couples requesting sex selection by preimplantation genetic diagnosis (PGD).

    PubMed

    Grazi, Richard V; Wolowelsky, Joel B

    2006-01-01

    We report here on ethical considerations addressing the idiosyncratic needs of two Orthodox Jewish couples requesting sex selection through PGD. The patients' considerations stem from generally healthy concerns, are not based on any gender biases and have little chance of having any major societal impact, given the idiosyncratic nature of the situation. Halakhah, the legal and ethical system of rabbinic Orthodox Judaism, generally opposes sex selection through PGD for nonmedical reasons, but would approve the procedure in these cases. Meeting these needs within the context of the doctor-patient relationship necessitates reconsidering to some extent the ASRM Ethics Committee guidelines. PMID:17136601

  14. Taskforce 5: preimplantation genetic diagnosis.

    PubMed

    Shenfield, F; Pennings, G; Devroey, P; Sureau, C; Tarlatzis, B; Cohen, J

    2003-03-01

    The European Society of Human Reproduction and Embryology (ESHRE) Ethics Task Force sets out a recommended multidisciplinary approach to the application of preimplantation genetic diagnosis (PGD). The statement includes consideration of fundamental ethical principles, specific problems in cases of high genetic risk, and PGD for aneuploidy screening, HLA typing and sex selection for non-medical reasons. PMID:12615840

  15. Reprogenetics: Preimplantational genetics diagnosis

    PubMed Central

    Coco, Roberto

    2014-01-01

    Preimplantational Genetics Diagnosis (PGD) is requested by geneticists and reproductive specialists. Usually geneticists ask for PGD because one or both members of the couple have an increased genetic risk for having an affected offspring. On the other hand, reproductive specialists ask for embryo aneuploidy screening (PGS) to assures an euploid embryo transfer, with the purpose to achieve an ongoing pregnancy, although the couple have normal karyotypes. As embryonic aneuploidies are responsible for pre and post implantation abortions, it is logical to considerer that the screening of the embryonic aneuploidies prior to embryo transfer could improve the efficiency of the in vitro fertilization procedures. Nevertheless, it is still premature to affirm this until well-designed clinical trials were done, especially in women of advanced age where the rate of embryos with aneuploidies is much greater. Although the indications of PGD are similar to conventional prenatal diagnosis (PND), PGD has less ethical objections than the PND. As with the PGD/PGS results only unaffected embryos are transferred, both methods can avoid the decision to interrupt the pregnancy due to a genetic problem; this makes an important difference when compared to conventional prenatal diagnosis. PMID:24764761

  16. Preimplantation genetic diagnosis.

    PubMed

    Ouhibi, N; Olson, S; Patton, P; Wolf, D

    2001-10-01

    Preimplantation genetic diagnosis (PGD) has now been used in human fertility centers for a decade. To this end, diagnostic analysis is conducted on polar bodies or single blastomeres from biopsied embryos before the embryos are transferred, allowing the selection of normal embryos before a pregnancy has been established. Advances in technology available for PGD are described, including fluorescent in situ hybridization (FISH), interphase chromosome conversion, comparative genomic hybridization (CGH), fluorescent polymerase chain reaction (PCR), multiplex PCR, and whole genome amplification. These techniques support the diagnosis of a number of diseases at the single-cell level. PMID:12112960

  17. Preimplantation genetic diagnosis in cattle: a review.

    PubMed

    Bodó, S; Baranyai, B; Gócza, E; Dohy, J; Markkula, M

    2001-01-01

    Preimplantation Genetic Diagnosis (PGD) is reviewed and novel fields where it may be applied are investigated. Technical advances of PGD in cattle embryos have already enabled its integration as a part of the MOET (Multiple Ovulation Embryo Transfer) breeding system. PGD for well-defined selection targets can enhance cattle breeding and embryo trade. It allows embryo selection according to their sex, and it may be used to breed special cow lines, or top bulls, by selecting embryos for valuable production traits using Marker Assisted Selection (MAS). A good allelic profile and/or the insertion of a transgene can be detected by PGD. This review article presents the technical requirements for PGD, and shows that this biotechnological method has great economic potential. PMID:11402695

  18. 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

  19. Social welfare, genetic welfare? Boundary-work in the IVF/PGD clinic.

    PubMed

    Ehrich, Kathryn; Williams, Clare; Scott, Rosamund; Sandall, Jane; Farsides, Bobbie

    2006-09-01

    Through the lens of the 'welfare of the child' assessment, this paper explores how staff working in the area of in vitro fertilisation and preimplantation genetic diagnosis (IVF/PGD) balance reflexive relations of legitimacy and accountability between the public and private spheres, and between medicine, the citizen and the state. The wider research of which this analysis is a part uses multiple methods to study two National Health Service Assisted Conception Units in England. Research methods used included observation clinics and interviews with staff from a range of disciplines. We illustrate how the staff reveal tensions between their views that the welfare of the child assessment can be seen as intrusive and discriminatory, and on the other hand that medical intervention in reproduction should be socially and professionally accountable. These tensions can be understood sociologically in terms of a gradual movement from socially based solutions to fertility problems and disabilities, towards a biomedical, and arguably genetically oriented worldview of such problems. Rather than being viewed as discrete, these two orientations should be seen as indicating an emergent direction of travel along a continuum, with elements of both being present in the accounts. We argue that consideration of the welfare of the child involves staff in ethical boundary-work across the two orientations and between the accountabilities and responsibilities of healthcare professionals, individuals and the state. PMID:16675085

  20. PGD for germline mosaicism.

    PubMed

    Altarescu, Gheona; Beeri, Rachel; Eldar-Geva, Talia; Varshaver, Irit; Margalioth, Ehud J; Levy-Lahad, Ephrat; Renbaum, Paul

    2012-10-01

    The aim of this study was to develop and perform a preimplantation genetic diagnosis (PGD) assay discriminating between wild-type and mutant alleles in two families with germline mosaicism. Family 1 had two children affected with severe myoclonic epilepsy (SCNA1A del exons 1-22). Family 2 had two children with tuberous sclerosis (TSC2 C1327T) and two healthy children. Neither mutation was detected in genomic DNA derived from the parents in either family. Informative microsatellite markers flanking SCNA1A and TSC2 along with the identified mutations were used to construct haplotypes. For tuberous sclerosis, single spermatozoa were analysed using a multiplex assay that included six informative markers and the TSC2 mutation. In family 1, deletion in the maternal allele was detected in the affected child. In family 2, both affected children and one healthy child shared the same paternal allele. To confirm mutant paternal transmission, single spermatozoa were analysed for the mutation along with six markers. Of 44 single spermatozoa, four showed the mutant T allele, allowing linkage between the mutation and the genetic markers. Both families delivered healthy children following IVF/PGD. In conclusion, germline mosaicism complicates allele assignment when constructing haplotypes for PGD. Sperm analysis is a useful tool for verifying allelic linkage. PMID:22884613

  1. Social sex selection by preimplantation genetic diagnosis.

    PubMed

    Pembrey, Marcus

    2002-01-01

    A personal view is presented, exploring the issue of social sex selection by preimplantation genetic diagnosis from the dual perspectives of protecting the autonomy of the couple and the professional duty of care. It is concluded that sex selection by PGD is acceptable in certain circumstances. PMID:12470579

  2. Reproductive management through integration of PGD and MPS-based noninvasive prenatal screening/diagnosis for a family with GJB2-associated hearing impairment.

    PubMed

    Xiong, WenPing; Wang, DaYong; Gao, Yuan; Gao, Ya; Wang, HongYang; Guan, Jing; Lan, Lan; Yan, JunHao; Zong, Liang; Yuan, Yuan; Dong, Wei; Huang, SeXin; Wu, KeLiang; Wang, YaoShen; Wang, ZhiLi; Peng, HongMei; Lu, YanPing; Xie, LinYi; Zhao, Cui; Wang, Li; Zhang, QiuJing; Gao, Yun; Li, Na; Yang, Ju; Yin, ZiFang; Han, Bing; Wang, Wei; Chen, Zi-Jiang; Wang, QiuJu

    2015-09-01

    A couple with a proband child of GJB2 (encoding the gap junction protein connexin 26)-associated hearing impairment and a previous pregnancy miscarriage sought for a reproductive solution to bear a healthy child. Our study aimed to develop a customized preconception-to-neonate care trajectory to fulfill this clinical demand by integrating preimplantation genetic diagnosis (PGD), noninvasive prenatal testing (NIPT), and noninvasive prenatal diagnosis (NIPD) into the strategy. Auditory and genetic diagnosis of the proband child was carried out to identify the disease causative mutations. The couple then received in-vitro-fertilization treatment, and eight embryos were obtained for day 5 biopsy. PGD was performed by short-tandem-repeat linkage analysis and Sanger sequencing of GJB2 gene. Transfer of a GJB2c.235delC heterozygous embryo resulted in a singleton pregnancy. At the 13th week of gestation, genomic DNA (gDNA) from the trio family and cell-free DNA (cfDNA) from maternal plasma were obtained for assessment of fetal chromosomal aneuploidy and GJB2 mutations. NIPT and NIPD showed the absence of chromosomal aneuploidy and GJB2-associated disease in the fetus, which was later confirmed by invasive procedures and postnatal genetic/auditory diagnosis. This strategy successfully prevented the transmission of hearing impairment in the newborn, thus providing a valuable experience in reproductive management of similar cases and potentially other monogenic disorders. PMID:26432548

  3. Preimplantation genetic diagnosis and reproductive autonomy.

    PubMed

    Krahn, T; Wong, S I

    2009-01-01

    This paper examines how reproductive autonomy of women and couples is affected by the availability of preimplantation genetic diagnosis (PGD). Libertarians have argued that PGD enhances reproductive autonomy by increasing options available to prospective parents. We acknowledge that PGD presents prospective parents with more options, but note that the libertarian view of reproductive autonomy overlooks important aspects of the social practice of PGD by focusing too narrowly on the absence of explicit constraints as the main guarantee of reproductive autonomy. We endorse instead a feminist relational account of autonomy in which exercising autonomy involves paying attention to the relevant contextual features that configure and shape prospective parents' choices and understanding of their reproductive options. On this view, PGD has a negative potential to constrain reproductive autonomy. We recommend that this negative potential be addressed by making sure the availability of PGD is accompanied by increased attention to the relevant educational needs of prospective parents and the general public, as well as the availability of adequate social supports for people with disabilities, their care providers and families. PMID:19891846

  4. [Extending preimplantation genetic diagnosis to HLA typing: the Paris experience].

    PubMed

    Steffann, J; Frydman, N; Burlet, P; Gigarel, N; Feyereisen, E; Kerbrat, V; Tachdjian, G; Munnich, A; Frydman, R

    2005-10-01

    Preimplantation genetic diagnosis (PGD) consists in the genetic analysis of one or two cells. These cells (blastomeres) are sampled from embryos, obtained by in vitro fertilization, at the third day of development. Since 1998, the bioethical laws (1994) and their decrees restricted PGD practices in France, strictly to the avoidance of the birth of a child affected with a genetic defect. In parallel, works on blood cord transplantation, taken at the birth of a compatible HLA sibling, showed very encouraging results, particularly for the treatment of Fanconi anemia. In 2001, Verlinsky et al., have reported the first PGD for Fanconi anaemia combined with HLA typing, allowing the birth of a healthy child, HLA-identical with his affected sister. The "designer baby" concept was born. The French law, which allowed PGD under specific conditions, i.e. when the genetic defect has been characterized in one parent at least, recently extended PGD to HLA typing when embryos are at risk of a genetic disorder. Article L.2131-4-1 (August 2004) allows the practice of HLA typing for PGD embryos when an elder sibling is affected with a genetic disorder and need stem cell transplantation. The HLA-matched offspring resulting from PGD can give cord blood at birth to supply the necessary therapy. This double selection give rise to serious ethical problems, but technical difficulties and legal restrictions will probably limit the development of such a procedure. PMID:16139553

  5. [The latest development in preimplantation genetic diagnosis].

    PubMed

    Xu, Yan-wen; Zhuang, Guang-lun

    2004-12-01

    Preimplantation genetic diagnosis is the integration of both assisted reproductive technologies and molecular genetic technologies. Since the birth of the first healthy females after PGD in 1990, remarkable advances have been achieved in this field. Most research in PGD is focused on new methods to improve the sensitivity and accuracy of single cell analysis. The principal problems in single cell PCR include amplification failure, ADO and contamination. Fluorescent PCR with multiplex amplifications of highly polymorphic markers is a highly effective strategy to avoid contamination and detect ADO. The advantages and disadvantages of fluorescence in situ hybridization to detect age-related aneuploidy are still under debate. We summarize the most recent developments in this review, and also introduce our own experiences in PGD. PMID:15605105

  6. Views of internists towards uses of PGD.

    PubMed

    Klitzman, Robert; Chung, Wendy; Marder, Karen; Shanmugham, Anita; Chin, Lisa J; Stark, Meredith; Leu, Cheng-Shiun; Appelbaum, Paul S

    2013-02-01

    Preimplantation genetic diagnosis (PGD) is increasingly available, but how physicians view it is unclear. Internists are gatekeepers and sources of information, often treating disorders for which PGD is possible. This quantitative study surveyed 220 US internists, who were found to be divided. Many would recommend PGD for cystic fibrosis (CF; 33.7%), breast cancer (BRCA; 23.4%), familial adenomatous polyposis (FAP; 20.6%) and familial hypertrophic cardiomyopathy (19.9%), but few for social sex selection (5.2%); however, in each case, >50% were unsure. Of those surveyed, 4.9% have suggested PGD to patients. Only 7.1% felt qualified to answer patient questions about it. Internists who would refer for PGD had completed medical training less recently and, for CF, were more likely to have privately insured patients (P<0.033) and patients who reported genetic discrimination (P<0.013). Physicians more likely to refer for BRCA and FAP were less likely to have patients ask about genetic testing. This study suggests that internists often feel they have insufficient knowledge about it and may refer for PGD based on limited understanding. They view possible uses of PGD differently, partly reflecting varying ages of onset and disease treatability. These data have critical implications for training, research and practice. Preimplantation genetic diagnosis (PGD) allows embryos to be screened prior to transfer to a woman's womb for various genetic markers. This procedure raises complex medical, social, psychological and ethical issues, but how physicians view it is unclear. Internists are gatekeepers and sources of information, often treating disorders for which PGD use is possible. We surveyed 220 US internists, who were found to be divided: many would recommend PGD for cystic fibrosis (CF; 33.7%), breast cancer (BRCA; 23.4%), familial adenomatous polyposis (FAP; 20.6%), and familial hypertrophic cardiomyopathy (FHC; 19.9%) and a few for sex selection (5.2%); but in each case, >50% were unsure. Of those surveyed, 4.9% have suggested PGD to patients. Only 7.1% felt qualified to answer patient questions. Internists who would refer for PGD completed medical training less recently and, for CF, were more likely to have privately insured patients and patients who reported genetic discrimination. Physicians more likely to refer for BRCA and FAP were less likely to have patients ask about genetic testing. This quantitative study suggests that internists often feel they have insufficient knowledge and may refer for PGD based on limited understanding. They view possible uses of PGD differently, partly reflecting varying ages of onset and disease treatability. Internists should be made aware of the potential benefit of PGD, but also be taught to refer patients, when appropriate, to clinical geneticists who could then refer the patient to an IVF/PGD team. These data thus have critical implications for training, research and practice. PMID:23276655

  7. Ethics and the future of preimplantation genetic diagnosis.

    PubMed

    Robertson, John A

    2005-03-01

    The future growth of preimplantation genetic diagnosis (PGD) will depend on refinements in genetic knowledge and genetic analysis of blastomeres. Equally important, however, is an acceptance of the ethical legitimacy of parents using technologies to select genetic traits of offspring. Objections based on embryo status, the giftedness of reproduction, eugenics, and protecting the child's welfare are not convincing grounds to oppose most uses of PGD. Whether PGD should be accepted for new medical or non-medical uses should depend upon a careful assessment of the proposed use's importance to the person or couple requesting it, and the harmful effects, if any, which it might cause. Such an approach leads to the conclusion that most new medical uses of PGD and some non-medical uses should be permitted. PMID:15820017

  8. Vitrified/warmed single blastocyst transfer in preimplantation genetic diagnosis/preimplantation genetic screening cycles

    PubMed Central

    Huang, Jin; Li, Rong; Lian, Ying; Chen, Lixue; Shi, Xiaodan; Qiao, Jie; Liu, Ping

    2015-01-01

    Objective: To investigate the single blastocyst transfer in preimplantation genetic diagnosis (PGD)/preimplantation genetic screening (PGS) cycles. Methods: 80 PGD/PGS cycles undergoing blastocyst biopsy were studied. There were 88 warming cycles during the study period. Only one warmed blastocyst was transferred per cycle. The outcomes were followed up to the infants were born. Results: The embryo implantation rate was 54.55% (48/88). The clinical pregnancy rate was 54.55% (48/88) per transfer cycle and 60% (48/80) per initial PGD/PGS cycle. There was no multi-pregnant in this study. The live birth rate was 42.05% (37/88) per transfer cycle and 46.25% (37/80) per initial PGD/PGS cycle. Conclusion: In PGD/PGS cycles, single blastocyst transfer reduces the multiple pregnancy rate without affecting the clinical outcomes. PMID:26885112

  9. 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

  10. 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. PMID:24072553

  11. 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

  12. Extending preimplantation genetic diagnosis: medical and non-medical uses.

    PubMed

    Robertson, J A

    2003-08-01

    New uses of preimplantation genetic diagnosis (PGD) to screen embryos prior to transfer raise ethical, legal, and policy issues that deserve close attention. Extensions for medical purposes, such as to identify susceptibility genes, late onset disease, and human leukocyte antigen (HLA) matching, are usually ethically acceptable. Whether embryo screening for gender, perfect pitch, or other non-medical characteristics are also acceptable depends upon the parental needs served and the harm posed to embryos, children, and society. Speculations about potential future uses of PGD should not prevent otherwise acceptable current uses of PGD. PMID:12930852

  13. Preimplantation genetic diagnosis of haemophilia.

    PubMed

    Lavery, Stuart

    2009-02-01

    Preimplantation genetic diagnosis (PGD) aims to increase the number of options available to couples who could have a child affected with haemophilia and reduce the anxiety these couples often associate with reproduction. The female partner must undergo an in vitro fertilization cycle, and the eggs or embryos are then biopsied. Embryos which are unaffected by haemophilia can then be transferred to the uterus. The clear advantage of this technique is that the woman knows from the very beginning that the pregnancy is unaffected by haemophilia, and she can avoid conventional invasive prenatal diagnosis and the difficult decision on whether or not to terminate an affected pregnancy. Several strategies for this single cell genetic diagnosis have been described. These include embryonic sexing using polymerase chain reaction, embryonic sexing using fluorescent in situ hybridization, specific diagnosis using restriction enzymes, sequencing and haplotype analysis. Over the years, PGD has attracted much ethical commentary, both supportive and critical, regarding the fundamental principles of embryo selection and destruction. New scientific advances and their potential applications are considered. PMID:19036080

  14. Whole genome amplification in preimplantation genetic diagnosis*

    PubMed Central

    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. PMID:21194180

  15. 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

  16. Preimplantation genetic diagnosis guided by single-cell genomics.

    PubMed

    Van der Aa, Niels; Zamani Esteki, Masoud; Vermeesch, Joris R; Voet, Thierry

    2013-01-01

    Preimplantation genetic diagnosis (PGD) aims to help couples with heritable genetic disorders to avoid the birth of diseased offspring or the recurrence of loss of conception. Following in vitro fertilization, one or a few cells are biopsied from each human preimplantation embryo for genetic testing, allowing diagnosis and selection of healthy embryos for uterine transfer. Although classical methods, including single-cell PCR and fluorescent in situ hybridization, enable PGD for many genetic disorders, they have limitations. They often require family-specific designs and can be labor intensive, resulting in long waiting lists. Furthermore, certain types of genetic anomalies are not easy to diagnose using these classical approaches, and healthy offspring carrying the parental mutant allele(s) can result. Recently, state-of-the-art methods for single-cell genomics have flourished, which may overcome the limitations associated with classical PGD, and these underpin the development of generic assays for PGD that enable selection of embryos not only for the familial genetic disorder in question, but also for various other genetic aberrations and traits at once. Here, we discuss the latest single-cell genomics methodologies based on DNA microarrays, single-nucleotide polymorphism arrays or next-generation sequence analysis. We focus on their strengths, their validation status, their weaknesses and the challenges for implementing them in PGD. PMID:23998893

  17. Preimplantation genetic diagnosis in Saudi Arabia.

    PubMed

    Abotalib, Zeinab

    2013-01-01

    Preimplantation genetic diagnosis (PGD) testing is the practice of obtaining a cellular biopsy sample from a developing human oocyte or embryo, acquired via a cycle of in vitro fertilization (IVF); evaluating the genetic composition of this sample; and using this information to determine which embryos will be optimal for subsequent uterine transfer. PGD has become an increasingly useful adjunct to IVF procedures. The ability to provide couples who are known carriers of genetic abnormalities the opportunity to deliver healthy babies has opened a new frontier in reproductive medicine. The purpose of the PGD is enables us to choose which embryos will be implanted into the mother. In the present study 137 families who had undergone IVF at Habib Medical Centre, were enrolled for the PGD analysis. The couple visited the clinic for the sex selection, recurrent fetal loss and with the recurrent IVF failure. 802 embryos were tested by the biopsy method and 512 are found to be normal and 290 were abnormal embryos. In this study only 24% of the embryos were transferred and the remaining was not transferred because of the abnormalities or undesired sex of the embryos. The structural and numerical abnormalities were found to be 16.8%. PMID:23750087

  18. Extending preimplantation genetic diagnosis: the ethical debate. Ethical issues in new uses of preimplantation genetic diagnosis.

    PubMed

    Robertson, John A

    2003-03-01

    The use of preimplantation genetic diagnosis (PGD) to screen embryos for aneuploidy and genetic disease is growing. New uses of PGD have been reported in the past year for screening embryos for susceptibility to cancer, for late-onset diseases, for HLA-matching for existing children, and for gender. These extensions have raised questions about their ethical acceptability and the adequacy of regulatory structures to review new uses. This article describes current and likely future uses of PGD, and then analyses the ethical issues posed by new uses of PGD to screen embryos for susceptibility and late-onset conditions, for HLA-matching for tissue donation to an existing child, and for gender selection. It also addresses ethical issues that would arise in more speculative scenarios of selecting embryos for hearing ability or sexual orientation. The article concludes that except for sex selection of the first child, most current extensions of PGD are ethically acceptable, and provides a framework for evaluating future extensions for nonmedical purposes that are still speculative. PMID:12615807

  19. 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

  20. Preimplantation Genetic Diagnosis in Marfan Syndrome

    PubMed Central

    Vlahos, N. F.; Triantafyllidou, O.; Vitoratos, N.; Grigoriadis, C.; Creatsas, G.

    2013-01-01

    Marfan syndrome (MFS) is a systemic hereditable disorder of the connective tissue with mainly cardiovascular manifestations, such as aortic dilatation and dissection. We describe a case of a 32-year-old Caucasian woman, clinically asymptomatic with MFS who presented for genetic consultation to prevent the transmission of disease to her offspring. She underwent controlled ovarian stimulation (COH), in vitro fertilization (IVF) combined with preimplantation genetic diagnosis (PGD), and a singleton pregnancy with positive fetal heart rate was revealed. At 34 weeks' gestation she delivered vaginally a healthy premature male infant weighting 2440 gr. The patient remained asymptomatic during pregnancy, delivery, and 3 months postpartum. It is has to be mentioned that the availability of PGD is essential to prevent the transmission of disease to the next generation. PMID:23781359

  1. 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

  2. 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

  3. FISH for Pre-implantation Genetic Diagnosis

    PubMed Central

    Scriven, Paul N.; Kirby, Toby L.; Ogilvie, Caroline Mackie

    2011-01-01

    Pre-implantation genetic diagnosis (PGD) is an established alternative to pre-natal diagnosis, and involves selecting pre-implantation embryos from a cohort generated by assisted reproduction technology (ART). This selection may be required because of familial monogenic disease (e.g. cystic fibrosis), or because one partner carries a chromosome rearrangement (e.g. a two-way reciprocal translocation). PGD is available for couples who have had previous affected children, and/or in the case of chromosome rearrangements, recurrent miscarriages, or infertility. Oocytes aspirated following ovarian stimulation are fertilized by in vitro immersion in semen (IVF) or by intracytoplasmic injection of an individual spermatozoon (ICSI). Pre-implantation cleavage-stage embryos are biopsied, usually by the removal of a single cell on day 3 post-fertilization, and the biopsied cell is tested to establish the genetic status of the embryo. Fluorescence in situ hybridization (FISH) on the fixed nuclei of biopsied cells with target-specific DNA probes is the technique of choice to detect chromosome imbalance associated with chromosome rearrangements, and to select female embryos in families with X-linked disease for which there is no mutation-specific test. FISH has also been used to screen embryos for spontaneous chromosome aneuploidy (also known as PGS or PGD-AS) in order to try and improve the efficiency of assisted reproduction; however, the predictive value of this test using the spreading and FISH technique described here is likely to be unacceptably low in most people's hands and it is not recommended for routine clinical use. We describe the selection of suitable probes for single-cell FISH, spreading techniques for blastomere nuclei, and in situ hybridization and signal scoring, applied to PGD in a clinical setting. PMID:21403624

  4. FISH for pre-implantation genetic diagnosis.

    PubMed

    Scriven, Paul N; Ogilvie, Caroline Mackie

    2010-01-01

    Pre-implantation genetic diagnosis (PGD) is an established alternative to pre-natal diagnosis, and involves selecting pre-implantation embryos from a cohort generated by assisted reproduction technology (ART). This selection may be required because of familial monogenic disease (e.g. cystic fibrosis), or because one partner carries a chromosome rearrangement (e.g. a two-way reciprocal translocation). PGD is available for couples who have had previous affected children, and/or in the case of chromosome rearrangements, recurrent miscarriages, or infertility. Oocytes aspirated following ovarian stimulation are fertilized by in vitro immersion in semen (IVF) or by intracytoplasmic injection of individual spermatocytes (ICSI). Pre-implantation cleavage-stage embryos are biopsied, usually by the removal of a single cell on day 3 post-fertilization, and the biopsied cell is tested to establish the genetic status of the embryo.Fluorescence in situ hybridization (FISH) on the fixed nuclei of biopsied cells with target-specific DNA probes is the technique of choice to detect chromosome imbalance associated with chromosome rearrangements, and to select female embryos in families with X-linked disease for which there is no mutation-specific test. FISH has also been used to screen embryos for sporadic chromosome aneuploidy (also known as PGS or PGD-AS) in order to try and improve the efficiency of assisted reproduction; however, due to the unacceptably low predictive accuracy of this test using FISH, it is not recommended for routine clinical use.This chapter describes the selection of suitable probes for single-cell FISH, assessment of the analytical performance of the test, spreading techniques for blastomere nuclei, and in situ hybridization and signal scoring, applied to PGD in a clinical setting. PMID:20809319

  5. Preimplantation genetic diagnosis: an overview of socio-ethical and legal considerations.

    PubMed

    Knoppers, Bartha M; Bordet, Sylvie; Isasi, Rosario M

    2006-01-01

    Preimplantation genetic diagnosis (PGD) permits the selection of embryos of a particular genotype prior to implantation. As a reproductive technology involving embryo selection, PGD has become associated with considerable controversy. This review examines some of the ethical, legal, and social issues raised by PGD. Relevant ethical considerations include the status of the embryo and the interests and duties of the parents. On a social policy level, considerations of access as well as the impact of this technology on families, women, and physician's duties also warrant consideration. An analysis of these issues in the context of using PGD for selecting embryos unaffected by a serious disorder and for sex selection is presented. We also present a brief survey of PGD-related regulatory schemes in several countries, including the United Kingdom and the United States. PMID:16724879

  6. Choosing between possible lives: legal and ethical issues in preimplantation genetic diagnosis.

    PubMed

    Scott, Rosamund

    2006-01-01

    This article critically appraises the current legal scope of the principal applications of preimplantation genetic diagnosis (PGD). This relatively new technique, which is available to some parents undergoing in vitro fertilization (IVF) treatment, aims to ensure that a child is not born with a seemingly undesirable genetic condition. The question addressed here is whether there should be serious reasons to test for genetic conditions in embryos in order to be able to select between them. The Human Fertilisation and Embryology Authority and the Human Genetics Commission have decided that there should be such reasons by broadly aligning the criteria for PGD with those for selective abortion. This stance is critically explored, as are its implications for the possible use of PGD to select either against or for marginal features or for significant traits. The government is currently reviewing the legal scope and regulation of PGD. PMID:17340769

  7. [Embryonal genetic diagnosis and reproductive freedom in assisted procreation].

    PubMed

    Abellán, Fernando

    2006-01-01

    This article analyses the repercussions that the Preimplantational Genetic Diagnosis (PGD) has in the bioethical as well as legal fields in relation with the so-called "reproductive freedom" of the couple. Besides analysing the legal situation of this technique in Spain as well as other surrounding States, the article studies the problems associated with some scenarios of PGD, such as the use in the selection of sex, for therapeutic purposes for third parties, in relation with diseases of a possible late onset, multifactorial or of a variable phenotype expression and for the selection of embryos affected by a disease or disability. All are based on real clinical cases. PMID:17393795

  8. Clinical guidelines for IVF with PGD for HLA matching.

    PubMed

    Tur-Kaspa, Ilan; Jeelani, Roohi

    2015-02-01

    Preimplantation genetic diagnosis (PGD) for human leukocyte antigen (HLA) typing is an established procedure for conceiving a child who may donate cord blood or haematopoietic stem cells for transplantation to save an ill sibling. Haematopoietic stem cell transplantation (HSCT) from related matched donors improves overall survival compared with unrelated or non-matched donors. Since HSCT from related matched-donors is unavailable for 70% of patients, IVF for PGD-HLA is a relevant clinical option. Recent success of HSCT after PGD-HLA, and excellent health and family support of the children born, suggests that debate over this kind of 'designer baby' and 'gift of life' should subside. Discussions about IVF for PGD-HLA should be held with families when a related matched-donor is unavailable, when HSCT can wait at least 9-12 months, within weeks of diagnosis irrespective of prognosis, and when the mother is of reproductive age. Related half-matched egg donors may also be considered. National and international collaborations should be established, and couples choosing this modality should be referred to experienced IVF and PGD centres. Clinical guidelines will improve physician and patient awareness of IVF for PGD-HLA and its role in advancing the clinical care of children in need of HSCT. PMID:25500181

  9. Quality control standards in PGD and PGS.

    PubMed

    SenGupta, S B; Dhanjal, S; Harper, J C

    2016-03-01

    Preimplantation genetic diagnosis (PGD) aims to test the embryo for specific conditions before implantation in couples at risk of transmitting genetic abnormality to their offspring. The couple must undergo IVF procedures to generate embryos in vitro. The embryos can be biopsied at either the zygote, cleavage or blastocyst stage. Preimplantation genetic screening uses the same technology to screen for chromosome abnormalities in embryos from patients undergoing IVF procedures as a method of embryo selection. Fluorescence in-situ hybridization was originally used for chromosome analysis, but has now been replaced by array comparative genomic hybridization or next generation sequencing. For the diagnosis of single gene defects, polymerase chain reaction is used and has become highly developed; however, single nucleotide polymorphism arrays for karyomapping have recently been introduced. A partnership between IVF laboratories and diagnostic centres is required to carry out PGD and preimplantation genetic screening. Accreditation of PGD diagnostic laboratories is important. Accreditation gives IVF centres an assurance that the diagnostic tests conform to specified standards. ISO 15189 is an international laboratory standard specific for medical laboratories. A requirement for accreditation is to participate in external quality assessment schemes. PMID:26776824

  10. Preimplantation genetic diagnosis for monogenic diseases: overview and emerging issues.

    PubMed

    Renwick, Pamela; Ogilvie, Caroline Mackie

    2007-01-01

    Preimplantation genetic diagnosis (PGD) is an established reproductive option for couples at risk of conceiving a pregnancy affected with a known genetic disease, who wish to avoid an (additional) affected child, termination of pregnancy or recurrent miscarriages. Early technologies concentrated on different approaches to direct mutation testing for monogenic diseases using single cell PCR protocols, or sex selection by fluorescent in situ hybridization for X-linked monogenic disease. Development of multiplex fluorescent PCR allowed simultaneously testing of linked markers alongside the mutation test, increasing the accuracy by controlling for contamination and identifying allele drop-out. The advent of highly effective whole genome amplification methods has opened the way for new technologies such as preimplantation genetic haplotyping and microarrays, thus increasing the number of genetic defects that can be detected in preimplantation embryos; the number of cases carried out and the new indications tested increases each year. Different countries have taken very different approaches to legislating and regulating PGD, giving rise to the phenomenon of reproductive tourism. PGD is now being performed for scenarios previously not undertaken using prenatal diagnosis, some of which raise significant ethical concerns. While PGD has benefited many couples aiming to have healthy children, ethical concerns remain over inappropriate use of this technology. PMID:17187482

  11. Preimplantation genetic diagnosis, an alternative to conventional prenatal diagnosis of the hemoglobinopathies.

    PubMed

    Traeger-Synodinos, J

    2013-12-01

    Prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) both represent highly important reproductive choices for couples with a high risk of transmitting a severe disease, such as a severe hemoglobinopathy. Conventional PND for hemoglobinopathies based on molecular analysis of trophoblast or amniocyte DNA has been applied for around 30 years, but the major disadvantages with this approach include 'invasive' fetal sampling, and the potential involvement of pregnancy termination when affected. In comparison, the major advantage of PGD over conventional PND is that it supports the initiation of unaffected pregnancies, avoiding the need to terminate affected pregnancies. However, it is a multistep technically demanding procedure requiring the close collaboration of experts from several fields. PGD is also limited by the need to involve assisted reproduction, even in couples without fertility problems. Furthermore, even for fertile couples, pregnancy rates rarely surpass 30-35%. Both PND and PGD have advantages and drawbacks. Before embarking on either procedure, couples should be carefully counseled by experts so that they can select the option most appropriate for them. Finally, whatever their choice, it is paramount that both prenatal and PGD be applied with the highest standards of clinical, laboratory, and ethical practice. PMID:23551498

  12. The decision to cancel a preimplantation genetic diagnosis cycle.

    PubMed

    Santaló, J; Grossmann, M; Giménez, C; Marina, F; Egozcue, J; Marina, S; Vidal, F

    2000-07-01

    It has been suggested that a minimum number (six) of cumulus-oocyte complexes (COCs) should be retrieved for fertilization to offer enough chances to ensure a pregnancy after a preimplantation genetic diagnosis (PGD) procedure. Therefore a decision to cancel a PGD cycle should be adequately weighted to offer the patients the highest chances to obtain a pregnancy. We describe a case where, after retrieving only three COCs suitable for fertilization, a triplet pregnancy was obtained. This case suggests that, although low numbers of COCs can reduce the effectiveness of the PGD procedure, other factors are involved in its final result. Thus, the opportunity of routinely cancelling such cycles should be reconsidered. In addition, this is, to our knowledge, the first case where sex selection was carried out to prevent the birth of carriers of the abnormal gene, and not of affected offspring. PMID:10913955

  13. 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. PMID:24835332

  14. Preimplantation genetic diagnosis: development and regulation.

    PubMed

    Thomas, C

    2006-06-01

    Pre-implantation genetic diagnosis (PGD) is used to biopsy and analyse embryos created through in vitro fertilisation (IVF) to avoid implanting an embryo affected by a mutation or chromosomal abnormality associated with serious illness. It reduces the chance that the parents will be faced with a difficult decision of whether to terminate the pregnancy, if the disorder is detected during the course of gestation. PGD is widely accepted for this purpose although there have been suggestions that such procedures have the effect of de-valuing persons in the community with disabilities. PGD potentially has other more controversial purposes, including the selection of the sex of the baby for personal preferences such as balancing the family, rather than to avoid a sex-linked disorder. Recently PGD has become available to create a donor child who is Human Leukocyte Antigen (HLA) matched with a sibling in need of stem cell transplant. In most cases the intention is to utilise the cord blood. However, an HLA-matched child could potentially be required to be a donor of tissues and organs throughout life. This may arise should the initial cord blood donation fail for any one of several reasons, such as inadequate cord blood cell dose, graft failure after cord blood transplant, or the recipient child experiencing a recurrence of the original illness after transplant. However, such on-going demands could also arise if a HLA-matched child was fortuitously conceived by natural means. As such, the issue is not PGD, but rather whether to harvest bone marrow or a solid organ from a child. This raises the question of whether there should be limits and procedures to protect such children from exploitation until they achieve sufficient competence to be able to make mature and autonomous decisions about whether to donate, even if the consequence may in some cases be that it is too late to save the sibling. Additionally, the parents may not be able to make a dispassionate decision, when they have a conflict of interests between their children. As such, parents may not be the best proxy decision-makers in this area and the decision might be better made by an independent authority or court. This paper considers ethical and legal issues arising from PGD. It will compare the willingness of the HFEA in the United Kingdom to allow this process to be used even in cases where the condition suffered by the sibling is non-heritable, with the more restrictive guidelines in New Zealand and questions the constitutional basis on which ethics committees develop policy in the absence of a legislative framework. PMID:16929812

  15. Successful polar body-based preimplantation genetic diagnosis for achondroplasia.

    PubMed

    Altarescu, G; Renbaum, P; Brooks P, B; Margalioth, E J; Ben Chetrit, A; Munter, G; Levy-Lahad, E; Eldar-Geva, T

    2008-02-01

    Achondroplasia, the most common form of dwarfism, is a candidate for preimplantation genetic diagnosis (PGD) because a single mutation accounts for almost all cases. Multiplex fluorescent assay including the common G380R mutation in the FGFR3 gene and eight close polymorphic markers was developed. First and second polar bodies (PB) were used for PGD analysis. An affected woman was treated with routine long-protocol ovarian stimulation and puncture. In the first PGD cycle, out of four fertilized oocytes, PB analysis revealed two mutant oocytes, one with total amplification failure of the maternal allele and one with inconclusive results. In the second PGD cycle, 14 oocytes were retrieved following a higher FSH dose and by performing oocyte retrieval and by placing the patient in the anti-Trendelenburg position using abdominal pressure to allow all follicles to be drained. Following PB analysis, two embryos containing the wild-type FGFR3 allele were transferred. This led to an uncomplicated pregnancy and delivery by Caesarean section at week 38 of a healthy boy, carrying the FGFR3 wild-type maternal allele. In conclusion, oocyte retrieval, while difficult in patients with achondroplasia, can be successfully performed. PB analysis is a reliable and sensitive method for PGD for maternal achondroplasia. PMID:18284886

  16. Preimplantation genetic diagnosis: the ethics of intermediate cases.

    PubMed

    de Wert, Guido

    2005-12-01

    According to the current guiding principle regarding preimplantation genetic diagnosis (PGD), the technique should focus on the diagnosis of genetic defects which (may) affect the health of this particular potential child--the so-called 'medical model'. I argue in favour of a more permissive view, also allowing PGD of characteristics which may be relevant for the health of 'third parties'. Two cases are analysed: PGD/HLA typing in order to save a sib, and PGD/sex selection in order to prevent the birth of healthy female carriers of X-linked recessive disorders, who are at high risk of conceiving affected sons. While these cases are at odds with the medical model stricto sensu, they do have a link with health problems. In the first case, the health benefit hoped for is intrafamilial, in the second case the health benefit is transgenerational. These cases illustrate that the traditional dichotomy between the medical model on the one hand and the 'designer' or autonomy model on the other hand is simplistic--they represent an intermediate category. PMID:16123097

  17. 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. PMID:9308807

  18. Pregnancy after preimplantation genetic diagnosis for brachydactyly type B.

    PubMed

    Hellani, Ali; Abu-Amero, Khaled; Azouri, Joseph; Al-Sharif, Hadeel; Barblet, Hamish; El-Akoum, Siham

    2009-01-01

    Brachydactyly type B (BDB) is an autosomal dominant disease caused by mutations in the ROR2 gene. Truncating mutations lead to the severe form of the disease, which is characterized by terminal deficiency of fingers and toes. Preimplantation genetic diagnosis (PGD) was carried out in a family suffering from severe BDB. The family was screened for mutations in exons 8 and 9 and found to harbour a known nonsense mutation (c.2265C-->A) in exon 9 of the ROR2 gene, which resulted in a premature stop-codon at residue 755. Three out of 10 linked markers tested were informative for this family and single cell work-up showed amplification efficiency in over 98% of the cells. Allele drop-out (ADO) was found in 0, 4.08 and 6.1% for D9S1803, D9S1842 and D9S280 respectively. The family underwent PGD using multiple displacement amplification, fluorescent polymerase chain reaction (informative short tandem repeat) and sequencing of exon 9. Two cells were taken from the three embryos generated in the PGD cycle and the diagnosis of both cells separately showed one normal embryo free of BDB abnormal allele. This embryo was transferred back to the mother and resulted in a singleton pregnancy. Postnatal DNA testing of the newborn confirmed the PGD result. PMID:19146779

  19. Sex selection and preimplantation genetic diagnosis at The Farah Hospital.

    PubMed

    Kilani, Z; Haj Hassan, L

    2002-01-01

    The issue of sex selection by using preimplantation genetic diagnosis (PGD) for non-medical reasons has been the subject of heated debate. Although the ethical arguments regarding this subject are complex, we would like to extend and express some views based on practical experience, with a special focus on individual needs in developing countries, taking into consideration: social, cultural, religious, financial and scientific aspects. PMID:12470356

  20. [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

  1. Clinical and counselling implications of preimplantation genetic diagnosis for Huntington's disease in the UK.

    PubMed

    Lashwood, A; Flinter, F

    2001-01-01

    Huntington's disease is an autosomal dominant neurodegenerative disorder that usually occurs in adult life. Individuals at risk can have a gene test before the onset of symptoms, and prenatal diagnosis is available. Preimplantation genetic diagnosis (PGD) for Huntington's disease is now available for couples in whom one partner has the gene for Huntington's disease. A licence to practise PGD is required from the Human Fertilisation and Embryology Authority, and there are several complex issues relating to PGD for Huntington's disease that require consideration. The partner of the Huntington's disease gene carrier should have a presymptomatic test to ensure accuracy in a PGD cycle. There should be a delay between blood sampling and testing for Huntington's disease to allow time for reflection and withdrawal from testing. All PGD treatment has an associated risk of misdiagnosis. If confirmatory prenatal testing is not undertaken after a successful PGD cycle, no confirmation of diagnosis will be obtained at birth. Guidelines indicate that individuals who are at risk cannot be tested before 18 years. There is concern over the ability of a child or adolescent to make an informed choice about testing before this age. Confirmatory testing at birth after PGD would be in direct contravention of these guidelines. In the UK, the law requires consideration of the welfare of children born after assisted conception treatment. Presenting symptoms of Huntington's disease may affect the parenting abilities of an affected individual. There is a need for an assessment of a patient's current Huntington's disease status and their planned provision of care of children if Huntington's disease affects parenting. It has been necessary to create a detailed working protocol for the management of PGD for Huntington's disease to address these issues. PMID:11719718

  2. 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 of prenatal diagnostic techniques, which for gynaecologists were clinically, technically and ethically less challenging than IVF. IVF was then regarded with a suspicion that only started to wane in the early 1980s following the first IVF births. Second, the UK Parliamentary reaction against human embryo research that greeted the Warnock Report in 1984 provided a positive stimulus to clinical PGD by prompting scientists to form a pro-research lobby, which was further galvanized in early 1985 by MP Enoch Powell’s almost-successful bid to ban human embryo research. We show that while Powell abhorred embryo research, he approved of PGD, a stance that fractured the unity of the anti-research lobby. Accordingly, the pro-research lobby emphasized that embryo research was needed to achieve PGD. Powell demanded evidence of such projects, thereby, we argue, stimulating PGD research from 1986. Our evidence shows that UK political debates about PGD played a critical role in stimulating the achievement of PGD clinically. PMID:21397558

  3. ESHRE task force on ethics and Law22: preimplantation genetic diagnosis.

    PubMed

    De Wert, G; Dondorp, W; Shenfield, F; Devroey, P; Tarlatzis, B; Barri, P; Diedrich, K; Provoost, V; Pennings, G

    2014-08-01

    This Task Force document discusses some relatively unexplored ethical issues involved in preimplantation genetic diagnosis (PGD). The document starts from the wide consensus that PGD is ethically acceptable if aimed at helping at-risk couples to avoid having a child with a serious disorder. However, if understood as a limit to acceptable indications for PGD, this 'medical model' may turn out too restrictive. The document discusses a range of possible requests for PGD that for different reasons fall outwith the accepted model and argues that instead of rejecting those requests out of hand, they need to be independently assessed in the light of ethical criteria. Whereas, for instance, there is no good reason for rejecting PGD in order to avoid health problems in a third generation (where the second generation would be healthy but faced with burdensome reproductive choices if wanting to have children), using PGD to make sure that one's child will have the same disorder or handicap as its parents, is ethically unacceptable. PMID:24927929

  4. 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

  5. [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. PMID:18330104

  6. Preimplantation genetic diagnosis: an ambiguous legal status for an ambiguous medical and social practice.

    PubMed

    Christian, B Y K

    2008-01-01

    Preimplantation Genetic Diagnosis (PGD) is a technique that is strictly regulated in most European countries where it is regularly practised, the legal status of PGD may appear to some as unethical because it may be viewed as a facilitator for those who would like to select children for reason other than medical. The need to test human embryos before birth and the consequences that may occur to those detected with some abnormalities also revives the issue of the respect due to the human embryo. In this paper the author analyse these matters. PMID:18942507

  7. 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

  8. Simultaneous preimplantation genetic diagnosis for Tay-Sachs and Gaucher disease.

    PubMed

    Altarescu, Gheona; Brooks, Barry; Margalioth, Ehud; Eldar Geva, Talia; Levy-Lahad, Ephrat; Renbaum, Paul

    2007-07-01

    Preimplantation genetic diagnosis (PGD) for single gene defects is described for a family in which each parent is a carrier of both Tay-Sachs (TS) and Gaucher disease (GD). A multiplex fluorescent polymerase chain reaction protocol was developed that simultaneously amplified all four familial mutations and 10 informative microsatellite markers. In one PGD cycle, seven blastomeres were analysed, reaching a conclusive diagnosis in six out of seven embryos for TS and in five out of seven embryos for GD. Of the six diagnosed embryos, one was wild type for both TS and GD, and three were wild type for GD and carriers of TS. Two remaining embryos were compound heterozygotes for TS. Two transferable embryos developed into blastocysts (wt/wt and wt GD/carrier TS) and both were transferred on day 5. This single cycle of PGD resulted in a healthy live child. Allele drop-out (ADO) was observed in three of 34 reactions, yielding an 8% ADO rate. The occurrence of ADO in single cell analysis and undetected recombination events are primary causes of misdiagnosis in PGD and emphasize the need to use multiple polymorphic markers. So far as is known, this is the first report of concomitant PGD for two frequent Ashkenazi Jewish recessive disorders. PMID:17623543

  9. 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

  10. Moral attitudes and beliefs among couples pursuing PGD for sex selection.

    PubMed

    Sharp, Richard R; McGowan, Michelle L; Verma, Jonathan A; Landy, David C; McAdoo, Sallie; Carson, Sandra A; Simpson, Joe Leigh; McCullough, Laurence B

    2010-12-01

    This article reports the results from a study of couples participating in a research protocol in which IVF/preimplantation genetic diagnosis (PGD) was available for non-medical sex selection. The study sought to characterize the moral attitudes and beliefs of couples actively pursuing IVF/PGD solely for purposes related to sex selection. Eighteen couples participated in ethnographic interviews from November 2005 to April 2006. These interviews explored couples' motivations for pursuing sex selection, moral beliefs and attitudes regarding sex selection and sources of moral ambivalence about the use of IVF/PGD for sex selection. Couples reported a combination of motivations for pursuing sex selection, including a desire to limit family size, concerns about parental age and financial concerns about multiple pregnancies. Many couples compared their decision to choices about abortion, maintaining that individuals have a right to make such decisions privately. Couples frequently expressed anxiety about telling their other children and family members about their plans to use IVF/PGD for sex selection. Few couples cited concerns about the physical or emotional burdens of IVF/PGD. The study's findings suggest that couples pursuing IVF/PGD for sex selection view this as an ethically complex decision and express considerable uncertainty about the ethical acceptability of this practice. PMID:21051290

  11. The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus.

    PubMed

    Girardet, Anne; Viart, Victoria; Plaza, Stéphanie; Daina, Gemma; De Rycke, Martine; Des Georges, Marie; Fiorentino, Francesco; Harton, Gary; Ishmukhametova, Aliya; Navarro, Joaquima; Raynal, Caroline; Renwick, Pamela; Saguet, Florielle; Schwarz, Martin; SenGupta, Sioban; Tzetis, Maria; Roux, Anne-Françoise; Claustres, Mireille

    2016-04-01

    Cystic fibrosis (CF) is one of the most common indications for preimplantation genetic diagnosis (PGD) for single gene disorders, giving couples the opportunity to conceive unaffected children without having to consider termination of pregnancy. However, there are no available standardized protocols, so that each center has to develop its own diagnostic strategies and procedures. Furthermore, reproductive decisions are complicated by the diversity of disease-causing variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene and the complexity of correlations between genotypes and associated phenotypes, so that attitudes and practices toward the risks for future offspring can vary greatly between countries. On behalf of the EuroGentest Network, eighteen experts in PGD and/or molecular diagnosis of CF from seven countries attended a workshop held in Montpellier, France, on 14 December 2011. Building on the best practice guidelines for amplification-based PGD established by ESHRE (European Society of Human Reproduction and Embryology), the goal of this meeting was to formulate specific guidelines for CF-PGD in order to contribute to a better harmonization of practices across Europe. Different topics were covered including variant nomenclature, inclusion criteria, genetic counseling, PGD strategy and reporting of results. The recommendations are summarized here, and updated information on the clinical significance of CFTR variants and associated phenotypes is presented. PMID:26014425

  12. 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

  13. Prevention of Lysosomal Storage Diseases and Derivation of Mutant Stem Cell Lines by Preimplantation Genetic Diagnosis

    PubMed Central

    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

  14. Preimplantation genetic diagnosis for mitochondrial DNA disorders: ethical guidance for clinical practice.

    PubMed

    Bredenoord, Annelien; Dondorp, Wybo; Pennings, Guido; de Die-Smulders, Christine; Smeets, Bert; de Wert, Guido

    2009-12-01

    Although morally acceptable in theory, preimplantation genetic diagnosis (PGD) for mitochondrial DNA (mtDNA) disorders raises several ethical questions in clinical practice. This paper discusses the major conditions for good clinical practice. Our starting point is that PGD for mtDNA mutations should as far as possible be embedded in a scientific research protocol. For every clinical application of PGD for mtDNA disorders, it is not only important to avoid a 'high risk of serious harm' to the future child, but also to consider to what extent it would be possible, desirable and proportional to try to reduce the health risks and minimize harm. The first issue we discuss is oocyte sampling, which may point out whether PGD is feasible for a specific couple. The second issue is whether one blastomere represents the genetic composition of the embryo as a whole -- and how this could (or should) be investigated. The third issue regards the cutoff points below which embryos are considered to be eligible for transfer. We scrutinize how to determine these cutoff points and how to use these cutoff points in clinical practice -- for example, when parents ask to take more or less risks. The fourth issue regards the number of cycles that can (or should) justifiably be carried out to find the best possible embryo. Fifth, we discuss whether follow-up studies should be conducted, particularly the genetic testing of children born after IVF/PGD. Finally, we offer the main information that is required to obtain a truly informed consent. PMID:19471315

  15. Perinatal genetics: Diagnosis and treatment

    SciTech Connect

    Porter, I.H.; Hatcher, N.H.; Willey, A.M.

    1986-01-01

    This book consists of six sections, each containing several chapters. Some of the chapter titles are: Prenatal Diagnosis of the Fragile X Syndrome; Prenatal Genetic Diagnosis by Chorionic Villus Sampling; Prenatal Treatment of Biochemical Disorders; H-Y Antigen, Sex Determination and Gender Control; and Environmental Factors and Human Birth Defects: Interpretation of Relative Risks in Clinical Genetics.

  16. 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

  17. Preimplantation genetic diagnosis for cystic fibrosis: the Montpellier center's 10-year experience.

    PubMed

    Girardet, A; Ishmukhametova, A; Willems, M; Coubes, C; Hamamah, S; Anahory, T; Des Georges, M; Claustres, M

    2015-02-01

    This study provides an overview of 10 years of experience of preimplantation genetic diagnosis (PGD) for cystic fibrosis (CF) in our center. Owing to the high allelic heterogeneity of CF transmembrane conductance regulator (CFTR) mutations in south of France, we have set up a powerful universal test based on haplotyping eight short tandem repeats (STR) markers together with the major mutation p.Phe508del. Of 142 couples requesting PGD for CF, 76 have been so far enrolled in the genetic work-up, and 53 had 114 PGD cycles performed. Twenty-nine cycles were canceled upon in vitro fertilization (IVF) treatment because of hyper- or hypostimulation. Of the remaining 85 cycles, a total of 493 embryos were biopsied and a genetic diagnosis was obtained in 463 (93.9%), of which 262 (without or with a single CF-causing mutation) were transferable. Twenty-eight clinical pregnancies were established, yielding a pregnancy rate per transfer of 30.8% in the group of seven couples with one member affected with CF, and 38.3% in the group of couples whose both members are carriers of a CF-causing mutation [including six couples with congenital bilateral absence of the vas deferens (CBAVD)]. So far, 25 children were born free of CF and no misdiagnosis was recorded. Our test is applicable to 98% of couples at risk of transmitting CF. PMID:24762087

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

    PubMed Central

    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. PMID:26713318

  19. Preimplantation genetic diagnosis for gender selection in the USA.

    PubMed

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

    2009-01-01

    Preimplantation genetic diagnosis (PGD) for gender selection for non-medical reasons has been considered an unethical procedure by several authors and agencies in the Western society on the basis that it could disrupt the sex ratio, that it discriminates against women and that it leads to 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 USA 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 embryos transferred of the non-desired gender, this fact being strongly linked to cultural and ethnic 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. PMID:19891844

  20. 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.

  1. 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

  2. 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. PMID:12470347

  3. Rapid and powerful decaplex and dodecaplex PGD protocols for Duchenne muscular dystrophy.

    PubMed

    Girardet, A; Fernandez, C; Claustres, M

    2009-12-01

    Duchenne muscular dystrophy (DMD) is a common childhood lethal X-linked recessive disorder, resulting from deletions, duplications and point mutations in the dystrophin gene. Single-cell protocols for preimplantation genetic diagnosis (PGD) still remain challenging due to the enormous size of the gene and the high risk of intragenic recombination, limitations that often lead to sex determination and selection of female embryos. This study describes direct and rapid decaplex and dodecaplex polymerase chain reaction protocols enabling the analysis of five or seven exons and four microsatellite markers scattered along the dystrophin gene, chosen to be located in the two deletion hotspots, and the analysis of amelogenin sequences for gender determination. The dodecaplex protocol may be applied to most of the couples requesting PGD for DMD in whom the female partner is a carrier of a deletion. This generic approach will allow prompt response to the PGD referrals by reducing the pre-clinical PGD work-up. It was successfully applied in three DMD families, resulting in the birth of a girl as well as in a healthy ongoing pregnancy. PMID:20031025

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

    PubMed

    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

  5. 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

  6. 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

  7. Live birth after PGD with confirmation by a comprehensive approach (karyomapping) for simultaneous detection of monogenic and chromosomal disorders.

    PubMed

    Natesan, Senthilkumar A; Handyside, Alan H; Thornhill, Alan R; Ottolini, Christian S; Sage, Karen; Summers, Michael C; Konstantinidis, Michalis; Wells, Dagan; Griffin, Darren K

    2014-11-01

    Preimplantation genetic diagnosis (PGD) for monogenic disorders has the drawback of time and cost associated with tailoring a specific test for each couple, disorder, or both. The inability of any single assay to detect the monogenic disorder in question and simultaneously the chromosomal complement of the embryo also limits its application as separate tests may need to be carried out on the amplified material. The first clinical use of a novel approach ('karyomapping') was designed to circumvent this problem. In this example, karyomapping was used to confirm the results of an existing PGD case detecting both chromosomal abnormalities and a monogenic disorder (Smith-Lemli-Opitz [SLO] syndrome) simultaneously. The family underwent IVF, ICSI and PGD, and both polar body and cleavage stage biopsy were carried out. Following whole genome amplification, array comparative genomic hybridisation of the polar bodies and minisequencing and STR analysis of single blastomeres were used to diagnose maternal aneuploidies and SLO status, respectively. This was confirmed, by karyomapping. Unlike standard PGD, karyomapping required no a-priori test development. A singleton pregnancy and live birth, unaffected with SLO syndrome and with no chromosome abnormality, ensued. Karyomapping is potentially capable of detecting a wide spectrum of monogenic and chromosome disorders and, in this context, can be considered a comprehensive approach to PGD. PMID:25154779

  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. Choosing embryos: ethical complexity and relational autonomy in staff accounts of PGD.

    PubMed

    Ehrich, Kathryn; Williams, Clare; Farsides, Bobbie; Sandall, Jane; Scott, Rosamund

    2007-11-01

    The technique of preimplantation genetic diagnosis (PGD) is commonly explained as a way of checking the genes of embryos produced by IVF for serious genetic diseases. However, complex accounts of this technique emerged during ethics discussion groups held for PGD staff. These form part of a study exploring the social processes, meanings and institutions that frame and produce 'ethical problems' for practitioners, scientists and others working in the specialty of PGD in the UK. Two 'grey areas' raised by staff are discussed in terms of how far staff are, or in the future may be, able to support autonomous choices of women/couples: accepting 'carrier' embryos within the goal of creating a 'healthy' child; and sex selection of embryos for social reasons. These grey areas challenged the staff's resolve to offer individual informed choice, in the face of their awareness of possible collective social effects that might ensue from individual choices. We therefore argue that these new forms of choice pose a challenge to conventional models of individual autonomy used in UK genetic and reproductive counselling, and that 'relational autonomy' may be a more suitable ethical model to describe the ethical principles being drawn on by staff working in this area. PMID:18092985

  10. Choosing embryos: ethical complexity and relational autonomy in staff accounts of PGD

    PubMed Central

    Ehrich, Kathryn; Williams, Clare; Farsides, Bobbie; Sandall, Jane; Scott, Rosamund

    2007-01-01

    The technique of preimplantation genetic diagnosis (PGD) is commonly explained as a way of checking the genes of embryos produced by IVF for serious genetic diseases. However, complex accounts of this technique emerged during ethics discussion groups held for PGD staff. These form part of a study exploring the social processes, meanings and institutions that frame and produce ‘ethical problems’ for practitioners, scientists and others working in the specialty of PGD in the UK. Two ‘grey areas’ raised by staff are discussed in terms of how far staff are, or in the future may be, able to support autonomous choices of women/couples: accepting ‘carrier’ embryos within the goal of creating a ‘healthy’ child; and sex selection of embryos for social reasons. These grey areas challenged the staff's resolve to offer individual informed choice, in the face of their awareness of possible collective social effects that might ensue from individual choices. We therefore argue that these new forms of choice pose a challenge to conventional models of individual autonomy used in UK genetic and reproductive counselling, and that ‘relational autonomy’ may be a more suitable ethical model to describe the ethical principles being drawn on by staff working in this area. PMID:18092985

  11. 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

  12. 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

  13. 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

  14. 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

  15. Preventing the transmission of mitochondrial DNA disorders using prenatal or preimplantation genetic diagnosis.

    PubMed

    Smeets, Hubert J M; Sallevelt, Suzanne C E H; Dreesen, Jos C F M; de Die-Smulders, Christine E M; de Coo, Irenaeus F M

    2015-09-01

    Mitochondrial disorders are among the most common inborn errors of metabolism; at least 15% are caused by mitochondrial DNA (mtDNA) mutations, which occur de novo or are maternally inherited. For familial heteroplasmic mtDNA mutations, the mitochondrial bottleneck defines the mtDNA mutation load in offspring, with an often high or unpredictable recurrence risk. Oocyte donation is a safe option to prevent the transmission of mtDNA disease, but the offspring resulting from oocyte donation are genetically related only to the father. Prenatal diagnosis (PND) is technically possible but usually not applicable because of limitations in predicting the phenotype. For de novo mtDNA point mutations, recurrence risks are low and PND can be offered to provide reassurance regarding fetal health. PND is also the best option for female carriers with low-level mutations demonstrating skewing to 0% or 100%. A fairly new option for preventing the transmission of mtDNA diseases is preimplantation genetic diagnosis (PGD), in which embryos with a mutant load below a mutation-specific or general expression threshold of 18% can be transferred. PGD is currently the best reproductive option for familial heteroplasmic mtDNA point mutations. Nuclear genome transfer and genome editing techniques are currently being investigated and might offer additional reproductive options for specific mtDNA disease cases. PMID:26312584

  16. Medium-Based Noninvasive Preimplantation Genetic Diagnosis for Human α-Thalassemias-SEA

    PubMed Central

    Wu, Haitao; Ding, Chenhui; Shen, Xiaoting; Wang, Jing; Li, Rong; Cai, Bing; Xu, Yanwen; Zhong, Yiping; Zhou, Canquan

    2015-01-01

    Abstract To develop a noninvasive medium-based preimplantation genetic diagnosis (PGD) test for α-thalassemias-SEA. The embryos of α-thalassemia-SEA carriers undergoing in vitro fertilization (IVF) were cultured. Single cells were biopsied from blastomeres and subjected to fluorescent gap polymerase chain reaction (PCR) analysis; the spent culture media that contained embryo genomic DNA and corresponding blastocysts as verification were subjected to quantitative-PCR (Q-PCR) detection of α-thalassemia-SEA. The diagnosis efficiency and allele dropout (ADO) ratio were calculated, and the cell-free DNA concentration was quantitatively assessed in the culture medium. The diagnosis efficiency of medium-based α-thalassemias–SEA detection significantly increased compared with that of biopsy-based fluorescent gap PCR analysis (88.6% vs 82.1%, P < 0.05). There is no significant difference regarding ADO ratio between them. The optimal time for medium-based α-thalassemias–SEA detection is Day 5 (D5) following IVF. Medium-based α-thalassemias–SEA detection could represent a novel, quick, and noninvasive approach for carriers to undergo IVF and PGD. PMID:25816038

  17. Improving preimplantation genetic diagnosis for Fragile X syndrome: two new powerful single-round multiplex indirect and direct tests.

    PubMed

    Kieffer, Emmanuelle; Nicod, Jean-Christophe; Gardes, Nathalie; Kastner, Claire; Becker, Nicolas; Celebi, Catherine; Pirrello, Olivier; Rongières, Catherine; Koscinski, Isabelle; Gosset, Philippe; Moutou, Céline

    2016-02-01

    Fragile X syndrome (FraX) is caused by the expansion of an unstable CGG repeat located in the Fragile X mental retardation 1 gene (FMR1) gene. Preimplantation genetic diagnosis (PGD) can be proposed to couples at risk of transmitting the disease, that is, when the female carries a premutation or a full mutation. We describe two new single-cell, single-round multiplex PCR for indirect and direct diagnosis of FraX on biopsied embryos. These tests include five unpublished, highly heterozygous simple sequence repeats, and the co-amplification of non-expanded CGG repeats for the direct test. Heterozygosity of the new markers ranged from 69 to 81%. The mean rate of non-informative marker included in the tests was low (26% and 23% for the new indirect and direct tests, respectively). This strategy allows offering a PGD for FraX to 96% of couples requesting it in our centre. A conclusive genotype was obtained in all cells with a rate of cells presenting an allele dropout ranging from 17% for the indirect test to 26% for the direct test. The new indirect test was applied for eight PGD cycles: 32 embryos were analysed, 9 were transferred and 3 healthy babies were born. By multiplexing these highly informative markers, robustness of the diagnosis is improved and the loss of potentially healthy embryos (because they are non-diagnosed or misdiagnosed) is limited. This may increase the chances of success of couples requesting a PGD for FraX, in particular, when premature ovarian insufficiency in premutated women leads to a reduced number of embryos available for analysis. PMID:25966634

  18. Can Characteristics of Reciprocal Translocations Predict the Chance of Transferable Embryos in PGD Cycles?

    PubMed

    Dul, Elsbeth; van Echten-Arends, Jannie; Groen, Henk; Kastrop, Peter; Wissen, Lucie Amory-van; Engelen, John; Land, Jolande; Coonen, Edith; van Ravenswaaij-Arts, Conny

    2014-01-01

    Translocation carriers have an increased risk of miscarriage or the birth of a child with congenital anomalies. Preimplantation genetic diagnosis (PGD) is performed in translocation carriers to select for balanced embryos and, thus, increase the chance of an ongoing pregnancy. However, a common experience is that reciprocal translocation carriers produce a high percentage of unbalanced embryos, which cannot be transferred. Therefore, the pregnancy rates in PGD in this patient group are low. In a cohort of 85 reciprocal translocation carriers undergoing PGD we have searched for cytogenetic characteristics of the translocations that can predict the percentage of balanced embryos. Using shape algorithms, the most likely segregation mode per translocation was determined. Shape algorithm, breakpoint location, and relative chromosome segment sizes proved not to be independent predictors of the percentage of balanced embryos. The ratio of the relative sizes of the translocated segments of both translocation chromosomes can give some insight into the chance of transferable embryos: Very asymmetrical translocations have a higher risk of unbalanced products (p = 0.048). Counseling of the couples on the pros and cons of all their reproductive options remains very important. PMID:26237378

  19. PGD gender selection for non-Mendelian disorders with unequal sex incidence.

    PubMed

    Amor, David J; Cameron, Carolyn

    2008-04-01

    Preimplantation genetic diagnosis (PGD) was originally developed for couples whose potential offspring were at risk of severe Mendelian disorders, but has since been extended to other indications. One possible use of PGD is to perform gender selection for couples whose offspring are at increased risk of disorders that do not follow Mendelian inheritance, but which are substantially more common in one sex than another (unequal sex incidence). Here, we examine the clinical and ethical issues to be considered prior to offering PGD gender selection to reduce the risk of a child being affected by a non-Mendelian condition with unequal sex incidence. Factors to be considered include: the risk that a child of either sex will be affected by the condition; the overall reduction in risk provided by gender selection and the potential harms of the procedure. Consideration should also be given to the interests of the family and the child to be born, the seriousness of the condition and the couple's procreative autonomy. To illustrate these issues we use the example of autism, a non-Mendelian disorder that is considerably more common in males than in females. PMID:18222917

  20. Number of embryos biopsied as a predictive indicator for the outcome of preimplantation genetic diagnosis by fluorescence in situ hybridisation in translocation cases.

    PubMed

    Tulay, P; Gultomruk, M; Findikli, N; Bahceci, M

    2016-02-01

    This study aimed to investigate the optimum number of embryos to be biopsied in order to increase the likelihood of obtaining a balanced/normal embryo following preimplantation genetic diagnosis (PGD) by fluorescence in situ hybridisation (FISH) for translocation carriers. Patients with low number of fertilised oocytes (?5) or low number of embryos available for PGD (<7) underwent multiple hormonal stimulation cycles and their embryos from each cycle were vitrified and accumulated to obtain at least three embryos for PGD. Fifty-seven PGD cycles were performed for translocation carriers by FISH on day 3 of embryo development. PGD and pregnancy outcomes were examined according to the number of embryos biopsied. The cancellation rates of embryo transfer for the reciprocal translocation carriers were 40% when more than eight embryos were biopsied and it was as high as 78% when low number of embryos (less than nine) were biopsied. For Robertsonian translocation carriers, when more than eight embryos were biopsied, there were no embryo transfer cancellations. This study showed that when there are more than nine embryos biopsied for PGD, the likelihood of obtaining a balanced embryo and positive pregnancy outcome is significantly higher (P < 0.05) in such the overall pregnancy rate was 63% for reciprocal and 86% for Robertsonian carriers. This was reduced to only 7% for reciprocal and 14% for Robertsonian translocation carriers when less than nine embryos were biopsied. One of the limitations of this study was that the analysis was performed by FISH and more studies should investigate the outcomes of embryo accumulation following comprehensive chromosome analysis. PMID:25601127

  1. A versatile strategy for preimplantation genetic diagnosis of haemophilia A based on F8-gene sequencing.

    PubMed

    Sánchez-García, Jorge F; Gallardo, Dominique; Navarro, Joaquima; Márquez, Carmen; Gris, Josep Maria; Sánchez, Maria Angeles; Altisent, Carme; Vidal, Francisco

    2006-12-01

    Preimplantation genetic diagnosis (PGD) of hemophilia A (HA) and other X-linked diseases through sex selection implies that male embryos will be systematically discarded, even though 50% are unaffected. The objective of the present work was to develop a PGD protocol for direct mutation identification that could be applied to first polar bodies (1PBs) in several HA clinical cases. Single buccal cells from controls and patients, and 1PBs were subjected to primer extension preamplification (PEP) PCR followed by amplification of F8 gene coding and intronic flanking regions, and direct sequencing. Moreover, multiplex fluorescent amplification of four short tandem repeats was adapted to a single cell preamplification in order to rule out contamination and allele drop-out, and for confirmatory indirect diagnosis. A couple at risk of HA transmission, with a familial mutation characterized as a 41-bp duplication in exon 14 of the F8 gene, was selected for the first clinical study. After optimizing the protocol, the complete F8 gene coding sequence was obtained from single cells to demonstrate the sensitivity of our methodology although in any clinical case only the relevant region, not the whole gene, must be amplified. The woman enrolled in the first clinical case has completed the first in-vitro fertilization cycle, and seven oocytes were analyzed with concordant results by both linkage analysis and direct sequencing method. Only one oocyte, among those diagnosed as mutation free, developed to embryo at day 3. It was transferred but pregnancy was not achieved. This PGD procedure enables non-affected and noncarrier embryo selection in families with any point or small-range mutation in the F8 gene, without the need for further custom-made modifications. PMID:17139381

  2. Setting up equine embryo gender determination by preimplantation genetic diagnosis in a commercial embryo transfer program.

    PubMed

    Herrera, C; Morikawa, M I; Bello, M B; von Meyeren, M; Centeno, J Eusebio; Dufourq, P; Martinez, M M; Llorente, J

    2014-03-15

    Preimplantation genetic diagnosis (PGD) allows identifying genetic traits in early embryos. Because in some equine breeds, like Polo Argentino, females are preferred to males for competition, PGD can be used to determine the gender of the embryo before transfer and thus allow the production of only female pregnancies. This procedure could have a great impact on commercial embryo production programs. The present study was conducted to adapt gender selection by PGD to a large-scale equine embryo transfer program. To achieve this, we studied (i) the effect on pregnancy rates of holding biopsied embryos for 7 to 10 hours in holding medium at 32 °C before transfer, (ii) the effect on pregnancy rates of using embryos of different sizes for biopsy, and (iii) the efficiency of amplification by heating biopsies before polymerase chain reaction. Equine embryos were classified by size (≤300, 300-1000, and >1000 μm), biopsied, and transferred 1 to 2 or 7 to 10 hours after flushing. Some of the biopsy samples obtained were incubated for 10 minutes at 95 °C and the rest remained untreated. Pregnancy rates were recorded at 25 days of gestation; fetal gender was determined using ultrasonography and compared with PGD results. Holding biopsied embryos for 7 to 10 hours before transfer produced pregnancy rates similar to those for biopsied embryos transferred within 2 hours (63% and 57%, respectively). These results did not differ from pregnancy rates of nonbiopsied embryos undergoing the same holding times (50% for 7-10 hours and 63% for 1-2 hours). Pregnancy rates for biopsied and nonbiopsied embryos did not differ between size groups or between biopsied and nonbiopsied embryos within the same size group (P > 0.05). Incubating biopsy samples for 10 minutes at 95 °C before polymerase chain reaction significantly increased the diagnosis rate (78.5% vs. 45.5% for treated and nontreated biopsy samples respectively). Gender determination using incubated biopsy samples matched the results obtained using ultrasonography in all pregnancies assessed (11/11, 100%); untreated biopsy samples were correctly diagnosed in 36 of 41 assessed pregnancies (87.8%), although the difference between treated and untreated biopsy samples was not significant. Our results demonstrated that biopsied embryos can remain in holding medium before being transferred, until gender diagnosis by PGD is complete (7-10 hours), without affecting pregnancy rates. This simplifies the management of an embryo transfer program willing to incorporate PGD for gender selection, by transferring only embryos of the desired sex. Embryo biopsy can be performed in a clinical setting on embryos of different sizes, without affecting their viability. Additionally, we showed that pretreating biopsy samples with a short incubation at 95 °C improved the overall efficiency of embryo sex determination. PMID:24439164

  3. Prenatal diagnosis of genetic disorders.

    PubMed Central

    Niermeijer, M F; Sachs, E S; Jahodova, M; Tichelaar-Klepper, C; Kleijer, W J; Galjaard, H

    1976-01-01

    Three hundred and fifty pregnancies were monitored by transabdominal amniocentesis in the fourteenth to sixteenth week of gestation followed by karyotyping or biochemica assays of cultured amniotic fluid cells and analysis of alpha-fetoprotein in the amniotic fluid supernatant. The pregnancy was interrupted in 36 cases (10%) either becasue of a fetal abnormality or the presence of a male fetus in pregnancies at risk for an X-linked disease. Four chromosomal aberrations were found in 87 pregnancies tested because of advanced maternal age. In 101 pregnancies with a recurrence risk of Down's syndrome, 2 fetuses with an abnormal karyotype were detected. In 11 cases, in which 1 parent was a carrier of a balanced translocation, 2 unbalanced fetal karyotypes were found. Fetal chromosome studies in 43 pregancies at risk for an X-linked disease indicated the presence of a male fetus in 21 cases. Prenatal diagnosis of 11 different metabolic diseases was performed in a total of 34 cases. Microchemical techniques were used to allow completion of the diagnosis of seven different enzyme deficiencies within 9 to 22 days after amniocentesis. Alpha-fetoprotein assay in the amniotic fluid supernatant of 47 pregnancies at risk for an open neural tube defect resulted in the detection of 3 anencephalic fetuses during the second half of pregnancy. The safety and reliability of amniocentesis and the possible effects on the outcome of pregnancy are evaluated. Prenatal diagnosis offers a promising alternative for parents who are at risk of having a child with a genetic disease which can be detected in amniotic fluid or in cultured amniotic fluid cells. Images PMID:58990

  4. Accreditation of the PGD laboratory.

    PubMed

    Harper, J C; Sengupta, S; Vesela, K; Thornhill, A; Dequeker, E; Coonen, E; Morris, M A

    2010-04-01

    Accreditation according to an internationally recognized standard is increasingly acknowledged as the single most effective route to comprehensive laboratory quality assurance, and many countries are progressively moving towards compulsory accreditation of medical testing laboratories. The ESHRE PGD Consortium and some regulatory bodies recommend that all PGD laboratories should be accredited or working actively towards accreditation, according to the internationally recognized standard ISO 15189, 'Medical laboratories-Particular requirements for quality and competence'. ISO 15189 requires comprehensive quality assurance. Detailed management and technical requirements are defined in the two major chapters. The management requirements address quality management including the quality policy and manual, document control, non-conformities and corrective actions, continual improvement, auditing, management review, contracts, referrals and resolution of complaints. Technical requirements include personnel competence (both technical and medical), equipment, accommodation and environment, and pre-analytical, analytical and post-analytical processes. Emphasis is placed on the particular requirements of patient care: notably sample identification and traceability, test validation and interpretation and reporting of results. Quality indicators must be developed to monitor contributions to patient care and continual improvement. We discuss the implementation of ISO 15189 with a specific emphasis on the PGD laboratory, highlight elements of particular importance or difficulty and provide suggestions of effective and efficient ways to obtain accreditation. The focus is on the European environment although the principles are globally applicable. PMID:20097923

  5. 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 ...

  6. The embryo as moral work object: PGD/IVF staff views and experiences

    PubMed Central

    Ehrich, Kathryn; Williams, Clare; Farsides, Bobbie

    2008-01-01

    We report on one aspect of a study that explored the views and experiences of practitioners and scientists on social, ethical and clinical dilemmas encountered when working in the field of preimplantation genetic diagnosis (PGD) for serious genetic disorders. The study produced an ethnography based on observation, interviews and ethics discussion groups with staff from two PGD/IVF Units in the UK. We focus here on staff perceptions of work with embryos that entails disposing of ‘affected’ or ‘spare’ embryos or using them for research. A variety of views were expressed on the ‘embryo question’ in contrast to polarised media debates. We argue that the prevailing policy acceptance of destroying affected embryos, and allowing research on embryos up to 14 days leaves some staff with rarely reported, ambivalent feelings. Staff views are under-researched in this area and we focus on how they may reconcile their personal moral views with the ethical framework in their field. Staff construct embryos in a variety of ways as ‘moral work objects’. This allows them to shift attention between micro-level and overarching institutional work goals, building on Casper's concept of ‘work objects’ and focusing on negotiation of the social order in a morally contested field. PMID:18444955

  7. Preimplantation genetic diagnosis for aneuploidy and translocations using array comparative genomic hybridization.

    PubMed

    Munné, Santiago

    2012-09-01

    At least 50% of human embryos are abnormal, and that increases to 80% in women 40 years or older. These abnormalities result in low implantation rates in embryos transferred during in vitro fertilization procedures, from 30% in women <35 years to 6% in women 40 years or older. Thus selecting normal embryos for transfer should improve pregnancy results. The genetic analysis of embryos is called Preimplantation Genetic Diagnosis (PGD) and for chromosome analysis it was first performed using FISH with up to 12 probes analyzed simultaneously on single cells. However, suboptimal utilization of the technique and the complexity of fixing single cells produced conflicting results. PGD has been invigorated by the introduction of microarray testing which allows for the analysis of all 24 chromosome types in one test, without the need of cell fixation, and with staggering redundancy, making the test much more robust and reliable. Recent data published and presented at scientific meetings has been suggestive of increased implantation rates and pregnancy rates following microarray testing, improvements in outcome that have been predicted for quite some time. By using markers that cover most of the genome, not only aneuploidy can be detected in single cells but also translocations. Our validation results indicate that array CGH has a 6Mb resolution in single cells, and thus the majority of translocations can be analyzed since this is also the limit of karyotyping. Even for translocations with smaller exchanged fragments, provided that three out of the four fragments are above 6Mb, the translocation can be detected. PMID:23448851

  8. 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

  9. Identification of a Novel Single Nucleotide Polymorphism of HADHA Gene at a Referred Primer-binding Site During Pre-diagnostic Tests for Preimplantation Genetic Diagnosis

    PubMed Central

    Lee, Hyoung-Song; Choi, Hye Won; Lim, Chun Kyu; Koong, Mi Kyoung; Kang, Inn Soo; Yoo, Han-Wook; Choi, Jin-Ho

    2006-01-01

    The pre-diagnostic test for preimplantation genetic diagnosis (PGD) of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency was performed by polymerase chain reaction (PCR) and direct sequencing for hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (HADHA) gene. We obtained unexpected genotyping results of HADHA gene by allele drop-out in the analysis of patients' genomic DNA samples with a referred PCR primer set. Upon further analysis with a re-designed primer set, we found a novel single nucleotide polymorphism (SNP) at the referred primer-binding site in the normal allele of HADHA gene (NT_022184, 5233296 a>t). We found that the frequency of this novel SNP was 0.064 in Korean population. Pre-diagnostic test using single lymphocytes and clinical PGD were successfully performed with the re-designed primer set. Nineteen embryos (95.0%) among 20 were successfully diagnosed to 5 homozygous mutated, 8 heterozygous carrier and 6 wild type. Among 6 normal embryos, well developed and selected 4 embryos were transferred into the mother's uterus, but a pregnancy was not achieved. We proposed that an unknown SNP at primer-binding sites would be a major cause of allele drop-out in the PGD for single gene disorder. PMID:17043408

  10. Preimplantation genetic diagnosis for elective sex selection, the IVF market economy, and the child--another long day's journey into night?

    PubMed

    Sills, E Scott; Palermo, Gianpiero D

    2002-09-01

    The promise of medical innovation has long evoked social commentary, particularly when personal reproductive autonomy may be involved. Development of the oral contraceptive, effective and safe surgical sterilization, and later IVF and ICSI are among the revolutionary developments where the initial reactions were dubious but were accorded mainstream status with sufficient clinical experience. In each instance, debate about the moral and social implications of these treatments accompanied their introduction into the medical marketplace. This pattern appears to be repeating itself in connection with the use of preimplantation genetic diagnosis (PGD) for elective sex selection of human embryos. As with prior challenges in reproductive medicine, the development of meaningful "guidelines" for this latest controversy has proven to be a contentious task. Indeed, the progression of ethics committee reports from the American Society for Reproductive Medicine seems to echo the ambivalence within society at large regarding this issue. In this report, we chronicle sex selection claims based on sperm sorting, and describe how flow cytometry and especially PGD have facilitated this selection at the gamete and embryo stage, respectively. In doing so, we also explore market forces and practitioner considerations associated with the application of PGD for this; related ethical issues with particular emphasis on the progeny derived from such treatment are also reviewed. PMID:12408539

  11. Pregnancy after preimplantation genetic diagnosis for Charcot-Marie-Tooth disease type 1A.

    PubMed

    De Vos, A; Sermon, K; Van de Velde, H; Joris, H; Vandervorst, M; Lissens, W; Mortier, G; De Sutter, P; Löfgren, A; Van Broeckhoven, C; Liebaers, I; Van Steirteghem, A

    1998-10-01

    Charcot-Marie-Tooth (CMT) disease type 1A is an autosomal dominant peripheral neuropathy characterized by slow progressive distal muscle wasting and weakness, and decreased nerve conduction velocities. Most CMT1A cases (>98%) are caused by a duplication of a 1.5 Mb region on the short arm of chromosome 17 containing the PMP22 gene. A couple with a previous history of CMT followed by termination of pregnancy was referred to our centre for preimplantation genetic diagnosis (PGD). The husband carries the CMT1A duplication which can be detected by polymerase chain reaction (PCR) analysis using polymorphic (CA)n markers localized within the duplication. PCR amplification of genomic DNA of the parents-to-be with one of the two primers labelled with fluorescein, followed by automated laser fluorescence (ALF) gel electrophoresis of the amplified fragments allows the distinction between both genotypes. Embryos obtained after intracytoplasmic sperm injection (ICSI) were evaluated for the presence of the normal allele of the father. PCR with single Epstein-Barr virus-transformed lymphoblasts and blastomeres resulted in 91.4 and 93.5% amplification efficiency respectively, whereas none of the blank controls gave a positive signal. Allele drop-out (ADO) was observed in eight out of 32 lymphoblasts (25%) or in five out of 21 blastomeres (23.8%). However, within this set-up ADO will never lead to transfer of an affected embryo. A first ICSI-PGD cycle did not result in embryo transfer for the patient. A second cycle involved 10 mature oocytes of which eight were fertilized, resulting in five embryos for biopsy. Two unaffected embryos were available for transfer and resulted in a singleton pregnancy. The genotype of the fetus has been confirmed healthy by chorionic villus sampling. PMID:9809680

  12. Personal desires of patients and social obligations of geneticists: applying preimplantation genetic diagnosis for non-medical sex selection.

    PubMed

    Pennings, Guido

    2002-12-01

    The arguments against the use of preimplantation genetic diagnosis (PGD) for non-medical sex selection are analysed. It is concluded that the distinction between medical and non-medical reasons is difficult to maintain, that the disproportionality of means and end is not a decisive counterargument and that the fear of damage to the reputation of PGD does not justify the refusal of controversial applications. Moreover, since non-medical sex selection does not belong to basic health care, it should not be equally accessible to all. The position defended in this article is founded on two basic principles: (1). medical reasons have priority on non-medical reasons, and (2). personal reasons do not qualify for public funding. In order to respect both principles, it is proposed that restrictions should be installed to control the number of requests for social sexing and that a tax should be imposed on these elective services. The tax should compensate the society for the investment it made in the training and education of the physician. PMID:12454971

  13. 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

  14. Preimplantation genetic diagnosis and the 'new' eugenics.

    PubMed Central

    King, D S

    1999-01-01

    Preimplantation genetic diagnosis (PID) is often seen as an improvement upon prenatal testing. I argue that PID may exacerbate the eugenic features of prenatal testing and make possible an expanded form of free-market eugenics. The current practice of prenatal testing is eugenic in that its aim is to reduce the numbers of people with genetic disorders. Due to social pressures and eugenic attitudes held by clinical geneticists in most countries, it results in eugenic outcomes even though no state coercion is involved. I argue that technological advances may soon make PID widely accessible. Because abortion is not involved, and multiple embryos are available, PID is radically more effective as a tool of genetic selection. It will also make possible selection on the basis of non-pathological characteristics, leading, potentially, to a full-blown free-market eugenics. For these reasons, I argue that PID should be strictly regulated. PMID:10226925

  15. Pheochromocytoma and Paraganglioma: Genetics, Diagnosis, and Treatment.

    PubMed

    Fishbein, Lauren

    2016-02-01

    Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare but unique neuroendocrine tumors. The hypersecretion of catecholamines from the tumors can be associated with high morbidity and mortality, even when tumors are benign. Up to 40% of PCCs/PGLs are associated with germline mutations in susceptibility genes. About one-quarter are malignant, defined by the presence of distant metastases. Treatment options for unresectable metastatic disease, including chemotherapy, (131)I-MIBG, and radiation, can offer limited tumor and hormone control, although none are curative. This article reviews the inherited genetics, diagnosis, and treatment of PCCs and PGLs. PMID:26614373

  16. Successful birth with preimplantation genetic diagnosis using single-cell allele-specific PCR and sequencing in a woman with hypochondroplasia due to FGFR3 mutation (c.1620C>A, p.N540K)

    PubMed Central

    Park, Kyung Eui; Kim, Sung Ah; Kang, Moon Joo; Kim, Hee Sun; Cho, Sung Im; Yoo, Kyoung Won; Kim, So Yeon; Lee, Hye Jun; Oh, Sun Kyung; Seong, Moon-Woo; Ku, Seung-Yup; Jun, Jong Kwan; Park, Sung Sup; Moon, Shin Yong

    2013-01-01

    Hypochondroplasia (HCH) is an autosomal dominant inherited skeletal dysplasia, usually caused by a heterozygous mutation in the fibroblast growth factor receptor 3 gene (FGFR3). A 27-year-old HCH woman with a history of two consecutive abortions of HCH-affected fetuses visited our clinic for preimplantation genetic diagnosis (PGD). We confirmed the mutation in the proband (FGFR3:c.1620C>A, p.N540K), and established a nested allele-specific PCR and sequence analysis for PGD using single lymphocyte cells. We performed this molecular genetic analysis to detect the presence of mutation among 20 blastomeres from 18 different embryos, and selected 9 embryos with the wild-type sequence (FGFR3:c.1620C). A successful pregnancy was achieved through a frozen-thawed cycle and resulted in the full-term birth of a normal neonate. To the best of our knowledge, this is the first report of a successful pregnancy and birth using single-cell allele-specific PCR and sequencing for PGD in an HCH patient. PMID:23614116

  17. New perspectives on preimplantation genetic diagnosis and preimplantation genetic screening.

    PubMed

    Chen, Chun-Kai; Yu, Hsing-Tse; Soong, Yung-Kuei; Lee, Chyi-Long

    2014-06-01

    Preimplantation genetic diagnosis is a procedure that involves the removal of one or more nuclei from oocytes (a polar body) or embryos (blastomeres or trophectoderm cells) in order to test for problems in genome sequence or chromosomes of the embryo prior to implantation. It provides new hope of having unaffected children, as well as avoiding the necessity of terminating an affected pregnancy for genetic parents who carry an affected gene or have balanced chromosomal status. Polymerase chain reaction-based molecular techniques are the methods used to detect gene defects with a known sequence and X-linked diseases. The indication for using this approach has expanded for couples who are prevented from having babies because they carry a serious genetic disorder to couples with conditions that are not immediately life threatening, such as cancer predisposition genes and Huntington disease. In addition, fluorescent in situ hybridization (FISH) has been widely applied for the detection of chromosome abnormalities. FISH allows the evaluation of many chromosomes at the same time, up to 15 chromosome pairs in a single cell. Preimplantation genetic screening, defined as a test that screens for aneuploidy, has been most commonly used in situations of advanced maternal age, a history of recurrent miscarriage, a history of repeated implantation failure, or a severe male factor. Unfortunately, randomized controlled trials have as yet shown no benefit with respect to preimplantation genetic screening using cleavage stage biopsy, which is probably attributable to the high levels of mosaicism at early cleavage stages and the limitations of FISH. Recently, two main types of array-based technology combined with whole genome amplification have been developed for use in preimplantation genetic diagnosis; these are comparative genomic hybridization and single nucleotide polymorphism-based arrays. Both allow the analysis of all chromosomes, and the latter also allows the haplotype of the sample to be determined. The promising results of these two approaches will inspire further validation of these array platforms, even at the single-cell level. It remains to be decided which embryo stage is the best for biopsy. Moreover, if randomized controlled trials are confirmed to play a role in increasing delivery rates, this will be a major step forward for assisted reproductive technology patients around the world. PMID:25017257

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

    PubMed

    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

  20. Normal birth following PGD for reciprocal translocation after serial vitrification of oocytes from a poor responder: a case report.

    PubMed

    Chung, Jin Tae; Son, Weon-Young; Zhang, Xiao Yun; Ao, Asangla; Tan, Seang Lin; Holzer, Hananel

    2012-11-01

    This case study reports the first successful birth outcome following preimplantation genetic diagnosis (PGD) for a chromosome translocation in embryos generated by serial vitrification of oocytes. A couple presented to the fertility clinic with 2 years of primary infertility. The woman was diagnosed with poor ovarian reserve and her partner was diagnosed with severe oligoteratozoospermia and the reciprocal translocation 46,XY,t(1;7)(p36.1;q11.23). Following counselling, the couple opted for serial vitrification of oocytes followed by PGD. A total of 31 oocytes were obtained in five egg collection cycles over a period of 12 months and 27 metaphase-II oocytes were vitrified. Nineteen of the 27 vitrified oocytes survived warming: 14 oocytes from the vitrified group and three oocytes from the fresh cycle were fertilized by intracytoplasmic sperm injection. Eleven embryos, including three from the fresh cycle, were biopsied on day 3 post insemination. Fluorescence in-situ hybridization was performed for the specific chromosomes involved in translocation. Only two embryos from the cryopreservation cycles were diagnosed as normal/balanced, one of which was transferred on day 5 post insemination. A normal healthy female infant was born at week 42 of gestation. PMID:22995749

  1. Preimplantation genetic diagnosis to improve pregnancy outcomes in subfertility.

    PubMed

    Simpson, Joe Leigh

    2012-12-01

    Pre-implantation genetic diagnosis provides prenatal genetic diagnosis before implantation, thus allowing detection of chromosomal abnormalities and their exclusion from embryo transfer in assisted reproductive technologies. Polar body, blastomere or trophectoderm can each be used to obtain requisite genetic or embryonic DNA. Pre-implantation genetic diagnosis for excluding unbalanced translocations is well accepted, and pre-implantation genetic diagnosis aneuploidy testing to avoid repeated pregnancy losses in couples having recurrent aneuploidy is efficacious in reducing miscarriages. Controversy remains about whether pre-implantation genetic diagnosis aneuploidy testing improves take home pregnancy rates, for which reason adherence to specific indications is recommended while the issue is being adjudicated. Current recommendations are for obligatory 24 chromosome testing, most readily using array comparative genome hybridisation. PMID:22749544

  2. Multiple displacement amplification on single cell and possible PGD applications.

    PubMed

    Hellani, Ali; Coskun, Serdar; Benkhalifa, Moncef; Tbakhi, Abelghani; Sakati, Nadia; Al-Odaib, Ali; Ozand, Pinar

    2004-11-01

    Multiple displacement amplification (MDA) is a technique used in the amplification of very low amounts of DNA and reported to yield large quantities of high-quality DNA. We used MDA to amplify the whole genome directly from a single cell. The most common techniques used in PGD are PCR and fluorescent in-situ hybridization (FISH). There are many limitations to these techniques including, the number of chromosomes diagnosed for FISH or the quality of DNA issued from a single cell PCR. This report shows, for the first time, use of MDA for single cell whole genome amplification. A total of 16 short tandem repeats (STRs) were amplified successfully with a similar pattern to the genomic DNA. Furthermore, allelic drop out (ADO) derived from MDA was assessed in 40 single cells by analysing (i) heterozygosity for a known beta globin mutation (IVSI-5 C-G) and by studying (ii) the heterozygous loci present in the STRs. ADO turned out to be 10.25% for the beta globin gene sequencing and 5% for the fluorescent PCR analysis of STRs. Moreover, the amplification accuracy of MDA permitted the detection of trisomy 21 on a single cell using comparative genome hybridization-array. Altogether, these data suggest that MDA can be used for single cell molecular karyotyping and the diagnosis of any single gene disorder in PGD. PMID:15465849

  3. The ethics of using genetic engineering for sex selection.

    PubMed

    Liao, S Matthew

    2005-02-01

    It is quite likely that parents will soon be able to use genetic engineering to select the sex of their child by directly manipulating the sex of an embryo. Some might think that this method would be a more ethical method of sex selection than present technologies such as preimplantation genetic diagnosis (PGD) because, unlike PGD, it does not need to create and destroy "wrong gendered" embryos. This paper argues that those who object to present technologies on the grounds that the embryo is a person are unlikely to be persuaded by this proposal, though for different reasons. PMID:15681683

  4. A pregnancy following PGD for X-linked dominant [correction of X-linked autosomal dominant] incontinentia pigmenti (Bloch-Sulzberger syndrome): case report.

    PubMed

    Pettigrew, R; Kuo, H C; Scriven, P; Rowell, P; Pal, K; Handyside, A; Braude, P; Ogilvie, C M

    2000-12-01

    Incontinentia Pigmenti (Bloch-Sulzberger syndrome) is a rare multisystem, ectodermal disorder associated with dermatological, dental and ocular features, and in <10% of cases, severe neurological deficit. Pedigree review suggests X-linked dominance with lethality in affected males. Presentation in female carriers is variable. Following genetic counselling, a mildly affected female carrier diagnosed in infancy with a de novo mutation was referred for preimplantation sexing, unusually selecting for male gender, with an acceptance of either normality or early miscarriage in an affected male. Following standard in-vitro fertilization and embryo biopsy, fluorescence in situ hybridization (FISH) unambiguously identified two male and two female embryos. A single 8-cell, grade 4 male embryo was replaced. A positive pregnancy test was reported 2 weeks after embryo transfer, although ultrasonography failed to demonstrate a viable pregnancy. Post abortive fetal tissue karyotyping diagnosed a male fetus with trisomy 16. This is an unusual report of preimplantation genetic diagnosis (PGD) being used for selection of males in an X-linked autosomal dominant disorder and demonstrates the value of PGD where amniocentesis or chorion villus sampling followed by abortion is not acceptable to the patient. This case also demonstrates the importance of follow-up prenatal diagnosis. PMID:11098039

  5. Molecular genetic analysis of single cells.

    PubMed

    Fiorentino, Francesco

    2012-08-01

    Preimplantation genetic diagnosis (PGD) has experienced a considerable technical evolution since its first application in the early 1990s. The technology for single-cell genetic analysis has reached an extremely high level of accuracy and enabled the possibility of performing multiple diagnoses from one cell. Diagnosis of a monogenic disease can now be combined with aneuploidy screening, human leukocyte antigen typing, and DNA fingerprinting. New technologies such as microarrays are opening the way for an increasing number of serious genetic defects to be detected in preimplantation embryos. The new PGD techniques will empower patients and clinicians to screen for almost any kind of genetic problem in embryos, with the potential to change completely the manner in which parents approach and manage genetic disease. PMID:22723008

  6. Identification of novel microsatellite markers <1 Mb from the HBB gene and development of a single-tube pentadecaplex PCR panel of highly polymorphic markers for preimplantation genetic diagnosis of beta-thalassemia.

    PubMed

    Chen, Min; Tan, Arnold S C; Cheah, Felicia S H; Saw, Eugene E L; Chong, Samuel S

    2015-12-01

    Beta (?)-thalassemia is one of the most common monogenic diseases worldwide. Affected pregnancies can be avoided through preimplantation genetic diagnosis (PGD), which commonly involves customized assays to detect the different combinations of ?-globin (HBB) gene mutations present in couples, in conjunction with linkage analysis of flanking microsatellite markers. Currently, the limited number of reported closely linked markers hampers their utility in indirect linkage-based PGD for this disorder. To increase the available markers closely flanking the HBB gene, an in silico search was performed to identify all markers within 1 Mb flanking the HBB gene. Fifteen markers with potentially high polymorphism information content (PIC) and heterozygosity values were selected and optimized into a single-tube pentadecaplex PCR panel. Allele frequencies and polymorphism and heterozygosity indices of each marker were assessed in five populations. A total of 238 alleles were observed from the 15 markers. PIC was >0.7 for all markers, with expected heterozygosity and observed heterozygosity values ranging from 0.74 to 0.90 and 0.72 to 0.88, respectively. Greater than 99% of individuals were heterozygous for at least seven markers, with at least two heterozygous markers on either side of the HBB gene. The pentadecaplex marker assay also performed reliably on single cells either directly or after whole genome amplification, thus validating its use in standalone linkage-based ?-thalassemia PGD or in conjunction with HBB mutation detection. PMID:26331357

  7. [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

  8. The Performance of Whole Genome Amplification Methods and Next-Generation Sequencing for Pre-Implantation Genetic Diagnosis of Chromosomal Abnormalities.

    PubMed

    Li, Na; Wang, Li; Wang, Hui; Ma, Minyue; Wang, Xiaohong; Li, Yi; Zhang, Wenke; Zhang, Jianguang; Cram, David S; Yao, Yuanqing

    2015-04-20

    Reliable and accurate pre-implantation genetic diagnosis (PGD) of patient's embryos by next-generation sequencing (NGS) is dependent on efficient whole genome amplification (WGA) of a representative biopsy sample. However, the performance of the current state of the art WGA methods has not been evaluated for sequencing. Using low template DNA (15 pg) and single cells, we showed that the two PCR-based WGA systems SurePlex and MALBAC are superior to the REPLI-g WGA multiple displacement amplification (MDA) system in terms of consistent and reproducible genome coverage and sequence bias across the 24 chromosomes, allowing better normalization of test to reference sequencing data. When copy number variation sequencing (CNV-Seq) was applied to single cell WGA products derived by either SurePlex or MALBAC amplification, we showed that known disease CNVs in the range of 3-15 Mb could be reliably and accurately detected at the correct genomic positions. These findings indicate that our CNV-Seq pipeline incorporating either SurePlex or MALBAC as the key initial WGA step is a powerful methodology for clinical PGD to identify euploid embryos in a patient's cohort for uterine transplantation. PMID:25953353

  9. 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

  10. Genetics for the diagnosis and treatment of mesenchymal tumors.

    PubMed

    Lasota, Jerzy; Fanburg-Smith, Julie C

    2007-09-01

    Cytogenetics and molecular genetics play an important role in the diagnosis of soft tissue and bone mesenchymal tumors. This update focuses on cytogenetic and molecular genetic techniques commonly used for evaluation of mesenchymal tumors, including karyotyping, fluorescent in situ hybridization, and polymerase chain reaction. Examples of different techniques, inherent technical problems, and interpretation of the results are discussed. Additionally, limitations related to the type of material available for genotyping (fresh, frozen, or formalin-fixed paraffin-embedded tissue) are covered. Cytogenetic and molecular genetic alterations identified in various mesenchymal tumors are often valuable for diagnosis, prognosis, and treatment strategies. PMID:18260032

  11. 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

  12. The importance of genetic diagnosis for Duchenne muscular dystrophy

    PubMed Central

    Aartsma-Rus, Annemieke; Ginjaar, Ieke B; Bushby, Kate

    2016-01-01

    Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are caused by mutations in the dystrophin-encoding DMD gene. Large deletions and duplications are most common, but small mutations have been found as well. Having a correct diagnosis is important for family planning and providing proper care to patients according to published guidelines. With mutation-specific therapies under development for DMD, a correct diagnosis is now also important for assessing whether patients are eligible for treatments. This review discusses different mutations causing DMD, diagnostic techniques available for making a genetic diagnosis for children suspected of DMD and the importance of having a specific genetic diagnosis in the context of emerging genetic therapies for DMD. PMID:26754139

  13. The importance of genetic diagnosis for Duchenne muscular dystrophy.

    PubMed

    Aartsma-Rus, Annemieke; Ginjaar, Ieke B; Bushby, Kate

    2016-03-01

    Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are caused by mutations in the dystrophin-encoding DMD gene. Large deletions and duplications are most common, but small mutations have been found as well. Having a correct diagnosis is important for family planning and providing proper care to patients according to published guidelines. With mutation-specific therapies under development for DMD, a correct diagnosis is now also important for assessing whether patients are eligible for treatments. This review discusses different mutations causing DMD, diagnostic techniques available for making a genetic diagnosis for children suspected of DMD and the importance of having a specific genetic diagnosis in the context of emerging genetic therapies for DMD. PMID:26754139

  14. Genetic Diagnosis and Testing in Clinical Practice

    PubMed Central

    McPherson, Elizabeth

    2006-01-01

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

  15. 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

  16. Screening and genetic diagnosis of haemoglobin disorders.

    PubMed

    Old, J M

    2003-03-01

    The inherited haemoglobinopathies are large group of disorders that include the thalassaemias and sickle cell disease. Carrier detection methods must be able to detect alpha-, beta- and deltabeta-thalassaemias, HPFH disorders and haemoglobin variants. Carrier diagnosis involves the accurate measurement of MCH, MCV, Hb A(2) and Hb F values in combination with an understanding of the haematological characteristics of the different types of thalassaemia genes and their interactions. The majority of the common thalassaemia mutations and abnormal haemoglobins can be identified by PCR-based techniques. The main applications of molecular analysis for carrier diagnosis are: the analysis of alpha-thalassaemia mutations by gap-PCR to discriminate between heterozygous alpha-thalassaemia and homozygous alpha-thalassaemia; the identification of beta-thalassaemia mutations for patients requiring prenatal diagnosis and for the prediction of the severity of the clinical phenotype of homozygous beta-thalassaemia; to discriminate between deltabeta-thalassaemia and HPFH deletions by gap-PCR. PMID:12490210

  17. Preimplantation genetic risk reduction: a new dilemma in the era of chromosomal microarrays and exome sequencing.

    PubMed

    Altarescu, Gheona; Beeri, Rachel; Lazer-Derbeko, Galit; Eldar-Geva, Talia; Steinberg, Avraham; Levy-Lahad, Ephrat; Renbaum, Paul

    2015-11-01

    New technologies are revealing genetic variants of unknown significance (VUS), raising questions about the indications that call for preimplanation genetic diagnosis (PGD). Two couples requesting PGD for VUS are presented. The first couple requested PGD for Lynch syndrome. Whole exome sequencing identified in a healthy male with a family history of Lynch-associated tumours, a MLH1 missense variant. The variant had not been reported as pathogenic, but was predicted as damaging by algorithms. The second couple had a child diagnosed with pervasive developmental disorder and intellectual disability, carrying a microduplication on chr:Xp.22.3, and a microdeletion on chr:17q21.31. The maternally inherited X linked microduplication was also present in the mother's healthy brother and daughter, whereas the chr17 microdeletion was a de-novo event. As chromosomal microarrays and whole-exome sequencing are becoming standard tests, couples are requesting PGD for these VUS. The risk of possible genetic diseases can be reduced by carrying out PGD for uncertain findings, yet will inevitably lead to the birth of affected children despite the transfer of embryos that are not carriers of the familial variants. Findings of unknown significance demand urgent discussion and guidelines for their use as a risk-reduction measure in the preimplantation setting. PMID:26380867

  18. New molecular genetic tests in the diagnosis of heart disease.

    PubMed

    Lebo, Matthew S; Baxter, Samantha M

    2014-03-01

    With the increasing use of next-generation sequencing applications, there has been an increase in identification of genetic causes of cardiac disease. This technology has also enabled the transition of these genes into the clinical setting and the rapid growth of large gene tests for the diagnosis of heart disorders. The ability to combine tests to include similar, but distinct, diseases has shown that many genes can be responsible for a wide variety of both syndromic and nonsyndromic disorders. This article discusses the current state of molecular genetic diagnosis for cardiac disorders, focusing on diseases with mendelian inheritance. PMID:24507793

  19. Genetics: update on prenatal screening and diagnosis.

    PubMed

    Evans, Mark I; Andriole, Stephanie; Evans, Shara M

    2015-06-01

    There have been tremendous advances in the ability to screen for the "odds" of having a genetic disorder (both mendelian and chromosomal). With microarray analyses on fetal tissue now showing a minimum risk for any pregnancy being at least 1 in 150 and ultimately greater than 1%, it is thought that all patients, regardless of age, should be offered chorionic villus sampling/amniocentesis and microarray analysis. As sequencing techniques replace other laboratory methods, the only question will be whether these tests are performed on villi, amniotic fluid cells, or maternal blood. PMID:26002161

  20. Genetic testing and early diagnosis and intervention: boon or burden?

    PubMed Central

    Hepburn, E R

    1996-01-01

    The possibility of early diagnosis and intervention is radically changed by the advent of genetic testing. The recent report of the Nuffield Council on Bioethics is timely and helpful. I have suggested, that not only the severity of the disability indicated by genetic information, and the accuracy of the data, ought to govern the approach to the implementation of screening for genetic disorders. In addition, assessment of the value of the information to those involved should be considered. The efficacy of the available therapeutic measures, combined with the prognostic data are important indices of the value of the information. These measures fall into three categories and thus indicate that three different courses of intervention may be appropriate. Three approaches to diagnosis and intervention are then outlined, drawing on the experience of various clinical initiatives. PMID:8731537

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

    PubMed

    Biazotti, Maria Cristina Santoro; Pinto Junior, Walter; Albuquerque, Maria Cecília Romano Maciel de; 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

  2. 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

  3. Validation of array comparative genome hybridization for diagnosis of translocations in preimplantation human embryos.

    PubMed

    Colls, Pere; Escudero, Tomas; Fischer, Jill; Cekleniak, Natalie A; Ben-Ozer, Snunit; Meyer, Bill; Damien, Miguel; Grifo, Jamie A; Hershlag, Avner; Munn, Santiago

    2012-06-01

    Fluorescent in-situ hybridization (FISH) for preimplantation genetic diagnosis (PGD) of structural chromosome abnormalities has limitations, including carrier testing, inconclusive results and limited aneuploidy screening. Array comparative genome hybridization (CGH) was used in PGD cases for translocations. Unbalances could be identified if three fragments were detectable. Smallest detectable fragments were ?6 Mbp and ?5 Mbp for blastomeres and trophectoderm, respectively. Cases in which three or more fragments were detectable by array CGH underwent PGD by FISH and concordance was obtained in 53/54 (98.1%). The error rate for array CGH was 1.9% (1/54). Of 402 embryos analysed, 81 were normal or balanced, 92 unbalanced but euploid, 123 unbalanced and aneuploid and 106 balanced but aneuploid. FISH with additional probes to detect other aneuploidies would have missed 28 abnormal embryos in the reciprocal group and 10 in the Robertsonian group. PGD cases (926) were retrospectively reviewed for reciprocal translocations performed by FISH to identify which could have been analysed by array CGH. This study validates array CGH in PGD for translocations and shows that it can identify all embryos with unbalanced reciprocal and Robertsonian translocations. Array CGH is a better approach than FISH since it allows simultaneous screening of all chromosomes for aneuploidy. PMID:22503275

  4. Conversion and non-conversion approach to preimplantation diagnosis for chromosomal rearrangements in 475 cycles.

    PubMed

    Kuliev, Anver; Janzen, Jeanine Cieslak; Zlatopolsky, Zev; Kirillova, Irina; Ilkevitch, Yury; Verlinsky, Yury

    2010-07-01

    Due to the limitations of preimplantation genetic diagnosis (PGD) for chromosomal rearrangements by interphase fluorescent in-situ hybridization (FISH) analysis, a method for obtaining chromosomes from single blastomeres was introduced by their fusion with enucleated or intact mouse zygotes, followed by FISH analysis of the resulting heterokaryons. Although this allowed a significant improvement in the accuracy of testing of both maternally and paternally derived translocations, it is still labour intensive and requires the availability of fertilized mouse oocytes, also creating ethical issues related to the formation of interspecies heterokaryons. This method was modified with a chemical conversion procedure that has now been clinically applied for the first time on 877 embryos from PGD cycles for chromosomal rearrangements and has become the method of choice for performing PGD for structural rearrangements. This is presented within the context of overall experience of 475 PGD cycles for translocations with pre-selection and transfer of balanced or normal embryos in 342 (72%) of these cycles, which resulted in 131 clinical pregnancies (38%), with healthy deliveries of 113 unaffected children. The spontaneous abortion rate in these cycles was as low as 17%, which confirms an almost five-fold reduction of spontaneous abortion rate following PGD for chromosomal rearrangements. PMID:20570563

  5. Single cell co-amplification of polymorphic markers for the indirect preimplantation genetic diagnosis of hemophilia A, X-linked adrenoleukodystrophy, X-linked hydrocephalus and incontinentia pigmenti loci on Xq28.

    PubMed

    Gigarel, Nadine; Frydman, Nelly; Burlet, Philippe; Kerbrat, Violaine; Steffann, Julie; Frydman, René; Munnich, Arnold; Ray, Pierre F

    2004-02-01

    Preimplantation genetic diagnosis (PGD) first consisted of the selection of female embryos for patients at risk of transmitting X-linked recessive diseases. Advances in molecular biology now allow the specific diagnosis of almost any Mendelian disease. For families with an identified X-linked recessive disease-causing mutation, non-specific diagnosis by sex identification can be considered as a sub-standard method, since it involves the unnecessary disposal of healthy male embryos and reduces success rate by diminishing the pool of embryos eligible for transfer. The most telomeric part of the X-chromosome long arm is a highly gene-rich region encompassing disease genes such as haemophilia A, X-linked adrenoleukodystrophy, X-linked hydrocephalus and incontinentia pigmenti. We developed five single-cell triplex amplification protocols with microsatellite markers DXS1073, DXS9901 (BGN), G6PD, DXS1108, DXS8087 and F8C-IVS13 located in this Xq terminal region. These tests allow the diagnosis of all diseases previously mentioned providing that the genetic material allowing the identification of the morbid allele can be obtained. The choice of the microsatellite set to use depends on the localisation of the gene responsible for the diagnosed pathology and on the informativity of the markers in particular families. Single-cell amplification efficiency was assessed on single lymphocytes. Amplification rate of the different markers ranged from 89-97% with an allele drop out rate of 2-19%. So far PGD has been carried out for three carrier females at risk of transmitting X-linked adrenoleukodystrophy, X-linked hydrocephalus and hemophilia A. The latter one is now pregnant. PMID:14673643

  6. Critical issues for dentistry: PGD program directors respond.

    PubMed

    Atchison, Kathryn A; Cheffetz, Susan E

    2002-06-01

    Discussion of critical issues facing postgraduate education in general dentistry (PGD) and dental education in general has been intense in the past decade. This study reports on critical issues raised by directors of PGD programs that may help direct future research and action within dental education and the larger profession. The analysis reports responses to an open-ended question sent to all U.S. PGD program directors regarding critical issues facing their training programs. Of 212 surveys, 169 program directors submitted written responses regarding critical issues. Twelve unique themes were identified: lack of postdoctoral applicants (two subthemes were high student debt and students' preference for private practice); student quality; professionalism and attitudes; number of postdoctoral positions; lack of funding; quality of facilities; special patient care; program curriculum; educator issues; mandatory or encouraged PGD year; value of dental program; and dentist shortage. Significant differences between AEGD and GPR directors were observed for two of the twelve areas: high student debt and value of dental program. The study provided insight into the thoughts of a large proportion of the U.S. PGD program directors "in the trenches." Some consideration of allowable expenses may be needed to align federal training support to best address program director needs. PMID:12117095

  7. PGD training and its impact on general dentist practice patterns.

    PubMed

    Atchison, Kathryn A; Mito, Ronald S; Rosenberg, Dara Jean; Lefever, Karen H; Lin, Sylvia; Engelhardt, Rita

    2002-12-01

    This study compares the practice patterns of general dentists with and without formal advanced training in AGED or GPR programs. The UCLA School of Dentistry surveyed a random selection of dentists from graduating years 1989, 1993, and 1997 as part of a Health Resources Services Administration (HRSA)-supported evaluation of the impact of federal funding on postgraduate general dentistry (PGD) programs. Using a sample drawn by the American Dental Association (ADA), 6,725 dentists were surveyed about their practice, advanced training, patients served, and services provided. Of the 2,029 dentists (30 percent) who responded, 49 percent were practicing dentists with no formal advanced training in general dentistry or one of the eight ADA specialties; 7 percent had Advanced Education in General Dentistry (AEGD) experience; 20 percent trained in a General Practice Residency (GPR); and 24 percent were specialists. Additionally, 7 percent of respondents had PGD training and a clinical specialty. GPR-trained dentists were significantly more likely to be on a hospital staff and to treat medically compromised patients even after ten years of practice. PGD dentists were less likely to seek specialty training. Major reasons for seeking PGD training were increasing treatment speed, learning to treat medically compromised patients, and wanting hospital experience. Primary reasons for not selecting training were starting a practice and having a great practice opportunity. Our conclusion is that PGD training has an enduring impact on practice patterns and improves access to dental care for underserved populations. PMID:12521061

  8. Confirmed versus suspected: The social significance of a genetic or non-genetic diagnosis of mitochondrial disease.

    PubMed

    Krieg, Elizabeth; Calderwood, Laurel; Campion, MaryAnn; Krepkovich, Katherine E

    2016-05-01

    This study assessed attitudes and beliefs regarding the importance of a genetic versus non-genetic diagnosis within the mitochondrial disease community. Survey respondents were categorized into two groups - those with a genetic diagnosis, and those with a non-genetic diagnosis of mitochondrial disease. We found that while both groups perceive problems with the support available to adult mitochondrial disease patients, the non-genetic group experiences less medical and social support due to lack of a definitive diagnosis. Understanding the efficacy of existing resources for mitochondrial disease sub-groups will allow for the development or improvement of resources designed to meet patient needs. PMID:27017995

  9. 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.

  10. Molecular diagnosis of genetic iron-overload disorders.

    PubMed

    Brissot, Pierre; Bardou-Jacquet, Edouard; Troadec, Marie-Bérengère; Mosser, Annick; Island, Marie-Laure; Detivaud, Lénaïck; Loréal, Olivier; Jouanolle, Anne-Marie

    2010-09-01

    Genetic iron overload has long been confined to the picture of classical hemochromatosis related to the HFE C282Y mutation (type 1 hemochromatosis). C282Y homozygosity affects approximately three people out of 1000 of the Caucasian population, representing one of the most frequent genetic predispositions. It has, however, rapidly become clear that the HFE C282Y mutation is not the sole culprit in genetic iron overload. Several novel mutations in HFE and other genes have been discovered and related to various entities, which are now known as types 2, 3 and 4 hemochromatosis. These diseases are far less frequent than the classical type 1 hemochromatosis but, by contrast, are not limited to the Caucasian population. Molecular diagnosis obviously plays a key role in the diagnostic strategy. In the future, it will undoubtedly enable not only identification of new diagnostic markers, but also provide potential molecular targets for pathophysiologically based innovative therapeutic approaches. PMID:20843199

  11. 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.

  12. Rapid molecular genetic diagnosis of hypertrophic cardiomyopathy by semiconductor sequencing

    PubMed Central

    2014-01-01

    Background Rapidly determining the complex genetic basis of Hypertrophic cardiomyopathy (HCM) is vital to better understanding and optimally managing this common polygenetic cardiovascular disease. Methods A rapid custom Ion-amplicon-resequencing assay, covering 30 commonly affected genes of HCM, was developed and validated in 120 unrelated patients with HCM to facilitate genetic diagnosis of this disease. With this HCM-specific panel and only 20 ng of input genomic DNA, physicians can, for the first time, go from blood samples to variants within a single day. Results On average, this approach gained 595628 mapped reads per sample, 95.51% reads on target (64.06 kb), 490-fold base coverage depth and 93.24% uniformity of base coverage in CDS regions of the 30 HCM genes. After validation, we detected underlying pathogenic variants in 87% (104 of 120) samples. Tested seven randomly selected HCM genes in eight samples by Sanger sequencing, the sensitivity and false-positive-rate of this HCM panel was 100% and 5%, respectively. Conclusions This Ion amplicon HCM resequencing assay provides a currently most rapid, comprehensive, cost-effective and reliable measure for genetic diagnosis of HCM in routinely obtained samples. PMID:24938736

  13. Development and clinical application of a strategy for preimplantation genetic diagnosis of single gene disorders combined with HLA matching.

    PubMed

    Fiorentino, F; Biricik, A; Karadayi, H; Berkil, H; Karlikaya, G; Sertyel, S; Podini, D; Baldi, M; Magli, M C; Gianaroli, L; Kahraman, S

    2004-06-01

    Preimplantation HLA matching has recently emerged as a tool for couples desiring to conceive a potential donor progeny for transplantation in a sibling with a life-threatening disorder. In this paper we describe a strategy optimized for preimplantation genetic diagnosis (PGD) of haemoglobinopathies combined with HLA matching. This procedure involves a minisequencing-based genotyping of HLA regions A, B, C and DRB combined with mutation analysis of the gene regions involved by mutation. Analysis of at least eight polymorphic short tandem repeat (STR) markers scattered through the HLA complex has also been included to detect potential contamination and crossing-over occurrences between HLA genes. The above assay can also be used for preimplantation HLA matching as a primary indication. The strategy was clinically applied for HLA matching in 17 cycles (14 for beta-thalassaemia, one for Wiscott-Aldrich syndrome and two for leukaemia). A reliable HLA genotype was achieved in 255/266 (95.9%) of the blastomeres. In total, 22 (14.8%) embryos were obtained that were HLA-matched with the affected siblings, 14 (9.4%) of which were unaffected and transferred back to the patients. Four clinical pregnancies were obtained, three of which (one twin, two singletons) are ongoing and were confirmed as healthy and HLA-identical with the affected children. Minisequencing-based HLA typing combined with HLA STR haplotyping has been shown to be a reliable strategy for preimplantation HLA matching. The major advantage of this approach is that the validation of a single assay can be done once and then used for the majority of the patients, reducing notably time needed for preclinical set-up of each case. PMID:15044607

  14. 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

  15. 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

  16. New canine models of copper toxicosis: diagnosis, treatment, and genetics.

    PubMed

    Fieten, Hille; Penning, Louis C; Leegwater, Peter A J; Rothuizen, Jan

    2014-05-01

    The One Health principle recognizes that human health, animal health, and environmental health are inextricably linked. An excellent example is the study of naturally occurring copper toxicosis in dogs to help understand human disorders of copper metabolism. Besides the Bedlington terrier, where copper toxicosis is caused by a mutation in the COMMD1 gene, more complex hereditary forms of copper-associated hepatitis were recognized recently in other dog breeds. The Labrador retriever is one such breed, where an interplay between genetic susceptibility and exposure to copper lead to clinical copper toxicosis. Purebred dog populations are ideal for gene mapping studies, and because genes involved in copper metabolism are highly conserved across species, newly identified gene mutations in the dog may help unravel the genetic complexity of different human forms of copper toxicosis. Furthermore, increasing knowledge with respect to diagnosis and treatment strategies will benefit both species. PMID:24758744

  17. 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;…

  18. 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;

  19. 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

  20. Analysis of the first polar body: preconception genetic diagnosis.

    PubMed

    Verlinsky, Y; Ginsberg, N; Lifchez, A; Valle, J; Moise, J; Strom, C M

    1990-10-01

    In women who are heterozygous for a genetic disease, genetic analysis of the first polar body allows the identification of oocytes that contain the maternal unaffected gene. These oocytes can be fertilized and transferred to the mother without risk of establishing a pregnancy with a genetically abnormal embryo. We have demonstrated that removal of the first polar body has no effect on subsequent fertilization rates or embryonic growth to the blastocyst stage. We have developed a PCR technique to successfully analyze the PI type Z and PI type M genotypes of alpha-1-antitrypsin deficiency and applied this technique for a couple at risk for PI type ZZ alpha-1-antitrypsin deficiency. After standard IVF treatment to stimulate multiple follicle development, eight oocytes were aspirated transvaginally. Polar bodies were removed by micromanipulation from seven oocytes and fertilization occurred in six cases. PCR analysis was successful in five oocytes. One was PI type M, two were PI type Z and two were heterozygous MZ due to crossing over. Embryos from the two oocytes containing the unaffected gene (polar body PI type Z) were transferred in the same cycle 48 h after insemination. No pregnancy was established. The accuracy of the polar body diagnosis was confirmed by polymerase chain reaction (PCR) analysis of an oocyte that failed to fertilize. PMID:2266156

  1. Preimplantation genetic diagnosis for gender selection for family balancing: a view from India.

    PubMed

    Malpani, A; Malpani, A

    2002-01-01

    The use of PGD for sex selection arouses considerable debate, especially in countries like India that have a marked cultural preference for boys. It is argued that using PGD for sex selection is a treatment option that can be ethically offered to couples who desire to use this technology to plan their families. PMID:12470342

  2. Genetic diagnosis and prognosis of Alzheimer's disease: challenges and opportunities.

    PubMed

    Reitz, Christiane

    2015-03-01

    Alzheimer's disease (AD), the most common form of dementia in western societies, is a pathologically and clinically heterogeneous disease with a strong genetic component. The recent advances in high-throughput genome technologies allowing for the rapid analysis of millions of polymorphisms in thousands of subjects has significantly advanced our understanding of the genomic underpinnings of AD susceptibility. During the last 5 years, genome-wide association and whole-exome- and whole-genome sequencing studies have mapped more than 20 disease-associated loci, providing insights into the molecular pathways involved in AD pathogenesis and hinting at potential novel therapeutic targets. This review article summarizes the challenges and opportunities of when using genomic information for the diagnosis and prognosis of AD. PMID:25634383

  3. Discussing options between patients and health care professionals in genetic diagnosis: ethical and legal criteria

    PubMed Central

    Nicolás, Pilar

    2007-01-01

    The specific characteristics of genetic data lead to ethical-legal conflicts in the framework of genetic diagnosis. Several international organisations, including UNESCO and the Council of Europe, have enacted rules referring to the use of genetic information. This paper discusses possible legal and ethical criteria that could be used in genetic testing. PMID:19725990

  4. 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

  5. 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

  6. 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

  7. 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

  8. Parents’ experiences of receiving their child’s genetic diagnosis: A qualitative study to inform clinical genetics practice

    PubMed Central

    Ashtiani, Setareh; Makela, Nancy; Carrion, Prescilla; Austin, Jehannine

    2014-01-01

    Purpose Little is currently known about how parents experience the medical genetics appointment at which their child receives a genetic diagnosis. Methods We conducted semi-structured in-person interviews with 13 parents of 10 index children to explore their experience in the medical genetics appointment in which they received their child’s genetic diagnosis. Guided by grounded theory, we used a constant comparative approach to data analysis, and the transcribed interviews were coded and sorted, and thematic categories identified. Results 61.5% of parents experienced the diagnosis session as negative, 23% felt the experience was positive, and 15.5% were ambivalent. Receiving emotional support, an outline of the follow-up plans, and messages of hope and perspective during the session seemed to positively influence parents’ experience, while feeling that their role was as a passive receiver of information and using difficult medical terminology negatively influenced parents’ overall experience. Parental preparedness for the information, and the parents’ emotional reaction to the diagnosis were also factors that influenced the parental experience. Few participants understood the role of the genetic counselor. Conclusion Our results provide in-depth insight into the parental experience of the pediatric medical genetics diagnosis session. We propose a mechanism through which parental experience shapes their perception of the medical genetics session. PMID:24706543

  9. Genetic testing and counseling in the diagnosis and management of young-onset dementias.

    PubMed

    Goldman, Jill S

    2015-06-01

    Young-onset dementia is hereditary, multifactorial, or sporadic. The most common hereditary dementias include Alzheimer disease, frontotemporal degeneration, Huntington disease, prion diseases, and cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Careful attainment of family history assists with diagnosis and determining the likelihood of a genetic cause, and can direct genetic testing. The type of genetic testing depends on confidence of the diagnosis, patient's and affected relatives' symptoms, and the number of disease genes. Single gene, disease-specific gene panels, and large dementia panels are available. Genetic counseling should be given and informed consent obtained. Predictive testing follows the Huntington disease protocol. PMID:25998117

  10. Direct diagnosis of Wilson disease by molecular genetics.

    PubMed

    Caprai, Silvia; Loudianos, Georgios; Massei, Francesco; Gori, Laura; Lovicu, Mario; Maggiore, Giuseppe

    2006-01-01

    In 3 children with chronic liver disease, although multiple studies of copper metabolism were normal, which made the diagnosis of Wilson disease unlikely, analysis of ATP7B gene showed disease causing mutations in all. Molecular diagnosis should be considered in children with enigmatic liver disease, especially those with features of nonalcoholic fatty liver disease. PMID:16423615

  11. Attitudes to reproductive genetic testing in women who had a positive BRCA test before having children: a qualitative analysis.

    PubMed

    Ormondroyd, Elizabeth; Donnelly, Louise; Moynihan, Clare; Savona, Cornelie; Bancroft, Elizabeth; Evans, D Gareth; Eeles, Rosalind; Lavery, Stuart; Watson, Maggie

    2012-01-01

    The scope of conditions for which preimplantation genetic diagnosis (PGD) is licensed has recently been expanded in the United Kingdom to include genetic predisposition to adult-onset cancer. This qualitative interview study explores reproductive decision making, knowledge of and attitudes to reproductive genetic testing (prenatal diagnosis and PGD) with 25 women aged 18-45 years who received a positive BRCA test in the United Kingdom before having children. In this cohort of younger women, BRCA testing was motivated by risk management decisions; for some, BRCA status has affected their later decisions about having children. The perceived severity of hereditary breast/ovarian cancer (HBOC) influences thoughts about passing on the mutation to children and willingness to consider reproductive genetic testing, but most participants do not believe HBOC is a condition for which pregnancy termination is justified. PGD is considered more acceptable and advantageous because it would prevent transmission to future generations, but women have concerns about selecting embryos and the fact that they and affected family members would not have been selected. Women would also be deterred by the need to undergo in vitro fertilisation (IVF) and ovarian stimulation for PGD. Awareness of reproductive testing options was very variable among the cohort. The findings highlight the complexities of reproductive decision making for young women who knowingly carry a BRCA mutation, and the dilemmas inherent to reproductive genetic testing when the condition being tested for also affects a prospective parent. Counselling and psychological support for BRCA-positive women and couples concerning reproductive options are strongly indicated. PMID:21811309

  12. Attitudes to reproductive genetic testing in women who had a positive BRCA test before having children: a qualitative analysis

    PubMed Central

    Ormondroyd, Elizabeth; Donnelly, Louise; Moynihan, Clare; Savona, Cornelie; Bancroft, Elizabeth; Evans, D Gareth; Eeles, Rosalind; Lavery, Stuart; Watson, Maggie

    2012-01-01

    The scope of conditions for which preimplantation genetic diagnosis (PGD) is licensed has recently been expanded in the United Kingdom to include genetic predisposition to adult-onset cancer. This qualitative interview study explores reproductive decision making, knowledge of and attitudes to reproductive genetic testing (prenatal diagnosis and PGD) with 25 women aged 1845 years who received a positive BRCA test in the United Kingdom before having children. In this cohort of younger women, BRCA testing was motivated by risk management decisions; for some, BRCA status has affected their later decisions about having children. The perceived severity of hereditary breast/ovarian cancer (HBOC) influences thoughts about passing on the mutation to children and willingness to consider reproductive genetic testing, but most participants do not believe HBOC is a condition for which pregnancy termination is justified. PGD is considered more acceptable and advantageous because it would prevent transmission to future generations, but women have concerns about selecting embryos and the fact that they and affected family members would not have been selected. Women would also be deterred by the need to undergo in vitro fertilisation (IVF) and ovarian stimulation for PGD. Awareness of reproductive testing options was very variable among the cohort. The findings highlight the complexities of reproductive decision making for young women who knowingly carry a BRCA mutation, and the dilemmas inherent to reproductive genetic testing when the condition being tested for also affects a prospective parent. Counselling and psychological support for BRCA-positive women and couples concerning reproductive options are strongly indicated. PMID:21811309

  13. 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

  14. 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

  15. Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development

    PubMed Central

    Arboleda, VA; Lee, H; Sánchez, FJ; Délot, EC; Sandberg, DE; Grody, WW; Nelson, SF; Vilain, E

    2013-01-01

    Disorders of sex development (DSD) are rare disorders in which there is discordance between chromosomal, gonadal, and phenotypic sex. Only a minority of patients clinically diagnosed with DSD obtains a molecular diagnosis, leaving a large gap in our understanding of the prevalence, management, and outcomes in affected patients. We created a novel DSD-genetic diagnostic tool, in which sex development genes are captured using RNA probes and undergo massively parallel sequencing. In the pilot group of 14 patients, we determined sex chromosome dosage, copy number variation, and gene mutations. In the patients with a known genetic diagnosis (obtained either on a clinical or research basis), this test identified the molecular cause in 100% (7/7) of patients. In patients in whom no molecular diagnosis had been made, this tool identified a genetic diagnosis in two of seven patients. Targeted sequencing of genes representing a specific spectrum of disorders can result in a higher rate of genetic diagnoses than current diagnostic approaches. Our DSD diagnostic tool provides for first time, in a single blood test, a comprehensive genetic diagnosis in patients presenting with a wide range of urogenital anomalies. PMID:22435390

  16. A decision tree for genetic diagnosis of hereditary periodic fever in unselected patients

    PubMed Central

    Federici, L; Rittore‐Domingo, C; Koné‐Paut, I; Jorgensen, C; Rodière, M; Quellec, A Le; Touitou, I

    2006-01-01

    Background The diagnostic value of molecular analysis of the familial Mediterranean fever (FMF) gene (Mediterranean fever (MEFV)) has been well established only in patients selected on the basis of ethnic background or clinical criteria. Genetic diagnosis for other hereditary periodic fever syndromes has been poorly evaluated. Objective To determine the diagnostic contribution of genetic tests for hereditary periodic syndromes in a large, unselected series of patients. Methods A retrospective study was conducted on 1941 patients referred to us for FMF genetic tests between 1997 and 2005. MEFV genotypes were compared with clinical data to appraise criteria for FMF diagnosis. Genetic tests for tumour necrosis factor receptor‐associated periodic syndrome (TRAPS), hyperimmunoglobulinaemia D syndrome (HIDS) and cryopyrin‐associated periodic syndromes (CAPS) were also reviewed. Results 71% of the 1574 patients with enough data had a clinical diagnosis of FMF according to the widely used Israeli criteria. Two MEFV mutations were found in only 409 patients of this subgroup (sensitivity = 37%) and in 15 (3.3%) of the patients with an improbable clinical diagnosis of FMF (specificity = 97%). Molecular diagnosis for alternate hereditary periodic syndromes was carried out in 456 of the patients having a non‐conclusive FMF genetic test. A positive diagnosis was obtained in 31 of these patients (TRAPS (n = 19), HIDS (n = 4) and CAPS (n = 8)). Conclusions First‐line MEFV mutation screening in patients with clinically typical FMF may be appropriate only in particular areas. To optimise genetic diagnosis, we propose a decision tree, which, with the advice of an expert practitioner, could help redirect test indications towards non‐FMF hereditary periodic syndromes. PMID:16707534

  17. Preimplantation Genetic Testing in the 21st Century: Uncharted Territory

    PubMed Central

    Brezina, Paul R.

    2013-01-01

    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

  18. Some Aids in the Diagnosis of Genetic Disorders

    PubMed Central

    Chute, A. L.

    1965-01-01

    Disorders of genetic origin may cause morphological or metabolic disturbances. A number of recognized screening procedures, e.g. palm printing, buccal smears and paper chromatography, are useful in the recognition of these disorders. Additional procedures for more detailed analysis of the genetic defects, e.g. aminoacid analysis, gas chromatography and chromosome analysis, have been developed and are employed in specialized centres. ImagesFig. 1Fig. 3Fig. 4Fig. 5aFig. 5bFig. 6aFig. 6bFig. 7aFig. 7b PMID:14328042

  19. Recent advances in prenatal screening and diagnosis of genetic disorders.

    PubMed

    Bozzette, Maryann

    2002-11-01

    In any pregnancy, there is an approximate 3% to 5% chance that a fetal complication will occur. The most familiar prenatal diagnostics cannot be performed until the fetus is well into gestation, and most involve invasive procedures along with their inherent risks. In light of these facts, many noninvasive prenatal screening and diagnostic tests have been developed, the newest using recombinant deoxyribonucleic acid (DNA) technology in the examination of fetal cells. Through these procedures, genetic coding errors and chromosomal disruptions may be detected. This article discusses the currently available prenatal and screening diagnostic tests for genetic disorders with a focus on the latest technology. PMID:12473913

  20. 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 diagnosis experience was also significantly associated with a more negative child disclosure experience. Conclusions As expected this study highlights how difficult most parents find the diagnosis experience. Importantly, the data indicates that the personal experiences the parents have can have a long-term impact on how well they cope with telling their child about the diagnosis. It is important for clinicians to consider the long-term ramifications of the diagnosis experience and give the parents opportunities; through, for instance, psychoeducation to prepare for telling their child about the diagnosis. Further research is warranted to explore what type of information would be useful for parents to receive. PMID:25059276

  1. Combined Genetic and High-Throughput Strategies for Molecular Diagnosis of Inherited Retinal Dystrophies

    PubMed Central

    de Castro-Mir, Marta; Pomares, Esther; Lors-Motta, Laura; Tonda, Raul; Dopazo, Joaqun; Marfany, Gemma; Gonzlez-Duarte, Roser

    2014-01-01

    Most diagnostic laboratories are confronted with the increasing demand for molecular diagnosis from patients and families and the ever-increasing genetic heterogeneity of visual disorders. Concerning Retinal Dystrophies (RD), almost 200 causative genes have been reported to date, and most families carry private mutations. We aimed to approach RD genetic diagnosis using all the available genetic information to prioritize candidates for mutational screening, and then restrict the number of cases to be analyzed by massive sequencing. We constructed and optimized a comprehensive cosegregation RD-chip based on SNP genotyping and haplotype analysis. The RD-chip allows to genotype 768 selected SNPs (closely linked to 100 RD causative genes) in a single cost-, time-effective step. Full diagnosis was attained in 17/36 Spanish pedigrees, yielding 12 new and 12 previously reported mutations in 9 RD genes. The most frequently mutated genes were USH2A and CRB1. Notably, RD3up to now only associated to Leber Congenital Amaurosis was identified as causative of Retinitis Pigmentosa. The main assets of the RD-chip are: i) the robustness of the genetic information that underscores the most probable candidates, ii) the invaluable clues in cases of shared haplotypes, which are indicative of a common founder effect, and iii) the detection of extended haplotypes over closely mapping genes, which substantiates cosegregation, although the assumptions in which the genetic analysis is based could exceptionally lead astray. The combination of the genetic approach with whole exome sequencing (WES) greatly increases the diagnosis efficiency, and revealed novel mutations in USH2A and GUCY2D. Overall, the RD-chip diagnosis efficiency ranges from 16% in dominant, to 80% in consanguineous recessive pedigrees, with an average of 47%, well within the upper range of massive sequencing approaches, highlighting the validity of this time- and cost-effective approach whilst high-throughput methodologies become amenable for routine diagnosis in medium sized labs. PMID:24516651

  2. Combined genetic and high-throughput strategies for molecular diagnosis of inherited retinal dystrophies.

    PubMed

    de Castro-Miró, Marta; Pomares, Esther; Lorés-Motta, Laura; Tonda, Raul; Dopazo, Joaquín; Marfany, Gemma; Gonzàlez-Duarte, Roser

    2014-01-01

    Most diagnostic laboratories are confronted with the increasing demand for molecular diagnosis from patients and families and the ever-increasing genetic heterogeneity of visual disorders. Concerning Retinal Dystrophies (RD), almost 200 causative genes have been reported to date, and most families carry private mutations. We aimed to approach RD genetic diagnosis using all the available genetic information to prioritize candidates for mutational screening, and then restrict the number of cases to be analyzed by massive sequencing. We constructed and optimized a comprehensive cosegregation RD-chip based on SNP genotyping and haplotype analysis. The RD-chip allows to genotype 768 selected SNPs (closely linked to 100 RD causative genes) in a single cost-, time-effective step. Full diagnosis was attained in 17/36 Spanish pedigrees, yielding 12 new and 12 previously reported mutations in 9 RD genes. The most frequently mutated genes were USH2A and CRB1. Notably, RD3-up to now only associated to Leber Congenital Amaurosis- was identified as causative of Retinitis Pigmentosa. The main assets of the RD-chip are: i) the robustness of the genetic information that underscores the most probable candidates, ii) the invaluable clues in cases of shared haplotypes, which are indicative of a common founder effect, and iii) the detection of extended haplotypes over closely mapping genes, which substantiates cosegregation, although the assumptions in which the genetic analysis is based could exceptionally lead astray. The combination of the genetic approach with whole exome sequencing (WES) greatly increases the diagnosis efficiency, and revealed novel mutations in USH2A and GUCY2D. Overall, the RD-chip diagnosis efficiency ranges from 16% in dominant, to 80% in consanguineous recessive pedigrees, with an average of 47%, well within the upper range of massive sequencing approaches, highlighting the validity of this time- and cost-effective approach whilst high-throughput methodologies become amenable for routine diagnosis in medium sized labs. PMID:24516651

  3. Epigenetic and genetic diagnosis of Silver-Russell syndrome.

    PubMed

    Eggermann, Thomas; Spengler, Sabrina; Gogiel, Magdalena; Begemann, Matthias; Elbracht, Miriam

    2012-06-01

    Silver-Russell syndrome (SRS) is a congenital imprinting disorder characterized by intrauterine and postnatal growth restriction and further characteristic features. SRS is genetically heterogenous: 7-10% of patients carry a maternal uniparental disomy of chromosome 7; >38% show a hypomethylation in imprinting control region 1 in 11p15; and a further class of mutations are copy number variations affecting different chromosomes, but mainly 11p15 and 7. The diagnostic work-up should thus aim to detect these three molecular subtypes. Numerous techniques are currently applied in genetic SRS testing, but none of them covers all known (epi)mutations, and they should therefore be used synergistically. However, future next-generation sequencing approaches will allow a comprehensive analysis of all types of alterations in SRS. PMID:22702363

  4. [Molecular genetic and bacteriological methods for the diagnosis of multidrug resistant M. tuberculosis].

    PubMed

    Agaev, F F; Aliev, K A; Salimova, N A; Abuzarov, R M; Gasymov, I A; Griadunov, D A

    2009-01-01

    For the early diagnosis of multidrug resistant tuberculosis, 67 sputum samples obtained from primary patients with different clinical forms of pulmonary tuberculosis were examined by the molecular genetic test using the TB-Biochip test system. Having a high sensitivity and specificity, the molecular genetic test for determining the drug sensitivity of Mycobacterium tuberculosis substantially accelerates its diagnosis (2-3 days) before the real-time mode of a patient's admission to the clinic. The method allows identification of mutations in the rpoB (resistance to R), katG, inhG, and ahpC (resistance to H) genes, which permits timely correction of performed specific treatment. PMID:19886013

  5. Genetic relationship between the addiction diagnosis in adults and their childhood measure of addiction liability.

    PubMed

    Vanyukov, Michael; Kim, Kevin; Irons, Daniel; Kirisci, Levent; Neale, Michael; Ridenour, Ty; Hicks, Brian; Tarter, Ralph; Reynolds, Maureen; Kirillova, Galina; McGue, Matt; Iacono, William

    2015-01-01

    Transmissible liability index (TLI), developed employing a high-risk design and item response theory, enables quantification of the latent trait of liability to drug use disorders (DUD) in children. TLI has been shown to have high heritability and predict DUD in young adulthood. This study extends prior research and determines the genetic contribution of DUD liability measured by TLI to adult liability as indexed by DUD diagnosis. The study utilizes data from a twin sample tracked from age 11 to age 25. In addition to confirming TLI's high heritability and predictive validity, it shows that the genetic component of variance in TLI assessed in childhood accounts for over half of the genetic variance in DUD diagnosis and the entire phenotypic relationship between the two liability measures. This validates TLI as an early measure of DUD liability and supports its utility in early-age genetic and other mechanistic studies of DUD. PMID:25502189

  6. Genetic relationship between the addiction diagnosis in adults and their childhood measure of addiction liability

    PubMed Central

    Vanyukov, Michael; Kim, Kevin; Irons, Daniel; Kirisci, Levent; Neale, Michael; Ridenour, Ty; Hicks, Brian; Tarter, Ralph; Reynolds, Maureen; Kirillova, Galina; McGue, Matt; Iacono, William

    2015-01-01

    Transmissible Liability Index (TLI), developed employing a high-risk design and item response theory, enables quantification of the latent trait of liability to drug use disorders (DUD) in children. TLI has been shown to have high heritability and predict DUD in young adulthood. This study extends prior research and determines the genetic contribution of DUD liability measured by TLI to adult liability as indexed by DUD diagnosis. The study utilizes data from a twin sample tracked from age 11 to age 25. In addition to confirming TLI’s high heritability and predictive validity, it shows that the genetic component of variance in TLI assessed in childhood accounts for over half of the genetic variance in DUD diagnosis and the entire phenotypic relationship between the two liability measures. This validates TLI as an early measure of DUD liability and supports its utility in early-age genetic and other mechanistic studies of DUD. PMID:25502189

  7. Aortopathies: etiologies, genetics, differential diagnosis, prognosis and management.

    PubMed

    Paterick, Timothy E; Humphries, Julie A; Ammar, Khawaja Afzal; Jan, M Fuad; Loberg, Rachel; Bush, Michelle; Khandheria, Bijoy K; Tajik, A Jamil

    2013-08-01

    Aortic root and ascending aortic dilatation are indicators associated with risk of aortic dissection, which varies according to underlying etiologic associations, indexed aortic root size, and rate of progression. Typical aortic involvement is most commonly seen in syndromic cases for which there is increasing evidence that aortic aneurysm represents a spectrum of familial inheritance associated with variable genetic penetrance and phenotypic expression. Aortic root and ascending aortic dimensions should be measured routinely with echocardiography. Pharmacologic therapy may reduce the rate of progression. Timing of surgical intervention is guided by indexed aortic size and rate of change of aortic root and ascending aorta dimensions. Lifelong surveillance is recommended. PMID:23800581

  8. Small Ruminant Lentiviruses: Genetic Variability, Tropism and Diagnosis

    PubMed Central

    Ramírez, Hugo; Reina, Ramsés; Amorena, Beatriz; de Andrés, Damián; Martínez, Humberto A.

    2013-01-01

    Small ruminant lentiviruses (SRLV) cause a multisystemic chronic disease affecting animal production and welfare. SRLV infections are spread across the world with the exception of Iceland. Success in controlling SRLV spread depends largely on the use of appropriate diagnostic tools, but the existence of a high genetic/antigenic variability among these viruses, the fluctuant levels of antibody against them and the low viral loads found in infected individuals hamper the diagnostic efficacy. SRLV have a marked in vivo tropism towards the monocyte/macrophage lineage and attempts have been made to identify the genome regions involved in tropism, with two main candidates, the LTR and env gene, since LTR contains primer binding sites for viral replication and the env-encoded protein (SU ENV), which mediates the binding of the virus to the host’s cell and has hypervariable regions to escape the humoral immune response. Once inside the host cell, innate immunity may interfere with SRLV replication, but the virus develops counteraction mechanisms to escape, multiply and survive, creating a quasi-species and undergoing compartmentalization events. So far, the mechanisms of organ tropism involved in the development of different disease forms (neurological, arthritic, pulmonary and mammary) are unknown, but different alternatives are proposed. This is an overview of the current state of knowledge on SRLV genetic variability and its implications in tropism as well as in the development of alternative diagnostic assays. PMID:23611847

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

    PubMed

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

    2015-06-01

    Cascade genetic screening is a methodology for identifying and testing close blood relatives of individuals at increased risk for heritable conditions and follows a sequential process, minimizing testing costs and the number of family members who need to be tested. It offers considerable potential for cost savings and increased awareness of heritable conditions within families. CDC-classified Tier 1 genomic applications for hereditary breast and ovarian cancer syndrome (HBOC), Lynch Syndrome (LS), and familial hypercholesterolemia (FH) are recommended for clinical use and support the use of cascade genetic screening. Most individuals are unaware of their increased risk for heritable conditions such as HBOC, LS, and FH. Consistent implementation of cascade genetic screening could significantly increase awareness and prevention of heritable conditions. Limitations to effective implementation of cascade genetic screening include: insufficient genetic risk assessment and knowledge by a majority of healthcare providers without genetics credentials; a shortage of genetic specialists, especially in rural areas; a low rate of reimbursement for comprehensive genetic counseling services; and an individual focus on prevention by clinical guidelines and insurance coverage. The family-centric approach of cascade genetic screening improves prevention and early diagnosis of heritable diseases on a population health level. Cascade genetic screening could be better supported and augmented through changes in health policy. PMID:25577298

  10. 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

  11. 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…

  12. Clinical applications of schizophrenia genetics: genetic diagnosis, risk, and counseling in the molecular era

    PubMed Central

    Costain, Gregory; Bassett, Anne S

    2012-01-01

    Schizophrenia is a complex neuropsychiatric disease with documented clinical and genetic heterogeneity, and evidence for neurodevelopmental origins. Driven by new genetic technologies and advances in molecular medicine, there has recently been concrete progress in understanding some of the specific genetic causes of this serious psychiatric illness. In particular, several large rare structural variants have been convincingly associated with schizophrenia, in targeted studies over two decades with respect to 22q11.2 microdeletions, and more recently in large-scale, genome-wide case-control studies. These advances promise to help many families afflicted with this disease. In this review, we critically appraise recent developments in the field of schizophrenia genetics through the lens of immediate clinical applicability. Much work remains in translating the recent surge of genetic research discoveries into the clinic. The epidemiology and basic genetic parameters (such as penetrance and expression) of most genomic disorders associated with schizophrenia are not yet well characterized. To date, 22q11.2 deletion syndrome is the only established genetic subtype of schizophrenia of proven clinical relevance. We use this well-established association as a model to chart the pathway for translating emerging genetic discoveries into clinical practice. We also propose new directions for research involving general genetic risk prediction and counseling in schizophrenia. PMID:23144566

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

    PubMed Central

    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. PMID:23961438

  14. Laboratory diagnosis of gonococcal infection by genetic transformation.

    PubMed Central

    Butler, L O; Knight, R D

    1982-01-01

    The transformation test for the detection of infection by Neisseria gonorrhoeae has been examined using pro gonococci as recipients and DNA preparations from 912 clinical isolates and from 240 direct swab specimens as donors. The reliability of the method was checked with DNA from clinical isolates; 82% of the N. meningitidis from throat swab specimens were capable of transforming the gonococcal recipients, but after identification of the meningococcus by the aminopeptidase profile, the transformation test was then 99.5% positive for the gonococcus with virtually no false-positives. The only other organism to give a positive reaction was N. lactamica, which occurred once in 912 specimens. When applied directly to swab specimens, the reliability of the test was reduced, but this may have been related to variability of the specimen itself. However, 7 of 15 specimens which were microscopically suspected to be gonococci but unculturable were positive; also, 9 out of 38 unculturable specimens that were not even suspected to be gonococci were positive. Hence the test was able to identify the presence of gonococci that were unculturable. The aminopeptidase activities were not sensitive enough to be detected in the direct swab specimens, and neither cys nor leu auxotrophs were suitable as recipients to give a differentiation between N. gonorrhoeae and N. meningitidis. Evidence was obtained which would support the proposition that the transfer of genetic material between N. gonorrhoeae and N. meningitidis may occur. PMID:6808013

  15. [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

  16. Professional phagocytic granulocyte-derived PGD2 regulates the resolution of inflammation in fish.

    PubMed

    Gómez-Abellán, Victoria; Montero, Jana; López-Muñoz, Azucena; Figueras, Antonio; Arizcun, Marta; Mulero, Victoriano; Sepulcre, María P

    2015-10-01

    Prostaglandins (PGs) play a key role in the development on the immune response through the regulation of both pro- and anti-inflammatory processes. PGD(2) can be either pro- or anti-inflammatory depending on the inflammatory milieu. Prostaglandin D synthase (PGDS) is the enzyme responsible for the conversion of PGH(2) to PGD(2). In mammals, two types of PGDS synthase have been described, the hematopoietic (H-PGDS) and the lipocalin (L-PGDS). In the present study we describe the existence of two orthologs of the mammalian L-PGDS (PGDS1 and PGDS2) in the gilthead seabream and characterize their gene expression profiles and biological activity. The results showed a dramatic induction of the gene coding for PGDS1 in acidophilic granulocytes (AGs), which are functionally equivalent to mammalian neutrophils, after a prolonged in vitro activation with different pathogen associated molecular patterns (PAMPs). In contrast PGDS2 was not expressed in these cells. The functional relevance of the induction of PGDS1 in AGs was confirmed by the ability of these cells to release PGD(2) upon PAMP stimulation. To gain further insight into the role of PGD(2) in the resolution of inflammation in fish, we examined the ability of PGD(2) or its cyclopentenone derivates (cyPGs) to modulate the main functional activities of AGs. It was found that both PGD(2) and cyPGs inhibited the production of reactive oxygen species and downregulated the transcript levels of the gene encoding interleukin-1β. Taken together, these results demonstrate that the use of PGD(2) and its metabolites in the resolution of inflammation was established before the divergence of fish from tetrapods more than 450 million years ago and support a critical role for granulocytes in the resolution of inflammation in vertebrates. PMID:26027798

  17. Next generation sequencing and the future of genetic diagnosis.

    PubMed

    Lohmann, Katja; Klein, Christine

    2014-10-01

    The introduction of next generation sequencing (NGS) has led to an exponential increase of elucidated genetic causes in both extremely rare diseases and common but heterogeneous disorders. It can be applied to the whole or to selected parts of the genome (genome or exome sequencing, gene panels). NGS is not only useful in large extended families with linkage information, but may also be applied to detect de novo mutations or mosaicism in sporadic patients without a prior hypothesis about the mutated gene. Currently, NGS is applied in both research and clinical settings, and there is a rapid transition of research findings to diagnostic applications. These developments may greatly help to minimize the "diagnostic odyssey" for patients as whole-genome analysis can be performed in a few days at reasonable costs compared with gene-by-gene analysis based on Sanger sequencing following diverse clinical tests. Despite the enthusiasm about NGS, one has to keep in mind its limitations, such as a coverage and accuracy of?

  18. Clinical findings and diagnosis in genetic prion diseases in Germany.

    PubMed

    Krasnianski, Anna; Heinemann, Uta; Ponto, Claudia; Kortt, Jasmine; Kallenberg, Kai; Varges, Daniela; Schulz-Schaeffer, Walter J; Kretzschmar, Hans A; Zerr, Inga

    2016-02-01

    To describe the clinical syndrome and diagnostic tests in patients with genetic prion diseases (gPD) in Germany. Clinical features, MRI, EEG, and CSF markers were studied in 91 patients (28 D178N, 20 E200K, 17 inserts, 13 V210I, 8 P102L, 5 E196K). Dementia (35 %) and ataxia (29 %) were the most common initial symptoms and signs. A wide variety and high frequency of neurological/psychiatric symptoms and signs was found during disease course in all patients independently of the type of the mutation. Psychiatric manifestations were frequent (87 %). Neuropsychological abnormalities were observed in 67 %, and aphasia was the most common disturbance (45 %). In E200K, V210I and D178N patients, visual/oculomotor deficits were followed by ataxia early in the disease. Dementia followed by ataxia at onset was common in patients with insert and E196K mutation. P102L patients had isolated ataxia over a longer time period followed by pyramidal signs. Dementia was present only late in the disease course. All clinical routine tests such as MRI, EEG and CSF tests were less sensitive than in sporadic CJD. We provide the first detailed analysis of clinical signs and symptoms in a large group of patients with gPD. Frequency of clinical symptoms and signs was similar in different mutations in a later disease course, but the sequence of occurrence may be of great diagnostic importance. CSF markers were shown to be more sensitive than MRI and EEG. PMID:26076917

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

    PubMed

    Parikh, Sumit; Bernard, Geneviève; 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; Patterson, Marc C; Taft, Ryan J; Vanderver, Adeline

    2015-04-01

    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, neuroimaging 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

  20. 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

  1. 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

  2. Regulation of endothelial nitric oxide synthase by PGD(2) in the developing choroid.

    PubMed

    Dumont, I; Hardy, P; Peri, K G; Hou, X; Molotchnikoff, S; Varma, D R; Chemtob, S

    2000-01-01

    We investigated if prostaglandins might regulate the increased choroidal endothelial (e) nitric oxide synthase (NOS) expression in the perinate. Prostaglandins, eNOS mRNA, immunoreactive protein and activity, and nitrite [stable metabolite of nitric oxide (NO)] production were markedly higher in newborn (1 day old) than juvenile (6-8 wk old) pig choroid. Treatment of isolated newborn choroids with the prostaglandin synthase inhibitor ibuprofen for 24 h reduced eNOS mRNA and nitrite production to values in juveniles. This effect was equally observed with the PGD(2) receptor (DP) blocker BW A868C and was prevented by cotreatment with PGD(2) but not other prostaglandins; similar observations were made on NOS activity in vivo. PGD(2) also increased eNOS expression on choroids of juveniles, and this effect was blocked by BW A868C. The manifestation of this upregulation of eNOS by PGD(2) on the control of choroidal vasomotor response was tested by using NO-dependent vasorelaxants, ACh, bradykinin (Bk), and substance P (SP). ACh-, Bk-, and SP-elicited choroidal vasorelaxation was greater in saline-treated newborn than juvenile pigs. Ibuprofen (24 h) decreased ACh-, Bk-, and SP-evoked vasorelaxation in newborns, whereas PGD(2) increased that in juveniles and prevented the ibuprofen-induced attenuated relaxation in newborns; infusion of N(omega)-monomethyl-L-arginine in choroids of those animals treated with PGD(2) reversed the augmented vasorelaxation to ACh, Bk, and SP. Finally, PGD(2)-induced upregulation of NOS in the perinate was also reflected by curtailed choroidal blood flow autoregulatory response to increased perfusion pressure. In conclusion, PGD(2) exhibits a major role in upregulating eNOS expression and activity in the choroid, which in turn results in greater NO-mediated vasorelaxation; a new mechanism for eNOS regulation via DP is hereby disclosed. The relationship between PGD(2) and eNOS in the developing subject provides an explanation for the interactive role of these two factors in the absent choroidal blood flow autoregulation in the perinate. PMID:10644584

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

    PubMed

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

    2016-04-01

    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

  4. 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.

  5. 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 an update of selected topics that have evolved since 2005. PMID:24225486

  6. 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 provide an update of selected topics that have evolved since 2005. PMID:24225486

  7. Online Diagnosis System: a webserver for analysis of Sanger sequencing-based genetic testing data.

    PubMed

    Sun, Kun; Yuen, Yuet-Ping; Wang, Huating; Sun, Hao

    2014-10-01

    Sanger sequencing is a well-established molecular technique for diagnosis of genetic diseases. In these tests, DNA sequencers produce vast amounts of data that need to be examined and annotated within a short period of time. To achieve this goal, an online bioinformatics platform that can automate the process is essential. However, to date, there is no such integrated bioinformatics platform available. To fulfill this gap, we developed the Online Diagnosis System (ODS), which is a freely available webserver and supports the commonly used file format of Sanger sequencing data. ODS seamlessly integrates base calling, single nucleotide variation (SNV) identification, and SNV annotation into one single platform. It also allows laboratorians to manually inspect the quality of the identified SNVs in the final report. ODS can significantly reduce the data analysis time therefore allows Sanger sequencing-based genetic testing to be finished in a timely manner. ODS is freely available at http://sunlab.lihs.cuhk.edu.hk/ODS/. PMID:25063568

  8. 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

  9. High resolution melting: improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohort

    PubMed Central

    2012-01-01

    Background Hypertrophic Cardiomyopathy (HCM) is a complex myocardial disorder with a recognized genetic heterogeneity. The elevated number of genes and mutations involved in HCM limits a gene-based diagnosis that should be considered of most importance for basic research and clinical medicine. Methodology In this report, we evaluated High Resolution Melting (HRM) robustness, regarding HCM genetic testing, by means of analyzing 28 HCM-associated genes, including the most frequent 4 HCM-associated sarcomere genes, as well as 24 genes with lower reported HCM-phenotype association. We analyzed 80 Portuguese individuals with clinical phenotype of HCM allowing simultaneously a better characterization of this disease in the Portuguese population. Results HRM technology allowed us to identify 60 mutated alleles in 72 HCM patients: 49 missense mutations, 3 nonsense mutations, one 1-bp deletion, one 5-bp deletion, one in frame 3-bp deletion, one insertion/deletion, 3 splice mutations, one 5'UTR mutation in MYH7, MYBPC3, TNNT2, TNNI3, CSRP3, MYH6 and MYL2 genes. Significantly 22 are novel gene mutations. Conclusions HRM was proven to be a technique with high sensitivity and a low false positive ratio allowing a rapid, innovative and low cost genotyping of HCM. In a short return, HRM as a gene scanning technique could be a cost-effective gene-based diagnosis for an accurate HCM genetic diagnosis and hopefully providing new insights into genotype/phenotype correlations. PMID:22429680

  10. Obtaining a genetic diagnosis in a child with disability: impact on parental quality of life.

    PubMed

    Lingen, M; Albers, L; Borchers, M; Haass, S; Gärtner, J; Schröder, S; Goldbeck, L; von Kries, R; Brockmann, K; Zirn, B

    2016-02-01

    Recent progress in genetic testing has facilitated obtaining an etiologic diagnosis in children with developmental delay/intellectual disability (DD/ID) or multiple congenital anomalies (MCA) or both. Little is known about the benefits of diagnostic elucidation for affected families. We studied the impact of a genetic diagnosis on parental quality of life (QoL) using a validated semiquantitative questionnaire in families with a disabled child investigated by array-based comparative genomic hybridization (aCGH). We received completed questionnaires from 95 mothers and 76 fathers of 99 families. We used multivariate analysis for adjustment of potential confounders. Taken all 99 families together, maternal QoL score (percentile rank scale 51.05) was significantly lower than fathers' QoL (61.83, p = 0.01). Maternal QoL score was 20.17 [95% CI (5.49; 34.82)] percentile rank scales higher in mothers of children with diagnostic (n = 34) aCGH as opposed to mothers of children with inconclusive (n = 65) aCGH (Hedges' g = 0.71). Comparison of these QoL scores with retrospectively recalled QoL before aCGH revealed an increase of maternal QoL after diagnostic clarification. Our results indicate a benefit for maternal QoL if a genetic test, here aCGH, succeeds to clarify the etiologic diagnosis in a disabled child. PMID:26084449

  11. 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

  12. Pitfalls in the molecular genetic diagnosis of Leber hereditary optic neuropathy (LHON)

    SciTech Connect

    Johns, D.R. ); Neufeld, M.J. )

    1993-10-01

    Pathogenetic mutations in mtDNA are found in the majority of patients with Leber hereditary optic neuropathy (LHON), and molecular genetic techniques to detect them are important for diagnosis. A false-positive molecular genetic error has adverse consequences for the diagnosis of this maternally inherited disease. The authors found a number of mtDNA polymorphisms that occur adjacent to known LHON-associated mutations and that confound their molecular genetic detection. These transition mutations occur at mtDNA nt 11779 (SfaNI site loss, 11778 mutation), nt 3459 (BsaHI site loss, 3460 mutation), nt 15258 (AccI site loss, 15257 mutation), nt 14485 (mismatch primer Sau3AI site loss, 14484 mutation), and nt 13707 (BstNI site loss, 13708 mutation). Molecular genetic detection of the most common pathogenetic mtDNA mutations in LHON, using a single restriction enzyme, may be confounded by adjacent polymorphisms that occur with a false-positive rate of 2%-7%. 19 refs.

  13. Best practice guidelines for the molecular genetic diagnosis of Type 1 (HFE-related) hereditary haemochromatosis

    PubMed Central

    King, Caitriona; Barton, David E

    2006-01-01

    Background Hereditary haemochromatosis (HH) is a recessively-inherited disorder of iron over-absorption prevalent in Caucasian populations. Affected individuals for Type 1 HH are usually either homozygous for a cysteine to tyrosine amino acid substitution at position 282 (C282Y) of the HFE gene, or compound heterozygotes for C282Y and for a histidine to aspartic acid change at position 63 (H63D). Molecular genetic testing for these two mutations has become widespread in recent years. With diverse testing methods and reporting practices in use, there was a clear need for agreed guidelines for haemochromatosis genetic testing. The UK Clinical Molecular Genetics Society has elaborated a consensus process for the development of disease-specific best practice guidelines for genetic testing. Methods A survey of current practice in the molecular diagnosis of haemochromatosis was conducted. Based on the results of this survey, draft guidelines were prepared using the template developed by UK Clinical Molecular Genetics Society. A workshop was held to develop the draft into a consensus document. The consensus document was then posted on the Clinical Molecular Genetics Society website for broader consultation and amendment. Results Consensus or near-consensus was achieved on all points in the draft guidelines. The consensus and consultation processes worked well, and outstanding issues were documented in an appendix to the guidelines. Conclusion An agreed set of best practice guidelines were developed for diagnostic, predictive and carrier testing for hereditary haemochromatosis and for reporting the results of such testing. PMID:17134494

  14. Massively Parallel Sequencing for Genetic Diagnosis of Hearing Loss: The New Standard of Care

    PubMed Central

    Shearer, A. Eliot; Smith, Richard J.H.

    2016-01-01

    Objective To evaluate the use of new genetic sequencing techniques for comprehensive genetic testing for hearing loss. Data Sources Articles were identified from PubMed and Google Scholar databases using pertinent search terms. Review Methods Literature search identified 30 studies as candidates that met search criteria. Three studies were excluded and eight studies were found to be case reports. 20 studies were included for review analysis including seven studies that evaluated controls and 16 studies that evaluated patients with unknown causes of hearing loss; three studies evaluated both controls and patients. Conclusions In the 20 studies included in review analysis, 426 control samples and 603 patients with unknown causes of hearing loss underwent comprehensive genetic diagnosis for hearing loss using massively parallel sequencing. Control analysis showed a sensitivity and specificity > 99%, sufficient for clinical use of these tests. The overall diagnostic rate was 41% (range 10% to 83%) and varied based on several factors including inheritance and pre-screening prior to comprehensive testing. There were significant differences in platforms available in regards to number and type of genes included and whether copy number variations were examined. Based on these results, comprehensive genetic testing should form the cornerstone of a tiered approach to clinical evaluation of patients with hearing loss along with history, physical exam, and audiometry and can determine further testing that may be required, if any. Implications for Practice Comprehensive genetic testing has become the new standard of care for genetic testing for patients with sensorineural hearing loss. PMID:26084827

  15. 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 results. PMID:25802885

  16. Combined genetic and imaging diagnosis for two large Chinese families affected with Pelizaeus-Merzbacher disease.

    PubMed

    Lv, Y; Cao, L H; Pang, H; Lu, L N; Li, J L; Fu, Y; Qi, S L; Luo, Y; Li-Ling, J

    2012-01-01

    Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive disorder characterized by nystagmus, impaired motor development, ataxia, and progressive spasticity. Genetically defective or altered levels of proteolipid protein (PLP1) or gap-junction alpha protein 12 gene have been found to be a common cause. Here we report on two large Han Chinese families affected with this disease. The probands of both families had produced sons featuring cerebral palsy that had never been correctly diagnosed. PMD was suspected after careful analysis of family history and clinical features. Three rounds of molecular testing, including RT-PCR, genetics linkage and SRY sequence analyses, in combination with fetal ultrasound and magnetic resonance imaging, confirmed the diagnosis. In Family 1, in addition to two patients, three carriers were identified, including one who was not yet married. Genetic testing indicated that a fetus did not have the disease. A healthy girl was born later. In Family 2, two patients and two carriers were identified, while a fetus was genetically normal. A healthy girl was born later. We concluded that by combining genetic testing and imaging, awareness of the symptoms of PMD and understanding of its molecular biology, there is great benefit for families that are at risk for producing offspring affected with this severe disease. PMID:22911587

  17. [Genetic and prenatal diagnosis for four families with Williams-Beuren syndrome].

    PubMed

    Liu, Yang; Xu, Zhi-Yong; Wu, Wei-Qing; Luo, Fu-Wei; Xie, Jian-Sheng

    2015-12-01

    Williams-Beuren syndrome is a common chromosome microdeletion syndrome. Early diagnosis and treatment are very helpful for patients and their families. This study identified the chromosome karyotype in one fetus with ultrasonography abnormalities and three children with developmental disorders from four families. This provided guidance for subsequent pregnancy and prenatal diagnosis by using routine G-banding chromosome karyotyping analysis, multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (array-CGH). In one amniotic fluid sample from a pregnant woman with fetal abnormalities on an ultrasound screen and three peripheral blood samples from three children with developmental disorders, the decreased signal of ELN gene probes at 7q11.23 and heterozygous deletions at 7q11.23 were detected by MLPA and array-CGH analysis. The laboratory genetic tests of amniotic fluid samples were normal when the mothers from the four families became pregnant again. It was concluded that MLPA and array-CGH are rapid and accurate tools for the diagnosis of Williams-Beuren syndrome and can provide more information for clinical genetic counseling. PMID:26695662

  18. Biotechnological advances in the diagnosis of avian coccidiosis and the analysis of genetic variation in Eimeria.

    PubMed

    Morris, G M; Gasser, R B

    2006-01-01

    Coccidiosis is an intestinal disease of chickens caused by various species of protozoan parasites within the genus Eimeria. This disease has a major economic impact to growers and to the poultry industry world-wide. The diagnosis and genetic characterization of the different species of Eimeria are central to the prevention, surveillance and control of coccidiosis, particularly now given the major problems with wide-spread resistance of Eimeria species against anticoccidial drugs (coccidiostats) and the residue problems associated with these compounds. While traditional methods have had major limitations in the specific diagnosis of coccidiosis, there have been significant advances in the development of molecular-diagnostic tools. The present article provides a background on coccidiosis, reviews the main molecular methods which have been used and describes recent advances in the establishment of polymerase chain reaction (PCR)-coupled electrophoretic approaches for the specific diagnosis of coccidiosis as well as the genetic characterization of species of Eimeria. These biotechnological advances are considered to represent a significant step toward the improved prevention and control of this important disease of poultry. PMID:16901674

  19. 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

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

    PubMed Central

    Zemojtel, Tomasz; Köhler, Sebastian; Mackenroth, Luisa; Jäger, Marten; Hecht, Jochen; Krawitz, Peter; Graul-Neumann, Luitgard; Doelken, Sandra; Ehmke, Nadja; Spielmann, Malte; Øien, 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.

    2015-01-01

    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

  1. 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

  2. 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. PMID:26198689

  3. Prenatal diagnosis of genetic disease in Canada: report of a collaborative study.

    PubMed Central

    Simpson, N. E.; Dallaire, L.; Miller, J. R.; Siminovich, L.; Hamerton, J. L.; Miller, J.; McKeen, C.

    1976-01-01

    A study of 1223 amniocenteses carried out during 1020 pregnancies in 990 women showed that 2nd-trimester amniocentesis at about 16 weeks' gestation is a safe, accurate and reliable procedure for the diagnosis of certain classes of genetic disease when it is monitored by ultrasound, performed by a trained obstetrician and carried out in a major health sciences centre. The percentage of fetal losses (4.7%) and neonatal deaths (0.5%) during the study was not greater than in control samples for women 35 years of age and older. The best results were obtained when needles of gauge 20 or 21 were used. The use of needles of gauge 19 or larger and more than two insertions during a single amniocentesis were associated with a significantly greater frequency of fetal loss than a second or even a third amniocentesis during the same pregnancy. For 39 fetuses (3.8%) a diagnosis of a genetic abnormality was made and 23 male fetuses were found to be potentially hemizygous for an X-linked gene. There were 51 therapeutic abortions as a result of the diagnosis. Sixty-six tests (5.4%) gave an inconclusive result and seven (0.6%) gave an erroneous diagnosis; five of the latter (two false-positives and three false-negatives) resulted from the alpha1-fetoprotein test for neural-tube defects and in two cases the sex was incorrectly determined. The frequency of all chromosome abnormalities was 1:20 when the mother's age was 40 years or more and 1:60 when the mother's age was between 35 and 39 years. When a mother had previously had a child with a chromosome abnormality the risk of recurrence of such an abnormality was 1:100 when the age of the mother was 35 years or more. PMID:61796

  4. Drug Induced Liver Injury: Review with a Focus on Genetic Factors, Tissue Diagnosis, and Treatment Options

    PubMed Central

    Khoury, Tawfik; Rmeileh, Ayman Abu; Yosha, Liron; Benson, Ariel A.; Daher, Saleh; Mizrahi, Meir

    2015-01-01

    Drug-induced liver injury (DILI) is a rare but potentially life threatening adverse drug reaction. DILI may mimic any morphologic characteristic of acute or chronic liver disease, and the histopathologic features of DILI may be indistinguishable from those of other causes of liver injury, such as acute viral hepatitis. In this review article, we provide an update on causative agents, clinical features, pathogenesis, diagnosis modalities, and outcomes of DILI. In addition, we review results of recently reported genetic studies and updates on pharmacological and invasive treatments. PMID:26356634

  5. 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

  6. Selecting barrenness: the use of preimplantation genetic diagnosis by congenitally infertile women to select for infertility.

    PubMed

    Shah, Kavita R

    2010-01-01

    Congenitally infertile women such as those with Turner syndrome or Mayer Rokitansky-Kuster-Hauser syndrome have available the technologies of oocyte harvesting, cryropreservation, in-vitro fertilization, and gestational surrogacy in order to have genetically related offspring. Since congenital infertility results in a variety of experiences that impacts on nearly every aspect of a person's life, in the future it is possible that these women might desire a congenitally infertile child through the use of preimplantation genetic diagnosis so as to share this common bond. While infertility results in a relatively normal quality of life, it is morally wrong to necessitate the future use of infertility services with its variable success rate on a child. Also, whereas the woman has fundamental reproductive autonomy, she lacks the substantive autonomy regarding the specific characteristics of her child. Finally, the infertile community does exhibit a strong presence, but it lacks characteristics that define it as a culture. PMID:21644427

  7. 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.

  8. Pentanucleotide repeat-primed PCR for genetic diagnosis of spinocerebellar ataxia type 31.

    PubMed

    Ishige, Takayuki; Sawai, Setsu; Itoga, Sakae; Sato, Kenichi; Utsuno, Emi; Beppu, Minako; Kanai, Kazuaki; Nishimura, Motoi; Matsushita, Kazuyuki; Kuwabara, Satoshi; Nomura, Fumio

    2012-12-01

    Spinocerebellar ataxia type 31 (SCA31) is defined by the presence of an insertion mutation containing a TGGAA repeat within the intron of the brain-expressed, associated with NEDD4 (BEAN) gene. Detecting this mutation is conventionally done by southern blotting or DNA sequencing, but these methods are technically demanding and not easily implemented in clinical diagnosis. Here, we adapted repeat-primed PCR (RP-PCR) to develop a clinical genetic test for SCA31 using only the PCR process to detect the TGGAA repeat within the insertion mutation. Pentanucleotide RP-PCR and subsequent DNA fragment analysis demonstrated characteristic ladder peaks with a 5-bp periodicity, originating from the TGGAA repeat, in 100% of samples (n=14) from SCA31 patients in whom the presence of the TGGAA repeat had been verified by DNA sequencing. No peaks were observed in a normal control and two non-SCA31 patients, in whom the TGGAA repeat was absent. This method is valuable for genetic diagnosis of SCA31 in clinical practice. PMID:22992774

  9. Collaborative Crowdsourcing for the Diagnosis of Rare Genetic Syndromes: The DYSCERNE Experience.

    PubMed

    Douzgou, Sofia; Pollalis, Yiannis A; Vozikis, Athanassios; Patrinos, George P; Clayton-Smith, Jill

    2016-01-01

    The big-data revolution is creating a challenge for the provision of services in the health sector to keep pace with the expectations of the general population. Utilization of crowdsourcing can impact positively on the quality, cost and speed of healthcare by involving large sections of professionals and the public and creating novel science within an ethical framework. In 2007, the DYSCERNE project was funded by the European Commission Public Health Executive Agency (EU DG Sanco) aimed at setting up a network of expertise for rare dysmorphic disorders. As part of DYSCERNE, a Dysmorphology Diagnostic System was set up to enable clinicians throughout the EU to submit cases electronically for diagnosis using a secure, web-based interface, hosted at specified access points (submitting nodes), in 26 different European countries. DYSCERNE utilized the process of crowdsourcing international expertise for the clinical diagnosis of very rare genetic syndromes of multiple congenital anomalies. This is the first reported account of collaborative crowd sourcing in dysmorphology, as part of a clinical genetics service. PMID:26447648

  10. 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.

  11. Impact of genetics on the diagnosis and clinical management of syndromic craniosynostoses

    PubMed Central

    Agochukwu, Nneamaka B.; Solomon, Benjamin D.; Muenke, Maximilian

    2014-01-01

    Purpose More than 60 different mutations have been identified to be causal in syndromic forms of craniosynostosis. The majority of these mutations occur in the fibroblast growth factor receptor 2 gene (FGFR2). The clinical management of syndromic craniosynostosis varies based on the particular causal mutation. Additionally, the diagnosis of a patient with syndromic craniosynostosis is based on the clinical presentation, signs, and symptoms. The understanding of the hallmark features of particular syndromic forms of craniosynostosis leads to efficient diagnosis, management, and long-term prognosis of patients with syndromic craniosynostoses. Methods A comprehensive literature review was done with respect to the major forms of syndromic craniosynostosis and additional less common FGFR-related forms of syndromic craniosynostosis. Additionally, information and data gathered from studies performed in our own investigative lab (lab of Dr. Muenke) were further analyzed and reviewed. A literature review was also performed with regard to the genetic workup and diagnosis of patients with craniosynostosis. Results Patients with Apert syndrome (craniosynostosis syndrome due to mutations in FGFR2) are most severely affected in terms of intellectual disability, developmental delay, central nervous system anomalies, and limb anomalies. All patients with FGFR-related syndromic craniosynostosis have some degree of hearing loss that requires thorough initial evaluations and subsequent follow-up. Conclusions Patients with syndromic craniosynostosis require management and treatment of issues involving multiple organ systems which span beyond craniosynostosis. Thus, effective care of these patients requires a multidisciplinary approach. PMID:22872262

  12. 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

  13. The clinical diagnosis and molecular genetics of kearns-sayre syndrome: a complex mitochondrial encephalomyopathy.

    PubMed

    Maceluch, Jaros Aw; Niedziela, Marek

    From the first description by Kearns and Sayre in 1958, this syndrome has been diagnosed in several hundred patients. However, the labile character of its clinical manifestations makes diagnosis difficult and delayed. Only recently, some thirty years from the first diagnosis, have we recognized mitochondrial DNA rearrangements as the molecular basis of the disease. This has lead to increasing interest in the contribution which mtDNA deletions make to Kearns-Sayre Syndrome (KSS) and other disorders. Although the true prevalence of this syndrome in the general population is unknown, a basic awareness of the KSS phenotype, as well as of the essential elements of patient evaluation is important for appropriate patient management. Although methods of assessing patients for mtDNA rearrangements are well developed, ambiguity in patient diagnosis often remains even after detailed, multisystem testing. Advances in our understanding of the genetic background and the tissue specific effects of mtDNA deletions, in addition to resolving the inheritance pattern, will also increase our ability to diagnose, manage and counsel patients with this disorder. PMID:17342029

  14. 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. PMID:26264719

  15. 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. PMID:9807244

  16. 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

  17. Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk.

    PubMed

    Cantu, E; Suzuki, Y; Diamond, J M; Ellis, J; Tiwari, J; Beduhn, B; Nellen, J R; Shah, R; Meyer, N J; Lederer, D J; Kawut, S M; Palmer, S M; Snyder, L D; Hartwig, M G; Lama, V N; Bhorade, S; Crespo, M; Demissie, E; Wille, K; Orens, J; Shah, P D; Weinacker, A; Weill, D; Wilkes, D; Roe, D; Ware, L B; Wang, F; Feng, R; Christie, J D

    2016-03-01

    The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they 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. Two hundred ninety-seven enrollees were evaluated in stage 1. Six 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% confidence interval 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

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

    NASA Astrophysics Data System (ADS)

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

    2015-12-01

    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.

  19. 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.

  20. Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer

    PubMed Central

    Coppedè, Fabio; Lopomo, Angela; Spisni, Roberto; Migliore, Lucia

    2014-01-01

    Colorectal cancer (CRC) is one of the most common cancer worldwide and results from the accumulation of mutations and epimutations in colonic mucosa cells ultimately leading to cell proliferation and metastasis. Unfortunately, CRC prognosis is still poor and the search of novel diagnostic and prognostic biomarkers is highly desired to prevent CRC-related deaths. The present article aims to summarize the most recent findings concerning the use of either genetic or epigenetic (mainly related to DNA methylation) biomarkers for CRC diagnosis, prognosis, and response to treatment. Recent large-scale DNA methylation studies suggest that CRC can be divided into several subtypes according to the frequency of DNA methylation and those of mutations in key CRC genes, and that this is reflected by different prognostic outcomes. Increasing evidence suggests that the analysis of DNA methylation in blood or fecal specimens could represent a valuable non-invasive diagnostic tool for CRC. Moreover, a broad spectrum of studies indicates that the inter-individual response to chemotherapeutic treatments depends on both epigenetic modifications and genetic mutations occurring in colorectal cancer cells, thereby opening the way for a personalized medicine. Overall, combining genetic and epigenetic data might represent the most promising tool for a proper diagnostic, prognostic and therapeutic approach. PMID:24574767

  1. 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

  2. Genetic diagnosis of familial hypercholesterolaemia by targeted next-generation sequencing

    PubMed Central

    Maglio, C; Mancina, R M; Motta, B M; Stef, M; Pirazzi, C; Palacios, L; Askaryar, N; Borén, J; Wiklund, O; Romeo, S

    2014-01-01

    Maglio C., Mancina R. M., Motta B. M., Stef M., Pirazzi C., Palacios L., Askaryar N., Borén J., Wiklund O., Romeo S. (University of Gothenburg, Gothenburg, Sweden; University Magna Graecia of Catanzaro, Italy; University of Milan, Italy; Progenika Biopharma SA, Derio, Spain). Genetic diagnosis of familial hypercholesterolaemia by targeted next-generation sequencing. Objectives The aim of this study was to combine clinical criteria and next-generation sequencing (pyrosequencing) to establish a diagnosis of familial hypercholesterolaemia (FH). Design, setting and subjects A total of 77 subjects with a Dutch Lipid Clinic Network score of ≥3 (possible, probable or definite FH clinical diagnosis) were recruited from the Lipid Clinic at Sahlgrenska Hospital, Gothenburg, Sweden. Next-generation sequencing was performed in all subjects using SEQPRO LIPO RS, a kit that detects mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDLR adapter protein 1 (LDLRAP1) genes; copy-number variations in the LDLR gene were also examined. Results A total of 26 mutations were detected in 50 subjects (65% success rate). Amongst these, 23 mutations were in the LDLR gene, two in the APOB gene and one in the PCSK9 gene. Four mutations with unknown pathogenicity were detected in LDLR. Of these, three mutations (Gly505Asp, Ile585Thr and Gln660Arg) have been previously reported in subjects with FH, but their pathogenicity has not been proved. The fourth, a mutation in LDLR affecting a splicing site (exon 6–intron 6) has not previously been reported; it was found to segregate with high cholesterol levels in the family of the proband. Conclusions Using a combination of clinical criteria and targeted next-generation sequencing, we have achieved FH diagnosis with a high success rate. Furthermore, we identified a new splicing-site mutation in the LDLR gene. PMID:24785115

  3. 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

  4. PCR from single cells for preimplantation diagnosis.

    PubMed

    Ray, P F; Handyside, A H

    1996-01-01

    The detection of genetic defects in human embryos following in vitro fertilization (IVF) or preimplantation genetic diagnosis (PGD) allows the selection and transfer of unaffected embryos in couples known to be at risk of transmitting an inherited disorder. This avoids the need to termiate an affected pregnancy, following prenatal diagnosis at later stages (1). Diagnosis of a single gene defect is usually performed on one or two single cells (blastomeres) biopsied from 8- to 10-cell embryos on the 3rd d postinsemination using nested polymerase chain reaction (PCR) to amplify informative fragments. Nested PCR allows amplification from a limited number of target sequences (2), and under carefully optimized conditions, amplification of as few as one or two target copies present in a single haploid or diploid cell is possible (3-5). PGD was first achieved for X-linked diseases by determining the sex of the embryos using a Y chromosome-specific repetitive sequence and selective transfer of only female embryos (6). More recently, specific diagnosis has been achieved for cystic fibrosis (CF), by amplifying across the cystic fibrosis transmembrane regulator (CFTR) gene †F508 locus (7) and for Lesch-Nyhan syndrome by amplifying across a familial base substitution nullifying a natural XhoI restriction site in the hypoxanthine phophoribosyl transferase (HPRT) gene (8). In both instances, nested PCR strategies were chosen to amplify the mutated sequence allowing sufficient amplification for detection on ethidium bromide-stained gels. The limited cycling with the outer primers (20 cycles) reduces nonspecific amplification, and only specific fragments that contain the complementary sequence to the internal primers are amplified to a detectable level in the second round of PCR. Although extra handling is involved, any genomic contaminant introduced after the first round of amplification would not be amplified to a detectable level by the inner primers alone. The efficiency of the second amplification is improved because the denaturation of the first amplification product (amplicon) is easier. Also, the great excess of these amplicons compared with nonspecific sequences eliminates competition, thereby enhancing specificity and yield. PMID:21374522

  5. Effect of the PGD2-DP signaling pathway on primary cultured rat hippocampal neuron injury caused by aluminum overload.

    PubMed

    Ma, Jie; Yang, Qunfang; Wei, Yuling; Yang, Yang; Ji, Chaonan; Hu, Xinyue; Mai, Shaoshan; Kuang, Shengnan; Tian, Xiaoyan; Luo, Ying; Liang, Guojuan; Yang, Junqing

    2016-01-01

    In the present study, the agonists and antagonists of DP receptor were used to examine whether the PGD2-DP signaling pathway affects neuronal function. Primary cultured hippocampal neuron was prepared and treated with aluminum maltolate (100 μM) to establish the neuronal damage model. PGD2 and cAMP content was detected by ELISA. L-PGDS and DPs mRNA and protein expression were measured by RT-PCR and Western blotting, respectively. The aluminium-load neuron was treated with the DP1 agonist BW245C, the DP1 antagonist BWA868C, the DP2 agonist DK-PGD2, and the DP2 antagonist CAY10471, respectively. Neuronal pathomorphology was observed using H-E staining. The cell viability and the lactate dehydrogenase leakage rates of neurons were measured with MTT and LDH kit, respectively. Ca(2+) level was detected by Fluo-3/AM. In the model group, the MTT values obviously decreased; LDH leakage rates and PGD2 content increased significantly; L-PGDS, DP1 mRNA and protein expressions increased, and DP2 level decreased. BW245C reduced the Ca(2+) fluorescence intensity and protected the neurons. DK-PGD2 increased the intensity of Ca(2+) fluorescence, while CAY10471 had the opposite effect. In conclusion, contrary to the effect of DP2, the PGD2-DP1 signaling pathway protects against the primary cultured rat hippocampal neuronal injury caused by aluminum overload. PMID:27089935

  6. PGD2 stimulates osteoprotegerin synthesis via AMP-activated protein kinase in osteoblasts: Regulation of ERK and SAPK/JNK.

    PubMed

    Kainuma, Shingo; Tokuda, Haruhiko; Kuroyanagi, Gen; Yamamoto, Naohiro; Ohguchi, Reou; Fujita, Kazuhiko; Matsushima-Nishiwaki, Rie; Kozawa, Osamu; Otsuka, Takanobu

    2015-10-01

    AMP-activated protein kinase (AMPK), a key enzyme sensing cellular energy metabolism, is currently known to regulate multiple metabolic pathways. Osteoprotegerin plays a pivotal role in the regulation of bone metabolism by inhibiting osteoclast activation. We have previously reported that prostaglandin D2 (PGD2) stimulates the synthesis of osteoprotegerin through the activation of p38 mitogen-activated protein (MAP) kinase, p44/p42 MAP kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. On the basis of these findings, we herein investigated the implication of AMPK in PGD2-stimulated osteoprotegerin synthesis in these cells. PGD2 induced the phosphorylation of AMPKα (Thr-172) and AMPKβ (Ser-108), and the phosphorylation of acetyl-coenzyme A carboxylase, a direct AMPK substrate. Compound C, an AMPK inhibitor, which suppressed the phosphorylation of acetyl-coenzyme A carboxylase, significantly attenuated both the release and the mRNA levels of osteoprotegerin stimulated by PGD2. The PGD2-induced phosphorylation of p44/p42 MAP kinase and SAPK/JNK but not p38 MAP kinase were markedly inhibited by compound C. These results strongly suggest that AMPK regulates the PGD2-stimulated osteoprotegerin synthesis at a point upstream of p44/p42 MAP kinase and SAPK/JNK in osteoblasts. PMID:26365271

  7. Effect of the PGD2-DP signaling pathway on primary cultured rat hippocampal neuron injury caused by aluminum overload

    PubMed Central

    Ma, Jie; Yang, Qunfang; Wei, Yuling; Yang, Yang; Ji, Chaonan; Hu, Xinyue; Mai, Shaoshan; Kuang, Shengnan; Tian, Xiaoyan; Luo, Ying; Liang, Guojuan; Yang, Junqing

    2016-01-01

    In the present study, the agonists and antagonists of DP receptor were used to examine whether the PGD2-DP signaling pathway affects neuronal function. Primary cultured hippocampal neuron was prepared and treated with aluminum maltolate (100 μM) to establish the neuronal damage model. PGD2 and cAMP content was detected by ELISA. L-PGDS and DPs mRNA and protein expression were measured by RT-PCR and Western blotting, respectively. The aluminium-load neuron was treated with the DP1 agonist BW245C, the DP1 antagonist BWA868C, the DP2 agonist DK-PGD2, and the DP2 antagonist CAY10471, respectively. Neuronal pathomorphology was observed using H-E staining. The cell viability and the lactate dehydrogenase leakage rates of neurons were measured with MTT and LDH kit, respectively. Ca2+ level was detected by Fluo-3/AM. In the model group, the MTT values obviously decreased; LDH leakage rates and PGD2 content increased significantly; L-PGDS, DP1 mRNA and protein expressions increased, and DP2 level decreased. BW245C reduced the Ca2+ fluorescence intensity and protected the neurons. DK-PGD2 increased the intensity of Ca2+ fluorescence, while CAY10471 had the opposite effect. In conclusion, contrary to the effect of DP2, the PGD2-DP1 signaling pathway protects against the primary cultured rat hippocampal neuronal injury caused by aluminum overload. PMID:27089935

  8. Genetic diagnosis and prognosis of Alzheimer’s disease: challenges and opportunities

    PubMed Central

    Reitz, Christiane

    2015-01-01

    Alzheimer’s disease (AD), the most common form of dementia in western societies, is a pathologically and clinically heterogeneous disease with a strong genetic component. The recent advances in high-throughput genome technologies allowing for the rapid analysis of millions of polymorphisms in thousands of subjects has significantly advanced our understanding of the genomic underpinnings of AD susceptibility. During the last 5 years, genome-wide association and whole-exome- and whole-genome sequencing studies have mapped more than 20 disease-associated loci, providing insights into the molecular pathways involved in AD pathogenesis and hinting at potential novel therapeutic targets. This review article summarizes the challenges and opportunities of when using genomic information for diagnosis and prognosis of Alzheimer’s disease. PMID:25634383

  9. 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

  10. Label-Free Electrochemical Diagnosis of Viral Antigens with Genetically Engineered Fusion Protein

    PubMed Central

    Heo, Nam Su; Zheng, Shun; Yang, MinHo; Lee, Seok Jae; Lee, Sang Yup; Kim, Hwa-Jung; Park, Jung Youn; Lee, Chang-Soo; Park, Tae Jung

    2012-01-01

    We have developed a simple electrochemical biosensing strategy for the label-free diagnosis of hepatitis B virus (HBV) on a gold electrode surface. Gold-binding polypeptide (GBP) fused with single-chain antibody (ScFv) against HBV surface antigen (HBsAg), in forms of genetically engineered protein, was utilized. This GBP-ScFv fusion protein can directly bind onto the gold substrate with the strong binding affinity between the GBP and the gold surface, while the recognition site orients toward the sample for target binding at the same time. Furthermore, this one-step immobilization strategy greatly simplifies a fabrication process without any chemical modification as well as maintaining activity of biological recognition elements. This system allows specific immobilization of proteins and sensitive detection of targets, which were verified by surface plasmon resonance analysis and successfully applied to electrochemical cyclic voltammetry and impedance spectroscopy upto 0.14 ng/mL HBsAg. PMID:23112590

  11. 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

  12. Preimplantation genetics: Improving access to stem cell therapy.

    PubMed

    Kuliev, Anver; Rechitsky, Svetlana; Tur-Kaspa, Ilan; Verlinsky, Yury

    2005-01-01

    There has been progress in the application of stem cell transplantation for treatment of an increasing number of severe congenital and acquired bone marrow disorders, currently restricted by the availability of human leukocyte antigen (HLA)-matched related donors. Preimplantation HLA typing has recently been introduced to improve the access to stem cell therapy for inherited bone marrow failures. Preimplantation genetic diagnosis (PGD) provides an option not only for avoiding an affected pregnancy with thalassemia and other inherited disorders but also for preselection of the HLA-compatible donors for affected siblings. Multiple short tandem repeat markers throughout the HLA region are applied for this purpose, allowing 100% accuracy of HLA typing, through picking up possible recombination in the HLA region, as well as the copy number of chromosome 6, which affect accuracy of preimplantation HLA typing. Present experience of preimplantation HLA typing includes preimplantation HLA typing in 180 cycles, 122 of which were done as part of PGD for Fanconi anemia, thalassemia, Wiscott-Aldrich syndrome, hyper-immunoglobulin M syndrome, hypohidrotic ectodermal dysplasia with immune deficiency, and X-linked adrenoleukodystrophy, and 58 for the sole purpose of HLA typing for leukemias and for aplastic and Diamond-Blackfan anemia. The applied method resulted in the accurate preselection and transfer of 100% HLA-matched embryos, yielding already three dozen clinical pregnancies and the birth of two dozen HLA-matched children to the siblings requiring stem cell transplantation. Successful therapy with HLA-matched stem cells, obtained from these PGD children, has been achieved already for Diamond-Blackfan anemia hypohidrotic ectodermal dysplasia with immune deficiency and thalassemia. PMID:16339669

  13. Diagnosis of gonorrhea using a genetic transformation test on mailed clinical specimens.

    PubMed

    Jaffe, H W; Kraus, S J; Edwards, T A; Weinberger, S S; Zubrzycki, L

    1982-08-01

    The genetic transformation test (GTT), a technique used for the detection of gonococcal DNA in clinical specimens, was compared with culture testing for the diagnosis of gonorrhea. At the De Kalb County Venereal Disease Clinic, Decatur, Ga., 454 cervical and 160 rectal specimens from women and 191 urethral specimens from men were collected in duplicate. One of each of the two specimens from each anatomic site was immediately plated on Martin-Lewis medium and incubated; the other specimen was mailed to Philadelphia for a GTT. Using culture results as a standard, the GTT had a specificity of 98.1% although some "false-positive" GTT results were probably a reflection of false-negative culture results. The sensitivity of the GTT was greater than 96% except when specimens were collected with Culturettes (Marion Laboratories, Kansas City, Mo.). In situations where Gram staining is not appropriate or where on-site culture facilities are not available, GTT may be the method of choice for the diagnosis of gonorrhea. PMID:6809844

  14. Clinical, radiographic, and genetic diagnosis of progressive pseudorheumatoid dysplasia in a patient with severe polyarthropathy.

    PubMed

    Ehl, Stephan; Uhl, Markus; Berner, Reinhard; Bonafé, Luisa; Superti-Furga, Andrea; Kirchhoff, Antje

    2004-01-01

    A 14-year-old boy presented with a 10-year history of the "sicca" form of seronegative juvenile idiopathic polyarthritis. Severely limited range of motion, pain, and capsular swelling in both small and large weight-bearing joints left him wheelchair-bound. Erythrocyte sedimentation rate and C-reactive protein were normal. Two-phase bone scan revealed tracer uptake of almost every joint at both early and late time points, indicating pathologic exudation and enhanced bone metabolism consistent with severe arthritis. However, radiographic studies revealed no erosive arthropathy but severe osteopenia, dysplastic bone changes, mega os trigonum, and platyspondylia. A magnetic resonance imaging (MRI) scan of the hips showed no signs of synovitis, pannus, or effusion but cartilage irregularities and subchondral cysts. These findings strongly suggested the diagnosis of progressive pseudorheumatoid dysplasia of childhood, an autosomal-recessive disorder of cartilage homeostasis. The patient carries a novel homozygous two-nucleotide deletion in exon 4 of the WISP3 gene. This genetic disorder is an important differential diagnosis of sicca polyarthritis. PMID:12819927

  15. Preimplantation genetic diagnosis in Welsh pony embryos after biopsy and cryopreservation.

    PubMed

    Guignot, F; Reigner, F; Perreau, C; Tartarin, P; Babilliot, J M; Bed'hom, B; Vidament, M; Mermillod, P; Duchamp, G

    2015-11-01

    Preimplantation genetic diagnosis and embryo cryopreservation are important tools to improve genetic management in equine species with marked consequences on the economic value, health, biodiversity, and preservation of the animals. This study aimed to develop a biopsy method at the blastocyst stage that provides viable genotyped cryopreserved Welsh pony embryos. Embryos were collected at d 6.75 to 7 after ovulation. Biopsies were performed with either a microblade or a micropipette. After biopsy, embryos were cryopreserved. The survival rate of biopsied embryos was evaluated on fresh and cryopreserved embryos either 24 h after in vitro culture or after transfer to recipients. Fresh and nonbiopsied embryos were used as controls. Sex, coat color genes, myotony (neuromuscular disorder) diagnosis, and markers of parentage were investigated using PCR on biopsied cells after whole-genome amplification and on remaining embryos. The embryo survival rate after transfer was not affected by the micropipette biopsy (50%, = 8; 43%, = 7; and 50%, = 12, at d 30 for fresh biopsied embryos, vitrified biopsied embryos, and control embryos, respectively) but was significantly reduced by the use of microblade biopsy: 9 ( = 11) vs. 67% ( = 12) for control embryos. Successful sex determination was achieved for 82% ( = 28) of the micropipette biopsies and 100% ( = 50) of the microblade biopsies. Sex determined on biopsied cells was found to correspond completely (100%) with that determined on the remaining embryo ( = 37). More than 90% of the parentage checking markers, coat color, and myotony diagnosis were successfully determined on biopsies obtained with either a micropipette or a microblade. Mendelian incompatibility (7.5 and 5.5%) and embryo genotyping errors (6.6 and 8.6%) were low and not significantly different between the 2 methods. In conclusion, for the first time, pregnancy at Day 30 was obtained after transfer of Welsh pony biopsied and vitrified embryos >300 μm in diameter to recipient pony mares. The biopsied cells collected enabled multigenetic embryo diagnoses to be performed to a high degree of accuracy. The micropipette biopsy is the better method to apply on Welsh pony embryos. PMID:26641042

  16. Use of the MLPA Assay in the Molecular Diagnosis of Gene Copy Number Alterations in Human Genetic Diseases

    PubMed Central

    Stuppia, Liborio; Antonucci, Ivana; Palka, Giandomenico; Gatta, Valentina

    2012-01-01

    Multiplex Ligation-dependent Probe Amplification (MLPA) assay is a recently developed technique able to evidence variations in the copy number of several human genes. Due to this ability, MLPA can be used in the molecular diagnosis of several genetic diseases whose pathogenesis is related to the presence of deletions or duplications of specific genes. Moreover, MLPA assay can also be used in the molecular diagnosis of genetic diseases characterized by the presence of abnormal DNA methylation. Due to the large number of genes that can be analyzed by a single technique, MLPA assay represents the gold standard for molecular analysis of all pathologies derived from the presence of gene copy number variation. In this review, the main applications of the MLPA technique for the molecular diagnosis of human diseases are described. PMID:22489151

  17. Neuropsychopharmacology and the genetics of schizophrenia: a history of the diagnosis of schizophrenia.

    PubMed

    Ban, Thomas A

    2004-08-01

    Development of the diagnostic concept of schizophrenia (dementia praecox) is traced from the fourth edition of [Kraepelin, E., 1893. Ein Kurzes Lehrbuch der Psychiatrie. 4 Aufl. Barth, Lepzig] textbook to the DSM-IV [American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders. Fourth ed. American Psychiatric Association, Washington, 273-316]. The differences between the criteria used by Bleuler [Bleuler, E., 1911. Dementia Praecox oder Gruppe der Schizophrenien. Deuticke, Leipzig] and Schneider [Fortschr. Neurol. Psychiatr. 25 (1957) 487] in the diagnosis of schizophrenia are discussed. The nosologic contributions of Kleist [Klin. Wochenschr. 2 (1923) 962] and Leonhard [Leonhard, K., 1957. Aufteilung der endogenen Psychosen. Akademie, Berlin]--which split schizophrenia into two major classes of disease with several forms and subforms--are outlined. Epidemiological findings--which show wide variations in the prevalence of schizophrenia in the general population and in the admission rate of schizophrenics to psychiatric clinics--are presented. Findings in genetic studies are reviewed with special reference to family, twin, and adoption studies which have raised the possibility that heredity plays an important role in the etiology of schizophrenia; mathematical analyses are examined which have ruled out monogenic transmission, as well as molecular genetic investigations indicating that the schizophrenic population is genetically heterogeneous. The relevance of findings with endophenotypes to the genetics of schizophrenia is questioned. The history of pharmacotherapy, neuropharmacology, and psychopharmacology of schizophrenia is outlined. Attention is focused on findings which indicate that the schizophrenic population is pharmacologically heterogenous. It is emphasized that neuropsychopharmacology, through its unique capability of linking the effects of psychotropic drugs to brain structures--encoded by genes which have been identified--offers a pioneering methodology for bridging the gap between the genes and psychiatric nosology. It is pointed out that for the detection of subpopulations within schizophrenia, clinical investigations with antipsychotic drugs have to proceed beyond the demonstration of therapeutic efficacy to the identification of treatment-responsive form(s) of illness. Early findings by Fish [L'Encephale 53 (1964) 245] are presented which indicate that affect-laden paraphrenia, one of the three forms of unsystematic schizophrenia in Leonhard [Leonhard, K., 1957. Aufteilung der endogenen Psychosen. Akademie, Berlin] classification, is the treatment-responsive subpopulation within schizophrenia for typical antipsychotic drugs. It is suggested that if the findings of Fish [L'Encephale 53 (1964) 245] could be verified, affect-laden paraphrenia would qualify for molecular genetic research. Another possible subpopulation that might qualify for genetic research is systematic hebephrenia, one of the three forms of systematic hebephrenia. The paper concludes that resolving the heterogeneity of the schizophrenic population would open up a new perspective for genetic research and for the pharmacotherapy of the different illnesses covered up for a century by the diagnostic label of schizophrenia. PMID:15363601

  18. Karyotype analysis with amniotic fluid in 12365 pregnant women with indications for genetic amniocentesis and strategies of prenatal diagnosis.

    PubMed

    Xiao, H; Yang, Y L; Zhang, C Y; Liao, E J; Zhao, H R; Liao, S X

    2016-04-01

    We explored the strategies of prenatal diagnosis by foetal karyotype analysis in pregnant women with indications for genetic amniocentesis. Karyotype analysis of amniotic fluid was performed on 12365 pregnant women with indications for genetic amniocentesis. The detection rates and distributions of abnormal karyotypes were observed in a variety of indications for genetic amniocentesis. The detection rates of abnormal karyotype were 57.4% in either a mother or father with chromosomal abnormality, 8.5% in the pregnant women with pathological ultrasound finding (PUF), 2.79% in the pregnant women with advanced age (35 years and over) and 2.23% in the women with abnormal maternal serum screening (MSS) tests. Foetal abnormal karyotype was found in 86 pregnant women with PUF; of the 86 pregnant women, 42 had trisomy 13, 18 or 21. Of the 12365 pregnant women, foetal abnormal karyotype was found in 428 (3.46%); of the 428 foetuses, only 154 had trisomy 13, 18 or 21. In the pregnant women with abnormal MSS, 111 foetuses had abnormal karyotype, but only 36 foetuses had trisomy 13, 18 or 21. We conclude that (1) ultrasound is an important approach to prevent the birth of foetuses with chromosomal disease. (2) Non-invasive prenatal DNA detection cannot completely replace invasive prenatal diagnosis and MSS. (3) The strategies of prenatal diagnosis: Genetic amniocentesis is strongly recommended for the pregnant women with indications for genetic amniocentesis. For pregnant women who refuse invasive prenatal diagnosis, non-invasive prenatal DNA detection is first performed. If the results of non-invasive prenatal DNA detection are negative, the pregnant women are followed up by ultrasound; if the results of non-invasive prenatal DNA detection are positive, the pregnant women should undergo invasive prenatal diagnosis. PMID:26445265

  19. Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management

    PubMed Central

    Gholam, C; Grigoriadou, S; Gilmour, K C; Gaspar, H B

    2011-01-01

    Familial haemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder of immune dysregulation associated with uncontrolled T cell and macrophage activation and hypercytokinaemia. The incidence of FHL is 0·12/100·000 children born per year, with a male to female ratio of 1:1. The disease is classified into six different types based on genetic linkage analysis and chromosomal localization; five specific genetic defects have been identified, which account for approximately 90% of all patients. Type 1 is due to an as yet unidentified gene defect located on chromosome nine. Type 2 is caused by mutations in the perforin (PRF1) gene, type 3 by mutations in the Munc-13–4 (UNC13D) gene, type 4 by mutations in the syntaxin 11 (STX11) gene and the recently described type 5 due to mutations in the gene encoding syntaxin binding protein 2 (STXBP-2). The incidence of the five types varies in different ethnic groups. The most common presenting features are pyrexia of unknown origin, pronounced hepatosplenomegaly and cytopenias. Neurological features tend to present later and are associated with poor prognosis. Absent or decreased lymphocyte cytotoxicity is the cellular hallmark of FHL. Biochemical features such as hyperferritinaemia, hypertriglyceridaemia and hypofibrinogenaemia are usually present, along with high levels of soluble interleukin 2 receptor in the blood and cerebrospinal fluid. Bone marrow aspirate may demonstrate the characteristic haemophagocytes, but initially is non-diagnostic in two-thirds of patients. Established international clinical, haematological and biochemical criteria now facilitate accurate clinical diagnosis. The disease is fatal unless a haematopoietic stem cell transplant (HSCT) is performed. The introduction of HSCT has dramatically improved the prognosis of the disease. However, the mortality of the disease is still significantly high and a number of challenges remain to be addressed. Active disease at the time of the transplant is the major significant poor prognostic factor. Delayed diagnosis, after irreversible organ damage has occurred, especially neurological damage, disease reoccurrence and pre-transplant mortality, remain a concern. PMID:21303357

  20. 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 therefore, even if an outright violation of Article 8 ECHR could not be found, there appears to be at least a breach of Article 8 in conjunction with Article 14 ECHR. PMID:23552505

  1. Carriers

    MedlinePlus

    ... available, such as adoption, prenatal testing, and pre-implantation genetic diagnosis (PGD). PGD screens embryos for genetic disorders and selects the unaffected embryos for implantation. Cure SMA believes that your family has the ...

  2. The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis.

    PubMed

    Wiesinger, Christoph; Eichler, Florian S; Berger, Johannes

    2015-01-01

    X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding a peroxisomal ABC transporter. In this review, we compare estimates of incidence derived from different populations in order to provide an overview of the worldwide incidence of X-ALD. X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN) to inflammatory demyelinating cerebral ALD (CALD). A large number of different mutations has been described, providing a unique opportunity for analysis of functional domains within ABC transporters. Yet the molecular basis for the heterogeneity of clinical symptoms is still largely unresolved, as no correlation between genotype and phenotype exists in X-ALD. Beyond ABCD1, environmental triggers and other genetic factors have been suggested as modifiers of the disease course. Here, we summarize the findings of numerous reports that aimed at identifying modifier genes in X-ALD and discuss potential problems and future approaches to address this issue. Different options for prenatal diagnosis are summarized, and potential pitfalls when applying next-generation sequencing approaches are discussed. Recently, the measurement of very long-chain fatty acids in lysophosphatidylcholine for the identification of peroxisomal disorders was included in newborn screening programs. PMID:25999754

  3. Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing.

    PubMed

    Høyer, Helle; Braathen, Geir J; Busk, Øyvind L; Holla, Øystein L; Svendsen, Marit; Hilmarsen, Hilde T; Strand, Linda; Skjelbred, Camilla F; Russell, Michael B

    2014-01-01

    Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven families (14%) carried the PMP22 duplication and one family carried a MPZ duplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency. PMID:25025039

  4. Diagnosis of gonorrhoea using a genetic transformation test at a venereal disease clinic in Thailand.

    PubMed

    Sangsue, S; McFarland, A; Duangmani, C; Echeverria, P; Zubrzycki, L

    1983-06-01

    A genetic transformation test (GTT), a technique in which gonococcal DNA is detected in clinical specimens, was used to search for Neisseria gonorrhoeae infections in 37 men and 159 women at the Venereal Disease clinic in Cholburi, Thailand. Swabs were collected in duplicate from cervical specimens from 159 women and from urethral specimens from 37 men. One of each specimen was cultured on Thayer-Martin media while the other was mailed to the United States at room temperature for the GTT which involved a delay of 10 to 14 days. With the urethral specimens N. gonorrhoeae was identified in 84% (31/37) of specimens and there was 100% concordance between the results of the GTT and culturing specimens directly on Thayer-Martin media. With cervical specimens N. gonorrhoeae was isolated from 26% (41/159) by the standard culture technique and 19% (13/159) by the GTT. Seventy-six percent of the culture positive specimens were positive with the GTT and two specimens from which N. gonorrhoeae were not isolated were positive in the GTT. The GTT technique enables physicians to send swab collected from patient with suspected gonorrhoea without any special transport media to a central laboratory for laboratory diagnosis of gonorrhoeal infections. This technique which uses reagents which are available in most bacteriology laboratories, should facilitate surveillance of gonorrhoea especially when specimens are collected in clinics where bacteriology laboratory facilities are not available. PMID:6415820

  5. Genetic Diagnosis of Charcot-Marie-Tooth Disease in a Population by Next-Generation Sequencing

    PubMed Central

    Høyer, Helle; Braathen, Geir J.; Busk, Øyvind L.; Holla, Øystein L.; Svendsen, Marit; Hilmarsen, Hilde T.; Strand, Linda; Skjelbred, Camilla F.; Russell, Michael B.

    2014-01-01

    Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven families (14%) carried the PMP22 duplication and one family carried a MPZ duplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency. PMID:25025039

  6. Optimizing the feature set for a Bayesian network for breast cancer diagnosis using genetic algorithm techniques

    NASA Astrophysics Data System (ADS)

    Wang, Xiao Hui; Zheng, Bin; Chang, Yuan-Hsiang; Good, Walter F.

    1999-05-01

    This study investigates the degree to which the performance of Bayesian belief networks (BBNs), for computer-assisted diagnosis of breast cancer, can be improved by optimizing their input feature sets using a genetic algorithm (GA). 421 cases (all women) were used in this study, of which 92 were positive for breast cancer. Each case contained both non-image information and image information derived from mammograms by radiologists. A GA was used to select an optimal subset of features, from a total of 21, to use as the basis for a BBN classifier. The figure-of-merit used in the GA's evaluation of feature subsets was Az, the area under the ROC curve produced by the corresponding BBN classifier. For each feature subset evaluated by the GA, a BBN was developed to classify positive and negative cases. Overall performance of the BBNs was evaluated using a jackknife testing method to calculate Az, for their respective ROC curves. The Az value of the BBN incorporating all 21 features was 0.851 plus or minus 0.012. After a 93 generation search, the GA found an optimal feature set with four non-image and four mammographic features, which achieved an Az value of 0.927 plus or minus 0.009. This study suggests that GAs are a viable means to optimize feature sets, and optimizing feature sets can result in significant performance improvements.

  7. Extraction of DNA from amniotic fluid cells for the early prenatal diagnosis of genetic disease.

    PubMed

    Rebello, M T; Hackett, G; Smith, J; Loeffler, F E; Robson, S; MacLachlan, N; Beard, R W; Rodeck, C H; Williamson, R; Coleman, D V

    1991-01-01

    Ten-ml samples of amniotic fluid were taken from pregnancies being terminated at 8-14 weeks' gestation. DNA was extracted from the amniotic cells by sequential centrifugation and analysed using the polymerase chain reaction (PCR). Fifteen samples were analysed for evidence of maternal contamination using Mfd5 oligonucleotide primers for repeat polymorphisms. Ten amniotic fluid samples were tested for the Delta-F508 deletion characteristic of cystic fibrosis to demonstrate a diagnostic application for the technique. In each case, DNA extracted from fetal tissue from the same pregnancy was included in the controls. In 14 of the 15 cases tested with the Mfd5 primers, both the amniotic fluid DNA and the fetal DNA showed no evidence of contaminating DNA. In one case, neither the amniotic fluid cells nor the fetal cells yielded results. In nine of the ten cases tested with the Delta-F508 primers, the amniotic fluid cell DNA provided accurate information about the genetic status of the fetus; in the tenth, the fetal DNA failed to amplify. The results indicate that adequate DNA can be extracted from amniotic fluid from 8 weeks' gestation onward and these samples are suitable for prenatal diagnosis using PCR. PMID:2027853

  8. The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis

    PubMed Central

    Wiesinger, Christoph; Eichler, Florian S; Berger, Johannes

    2015-01-01

    X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding a peroxisomal ABC transporter. In this review, we compare estimates of incidence derived from different populations in order to provide an overview of the worldwide incidence of X-ALD. X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN) to inflammatory demyelinating cerebral ALD (CALD). A large number of different mutations has been described, providing a unique opportunity for analysis of functional domains within ABC transporters. Yet the molecular basis for the heterogeneity of clinical symptoms is still largely unresolved, as no correlation between genotype and phenotype exists in X-ALD. Beyond ABCD1, environmental triggers and other genetic factors have been suggested as modifiers of the disease course. Here, we summarize the findings of numerous reports that aimed at identifying modifier genes in X-ALD and discuss potential problems and future approaches to address this issue. Different options for prenatal diagnosis are summarized, and potential pitfalls when applying next-generation sequencing approaches are discussed. Recently, the measurement of very long-chain fatty acids in lysophosphatidylcholine for the identification of peroxisomal disorders was included in newborn screening programs. PMID:25999754

  9. 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. PMID:26776178

  10. Diagnosis-Guided Method For Identifying Multi-Modality Neuroimaging Biomarkers Associated With Genetic Risk Factors In Alzheimer's Disease

    PubMed Central

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

    2015-01-01

    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. PMID:26776178

  11. 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

  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

    2015-01-01

    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

  13. 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. PMID:22814726

  14. 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. PMID:19580100

  15. Perinatal differential diagnosis of cystic kidney disease and urinary tract obstruction: anatomic pathologic, ultrasonographic and genetic findings.

    PubMed

    Friedmann, W; Vogel, M; Dimer, J S; Luttkus, A; Büscher, U; Dudenhausen, J W

    2000-04-01

    According to the classification of Osathanondh and Potter of cystic kidney diseases an antenatal differential diagnosis is presented, which is based on the anatomic pathologic, ultrasonographic and genetic findings. Since the ultrasound evaluation influences the obstetric and neonatal management, each second and third trimester sonography should consider the most common malformations in pediatric autopsies. The autosomal recessive polycystic kidney disease (ARPK), autosomal dominant polycystic kidney disease (ADPK), multicystic renal dysplasia, obstructive multicystic kidneys and cystic renal malformations found in other syndromes with genetic linkage are discussed in this review. PMID:10725570

  16. Update on autosomal recessive congenital ichthyosis: mRNA analysis using hair samples is a powerful tool for genetic diagnosis.

    PubMed

    Sugiura, Kazumitsu; Akiyama, Masashi

    2015-07-01

    Research on the molecular genetics and pathomechanisms of autosomal recessive congenital ichthyosis (ARCI) has advanced considerably and several causative genes and molecules underlying the disease have been identified. Three major ARCI phenotypes are harlequin ichthyosis (HI), lamellar ichthyosis (LI), and congenital ichthyosiform erythroderma (CIE). Skin barrier defects are involved in the pathogenesis of ARCI. In this review, the causative genes of ARCI and its phenotypes as well as recent advances in the field are summarized. The known causative molecules underlying ARCI include ABCA12, TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22, PNPLA1, CERS3, and LIPN. It is important to examine genetic associations and to elucidate the pathomechanisms of ARCI to establish effective therapies and beneficial genetic counseling. Next-generation sequencing is a promising method that enables the detection of causative disease mutations, even in cases of unexpected concomitant genetic diseases. For genetic diagnosis, obtaining mRNA from hair follicle epithelial cells, which are analogous to keratinocytes in the interfollicular epidermis, is convenient and minimally invasive in patients with ARCI. We confirmed that our mRNA analysis method using hair follicle samples can be applied not only to keratinization disorders, but also to other genetic diseases in the dermatology field. Studies that suggest potential next-generation therapies using ARCI model mice are also reviewed. PMID:25982146

  17. 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. PMID:24862219

  18. Dominant feature selection for the fault diagnosis of rotary machines using modified genetic algorithm and empirical mode decomposition

    NASA Astrophysics Data System (ADS)

    Lu, Lei; Yan, Jihong; de Silva, Clarence W.

    2015-05-01

    This paper develops a novel dominant feature selection method using a genetic algorithm with a dynamic searching strategy. It is applied in the search for the most representative features in rotary mechanical fault diagnosis, and is shown to improve the classification performance with fewer features. First, empirical mode decomposition (EMD) is employed to decompose a vibration signal into intrinsic mode functions (IMFs) which represent the signal characteristic with sample oscillatory modes. Then, a modified genetic algorithm with variable-range encoding and dynamic searching strategy is used to establish relationships between optimized feature subsets and the classification performance. Next, a statistical model that uses receiver operating characteristic (ROC) is developed to select dominant features. Finally, support vector machine (SVM) is used to classify different fault patterns. Two real-world problems, rotor-unbalance vibration and bearing corrosion, are employed to evaluate the proposed feature selection scheme and fault diagnosis system. Statistical results obtained by analyzing the two problems, and comparative studies with five well-known feature selection techniques, demonstrate that the method developed in this paper can achieve improvements in identification accuracy with lower feature dimensionality. In addition, the results indicate that the proposed method is a promising tool to select dominant features in rotary machinery fault diagnosis.

  19. 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

  20. PGD and aneuploidy screening for 24 chromosomes: advantages and disadvantages of competing platforms.

    PubMed

    Bisignano, A; Wells, D; Harton, G; Munné, S

    2011-12-01

    Diagnosis of embryos for chromosome abnormalities, i.e. aneuploidy screening, has been invigorated by the introduction of microarray-based testing methods allowing analysis of 24 chromosomes in one test. Recent data have been suggestive of increased implantation and pregnancy rates following microarray testing. Preimplantation genetic diagnosis for infertility aims to test for gross chromosome changes with the hope that identification and transfer of normal embryos will improve IVF outcomes. Testing by some methods, specifically single-nucleotide polymorphism (SNP) microarrays, allow for more information and potential insight into parental origin of aneuploidy and uniparental disomy. The usefulness and validity of reporting this information is flawed. Numerous papers have shown that the majority of meiotic errors occur in the egg, while mitotic errors in the embryo affect parental chromosomes at random. Potential mistakes made in assigning an error as meiotic or mitotic may lead to erroneous reporting of results with medical consequences. This study's data suggest that the bioinformatic cleaning used to 'fix' the miscalls that plague single-cell whole-genome amplification provides little improvement in the quality of useful data. Based on the information available, SNP-based aneuploidy screening suffers from a number of serious issues that must be resolved. PMID:21856229

  1. DNA Meets DSM: The Growing Importance of Genetic Syndromes in Dual Diagnosis.

    ERIC Educational Resources Information Center

    Dykens, Elisabeth M.

    1996-01-01

    This article notes a current de-emphasis on genetic syndromes in published articles concerning mental retardation despite major deoxyribonucleic acid (DNA) advances in determining mental retardation causes. The article calls for incorporation of these genetic advances into behavioral research of mental retardation, especially as reflected in the…

  2. Distal hereditary motor neuropathy with vocal cord paresis: from difficulty in choral singing to a molecular genetic diagnosis.

    PubMed

    Ingram, Gillian; Barwick, Katy E S; Hartley, Louise; McEntagart, Meriel; Crosby, Andrew H; Llewelyn, Gareth; Morris, Huw R

    2016-06-01

    Patients presenting with distal weakness can be a diagnostic challenge; the eventual diagnosis often depends upon accurate clinical phenotyping. We present a mother and daughter with a rare form of distal hereditary motor neuropathy type 7 in whom the diagnosis became apparent by initial difficulty in singing, from early vocal cord dysfunction. This rare neuropathy has now been identified in two apparently unrelated families in Wales. This family's clinical presentation is typical of distal hereditary motor neuropathy type 7, and they have the common truncating mutation in the SLC5A7 gene. Advances in genetic analysis of these rare conditions broaden our understanding of their potential molecular mechanisms and may allow more directed therapy. PMID:26786006

  3. 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 application in the plant biotechnology sector. Endopiceasin appears to derive from an endo- or epiphytic fungal strain rather than from the plant itself. PMID:23035776

  4. Prenatal genetic diagnosis of retinoblastoma – clinical correlates on follow-up

    PubMed Central

    Neriyanuri, Srividya; Raman, Rajiv; Rishi, Pukhraj; Govindasamy, Kumaramanickavel; Ramprasad, V L; Sharma, Tarun

    2015-01-01

    Retinoblastoma is the most common malignant intraocular tumor in pediatric age group if undetected leads to ocular mortality. Prenatal diagnosis is an emerging technology to detect fatal diseases in utero such that subsequent management is planned to reduce the ocular morbidity. We describe a case demonstrating the importance of prenatal diagnosis in a child with a strong family history of retinoblastoma and importance of a long-term clinical follow-up in these cases. PMID:26632134

  5. 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

  6. Permissibility of prenatal diagnosis and abortion for fetuses with severe genetic disorder: type 1 spinal muscular atrophy

    PubMed Central

    Sasongko, Teguh H.; Salmi, Abd Razak; Zilfalil, Bin Alwi; Albar, Mohammed Ali; Mohd Hussin, Zabidi Azhar

    2010-01-01

    Abortion has been largely avoided in Muslim communities. However, Islamic jurists have established rigorous parameters enabling abortion of fetuses with severe congenital abnormalities. This decision-making process has been hindered by an inability to predict the severity of such prenatally-diagnosed conditions, especially in genetic disorders with clinical heterogeneity, such as spinal muscular atrophy (SMA). Heterogeneous phenotypes of SMA range from extremely severe type 1 to very mild type 4. Advances in molecular genetics have made it possible to perform prenatal diagnosis and to predict the types of SMA with its potential subsequent severity. Such techniques will make it possible for clinicians working in predominantly Muslim countries to counsel their patients accurately and in harmony with their religious beliefs. In this paper, we discuss and postulate that with our current knowledge of determining SMA types and severity with great accuracy, abortion is legally applicable for type 1 SMA. PMID:21060155

  7. Existing challenges associated with offering prenatal genetic diagnosis in an Arab society in the Sultanate of Oman.

    PubMed

    Bruwer, Zandrè; Achandira, Udayakumar; Al Kharousi, Khalsa; Al-Kindy, Adila

    2014-12-01

    The incidence of congenital anomalies and/or genetic disorders in the Omani population has reached figures greater than double the global statistics. Preference for consanguineous unions together with the fact that termination of pregnancy in Muslim communities are largely avoided, have been highlighted as contributing factors. This overview identifies a third significant aspect contributing to the elevated rate of genetic disorders in the Omani population. Namely, a lack of services that are able to offer termination of pregnancy for severe congenital anomalies, to requesting parents. In this report we select an unusual case of a family at risk for two distinct genetic disorders--6q micro-deletion and unbalanced products of conception attributed to a balanced parental translocation involving chromosome 3 and 13, to portray and examine the current situation faced by Omani couples interested in prenatal diagnosis for termination of pregnancy. Additional challenges and pitfalls to developing a prenatal diagnostic service as part of the genetic service in Oman are discussed. PMID:25236482

  8. 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.

  9. 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.

  10. Statistical model for whole genome sequencing and its application to minimally invasive diagnosis of fetal genetic disease.

    PubMed

    Chu, Tianjiao; Bunce, Kimberly; Hogge, W Allen; Peters, David G

    2009-05-15

    There is currently great interest in the development of methods for the minimally invasive diagnosis of fetal genetic disease using cell-free DNA from maternal plasma samples obtained in the first trimester of pregnancy. With the rapid development of high-throughput sequencing technology, the possibility of detecting the presence of trisomy fetal genomes in the maternal plasma DNA sample has recently been explored. The major concern of this whole genome sequencing approach is that, while detecting the karyotype of the fetal genome from the maternal plasma requires extremely high accuracy of copy number estimation, the majority of the available high-throughput sequencing technologies require polymerase chain reaction (PCR) and are subject to the substantial bias that is inherent to the PCR process. We introduce a novel and sophisticated statistical model for the whole genome sequencing data, and based on this model, develop a highly sensitive method of Minimally Invasive Karyotyping (MINK) for the diagnosis of the fetal genetic disease. Specifically we demonstrate, by applying our statistical method to ultra high-throughput whole sequencing data, that trisomy 21 can be detected in a minor ('fetal') genome when it is mixed into a major ('maternal') background genome at frequencies as low as 5%. This observation provides additional proof of concept and justification for the further development of this method towards its eventual clinical application. Here, we describe the statistical and experimental methods that illustrate this approach and discuss future directions for technical development and potential clinical applications. PMID:19307238

  11. Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis.

    PubMed

    Donker, Albertine E; Raymakers, Reinier A P; Vlasveld, L Thom; van Barneveld, Teus; Terink, Rieneke; Dors, Natasja; Brons, Paul P T; Knoers, Nine V A M; Swinkels, Dorine W

    2014-06-19

    During recent years, our understanding of the pathogenesis of inherited microcytic anemias has gained from the identification of several genes and proteins involved in systemic and cellular iron metabolism and heme syntheses. Numerous case reports illustrate that the implementation of these novel molecular discoveries in clinical practice has increased our understanding of the presentation, diagnosis, and management of these diseases. Integration of these insights into daily clinical practice will reduce delays in establishing a proper diagnosis, invasive and/or costly diagnostic tests, and unnecessary or even detrimental treatments. To assist the clinician, we developed evidence-based multidisciplinary guidelines on the management of rare microcytic anemias due to genetic disorders of iron metabolism and heme synthesis. These genetic disorders may present at all ages, and therefore these guidelines are relevant for pediatricians as well as clinicians who treat adults. This article summarizes these clinical practice guidelines and includes background on pathogenesis, conclusions, and recommendations and a diagnostic flowchart to facilitate using these guidelines in the clinical setting. PMID:24665134

  12. Discrepancy in compliance between the clinical and genetic diagnosis of choroidal hypoplasia in Danish Rough Collies and Shetland Sheepdogs.

    PubMed

    Fredholm, M; Larsen, R C; Jönsson, M; Söderlund, M A; Hardon, T; Proschowsky, H F

    2016-04-01

    Collie eye anomaly (CEA) is a congenital, inherited ocular disorder which is widespread in herding breeds. Clinically, the two major lesions associated with CEA are choroidal hypoplasia (CH) and coloboma, and both lesions are diagnosed based on ophthalmological examination. A 7.8-kb intronic deletion in the gene encoding non-homologous end-joining factor 1 (NHEJ1) has been reported to be the causative mutation underlying CH when present in the homozygous state. In this study, we have investigated the compliance between the clinical and genetic diagnosis of CH in the Danish Rough Collie and Shetland Sheepdog populations. Our results show that the deletion in NHEJ1 is not predictive for CH in the Danish Rough Collie population, whereas the clinical and genetic diagnosis is in accordance with each other in the Shetland Sheepdog population. Based on these results, it can be concluded that the intronic deletion in NHEJ1 is not the causative mutation but, rather, a marker linked to the locus underlying the trait in some populations but linked to both the wild-type and CH-causing locus in most dogs in the Danish Rough Collie population. PMID:26732749

  13. 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

  14. 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

  15. Genetic Identification Is Critical for the Diagnosis of Parkinsonism: A Chinese Pedigree with Early Onset of Parkinsonism

    PubMed Central

    Yang, Yang; Tang, Bei-sha; Weng, Ling; Li, Nan; Shen, Lu; Wang, Jian; Zuo, Chuan-tao; Yan, Xin-xiang; Xia, Kun; Guo, Ji-feng

    2015-01-01

    Background A number of hereditary neurological diseases display indistinguishable features at the early disease stage. Parkinsonian symptoms can be found in numerous diseases, making it difficult to get a definitive early diagnosis of primary causes for patients with onset of parkinsonism. The accurate and early diagnosis of the causes of parkinsonian patients is important for effective treatments of these patients. Methods We have identified a Chinese family (82 family members over four generations with 21 affected individuals) that manifested the characterized symptoms of parkinsonism and was initially diagnosed as Parkinson’s disease. We followed up with the family for two years, during which we carried out clinical observations, Positron Emission Tomography-Computed Tomography neuroimaging analysis, and exome sequencing to correctly diagnose the case. Results During the two-year follow-up period, we performed comprehensive medical history collection, physical examination, and structural and functional neuroimaging studies of this Chinese family. We found that the patient exhibited progressive deteriorated parkinsonism with Parkinson disease-like neuropathology and also had a good response to the initial levodopa treatment. However, exome sequencing identified a missense mutation, N279K, in exon 10 of MAPT gene, verifying that the early parkinsonian symptoms in this family are caused by the genetic mutation for hereditary frontotemporal lobar dementia. Conclusions For the inherited parkinsonian patients who even show the neuropathology similar to that in Parkinson’s disease and have initial response to levodopa treatment, genetic identification of the molecular basis for the disease is still required for defining the early diagnosis and correct treatment. PMID:26295349

  16. Diagnosis of Fanconi Anemia: Mutation Analysis by Multiplex Ligation-Dependent Probe Amplification and PCR-Based Sanger Sequencing

    PubMed Central

    Gille, Johan J. P.; Floor, Karijn; Kerkhoven, Lianne; Ameziane, Najim; Joenje, Hans; de Winter, Johan P.

    2012-01-01

    Fanconi anemia (FA) is a rare inherited disease characterized by developmental defects, short stature, bone marrow failure, and a high risk of malignancies. FA is heterogeneous: 15 genetic subtypes have been distinguished so far. A clinical diagnosis of FA needs to be confirmed by testing cells for sensitivity to cross-linking agents in a chromosomal breakage test. As a second step, DNA testing can be employed to elucidate the genetic subtype of the patient and to identify the familial mutations. This knowledge allows preimplantation genetic diagnosis (PGD) and enables prenatal DNA testing in future pregnancies. Although simultaneous testing of all FA genes by next generation sequencing will be possible in the near future, this technique will not be available immediately for all laboratories. In addition, in populations with strong founder mutations, a limited test using Sanger sequencing and MLPA will be a cost-effective alternative. We describe a strategy and optimized conditions for the screening of FANCA, FANCB, FANCC, FANCE, FANCF, and FANCG and present the results obtained in a cohort of 54 patients referred to our diagnostic service since 2008. In addition, the follow up with respect to genetic counseling and carrier screening in the families is discussed. PMID:22778927

  17. 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. PMID:26980585

  18. Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation

    PubMed Central

    Cantu, Edward; Shah, Rupal J.; Lin, Wei; Daye, Zhongyin J.; Diamond, Joshua M.; Suzuki, Yoshikazu; Ellis, John H.; Borders, Catherine F.; Andah, Gerald A.; Beduhn, Ben; Meyer, Nuala J.; Ruschefski, Melanie; Aplenc, Richard; Feng, Rui; Christie, Jason D.

    2014-01-01

    Objective Oxidant stress pathway activation during ischemia reperfusion injury may contribute to the development of primary graft dysfunction (PGD) after lung transplantation. We hypothesized oxidant stress gene variation in recipients and donors is associated with PGD. Methods Donors and recipients from the Lung Transplant Outcomes Group (LTOG) cohort were genotyped using the Illumina IBC chip filtered for oxidant stress pathway genes. Single nucleotide polymorphisms (SNPs) grouped into SNP-sets based on haplotype blocks within 49 oxidant stress genes selected from gene ontology pathways and literature review were tested for PGD association using a sequencing kernel association test. Analyses were adjusted for clinical confounding variables and population stratification. Results 392 donors and 1038 recipients met genetic quality control standards. 30% of subjects developed grade 3 PGD within 72 hours. Donor NADPH Oxidase 3 (NOX3) was associated with PGD (p=0.01) with 5 individual significant loci (p-values between 0.006 and 0.03). In recipients, variation in glutathione peroxidase (GPX1) and NRF-2 (NFE2L2) was significantly associated with PGD (p=0.01 for both). The GPX1 association included 3 individual loci (p-values between 0.006 and 0.049) and the NFE2L2 association included 2 loci (p=0.03 and 0.05). Significant epistatic effects influencing PGD susceptibility were evident between three different donor blocks of NOX3 and recipient NFE2L2 (p=0.026, p=0.017 and p=0.031). Conclusions Our study prioritizes GPX1, NOX3, and NFE2L2 genes for future research in PGD pathogenesis, and highlights a donor-recipient interaction of NOX3 and NFE2L2 that increases PGD risk. PMID:25439478

  19. 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

  20. 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

  1. Mosaic small supernumerary marker chromosome 1 at amniocentesis: prenatal diagnosis, molecular genetic analysis and literature review.

    PubMed

    Chen, Chih-Ping; Chen, Ming; Su, Yi-Ning; Huang, Jian-Pei; Chern, Schu-Rern; Wu, Peih-Shan; Su, Jun-Wei; Chang, Shun-Ping; Chen, Yu-Ting; Lee, Chen-Chi; Chen, Li-Feng; Pan, Chen-Wen; Wang, Wayseen

    2013-10-15

    We present prenatal diagnosis and molecular cytogenetic analysis of mosaic small supernumerary marker chromosome 1 [sSMC(1)]. We review the literature of sSMC(1) at amniocentesis and chromosome 1p21.1-p12 duplication syndrome. We discuss the genotype-phenotype correlation of the involved genes of ALX3, RBM15, NTNG1, SLC25A24, GPSM2, TBX15 and NOTCH2 in this case. PMID:23933412

  2. 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. PMID:27017833

  3. Accurate genetic diagnosis of Finnish pulmonary arterial hypertension patients using oligonucleotide-selective sequencing

    PubMed Central

    Vattulainen, Sanna; Aho, Joonas; Salmenperä, Pertteli; Bruce, Siina; Tallila, Jonna; Gentile, Massimiliano; Sankelo, Marja; Laitinen, Tarja; Koskenvuo, Juha W; Alastalo, Tero-Pekka; Myllykangas, Samuel

    2015-01-01

    The genetic basis of pulmonary arterial hypertension (PAH) among Finnish PAH patients is poorly understood. We adopted a novel-targeted next-generation sequencing (NGS) approach called Oligonucleotide-Selective Sequencing (OS-Seq) and developed a custom data analysis and interpretation pipeline to identify pathogenic base substitutions, insertions, and deletions in seven genes associated with PAH (BMPR2, BMPR1B, ACVRL1, ENG, SMAD9, CAV1, and KCNK3) from Finnish PAH patients. This study represents the first clinical study with OS-Seq technology on patients suffering from a rare genetic disorder. We analyzed DNA samples from 21 Finnish PAH patients, whose BMPR2 and ACVRL1 mutation status had been previously studied using Sanger sequencing. Our sequencing panel covered 100% of the targeted base pairs with >15× sequencing depth. Pathogenic base substitutions were identified in the BMPR2 gene in 29% of the Finnish PAH cases. Two of the pathogenic variant-positive patients had been previously tested negative using Sanger sequencing. No clinically significant variants were identified in the six other PAH genes. Our study validates the use of targeted OS-Seq for genetic diagnostics of PAH and revealed pathogenic variants that had been previously missed using Sanger sequencing. PMID:26247051

  4. [Dilated cardiomyopathy (DCM) in dogs--pathological, clinical, diagnosis and genetic aspects].

    PubMed

    Broschk, C; Distl, O

    2005-10-01

    Dilated cardiomyopathy (DCM) is a heart disease which is often found in humans and animals. The age of onset of this progressive disease varies between 3 and 7 years of age. A juvenile form of DCM has been found in Portuguese Water Dogs and Doberman Pinscher Dogs. Some breeds such as Doberman pinscher, Newfoundland, Portuguese Water dog, Boxer, Great Dane, Cocker Spaniel and Irish Wolfhound exhibit a higher prevalence to DCM. There also seems to be a sex predisposition as male dogs are affected more often than female dogs and in Great Danes an X-linked recessive inheritance is likely. In Newfoundland and Boxer an autosomal dominant inheritance was found whereas an autosomal recessive inheritance was described in Portuguese Water Dogs. Atrial fibrillation as a cause or consequence of DCM is assumed for certain breeds. The causes of DCM are widely unknown in dogs. A genetic basis for this heart disease seems to exist. Apart from a few exceptions the mode of inheritance and the possible underlying gene mutations are not known for DCM in dogs. In humans mutations in several genes responsible for DCM have been identified. Comparative genetic analyses in dogs using genes causing DCM in men and a genome-wide scan with anonymus markers were not able to detect causative mutations or genomic regions harboring gene loci linked to DCM. The investigation of the genetic basis of canine DCM may lead to new insights into the pathogenesis of DCM and may result in new therapeutic approaches and breeding strategies. PMID:16320572

  5. 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

  6. Erythrocytosis due to PHD2 Mutations: A Review of Clinical Presentation, Diagnosis, and Genetics.

    PubMed

    Wilson, Rachel; Syed, Nausheen; Shah, Prabodh

    2016-01-01

    The association of mutations in the PHD2 protein of the hypoxia-sensing pathway and erythrocytosis has only been established in the last decade. Here we report the case of a novel PHD2 gene mutation in a patient with erythrocytosis and summarize all reported cases to date. Case Report. A 55-year-old man presented with dyspnea and a previous diagnosis of idiopathic erythrocytosis. PHD gene sequencing revealed a mutation on exon 2. The mutation was recognized as p.(Trp334(⁎)) (c. 1001G>A) resulting in a truncation of a highly conserved amino acid residue in catalytic domain. A diagnosis of erythrocytosis secondary to mutant PHD2 gene was made. Conclusions. Our findings indicate that with PHD2 mutations there is moderate erythrocytosis and erythropoietin (Epo) levels are generally low to normal. Two patients with PHD2 substitution mutations were found to have paraganglioma and one of these patients had a concurrent pheochromocytoma. In addition, one mutation was associated with sagittal sinus thrombosis. Given the severity of some of the clinical features of these mutations, we conclude that clinical guidelines should include the PHD2 mutation in the idiopathic erythrocytosis workup. PMID:27034858

  7. Epidemiology, medical genetics, diagnosis and treatment of harlequin ichthyosis in Japan.

    PubMed

    Shibata, Akitaka; Akiyama, Masashi

    2015-08-01

    Ichthyoses are a group of disorders marked by whitish, brown or dark-brown scales on the skin of almost the whole body. Harlequin ichthyosis (HI) is the most severe form. Neonatal death from HI was once common. Due to intensive neonatal care and, probably, to the early introduction of oral retinoids, HI outcome has improved. For definitive diagnosis and the exclusion of other disorders, such as lamellar ichthyosis, which also shows a collodion baby phenotype, it is helpful to refer to electron microscopy of abnormal or absent lamellar granules and a heavy accumulation of lipid droplets in the keratinocytes. ATP-binding cassette transporter A12 (ABCA12) is known as the causative gene of HI. Severe ABCA12 deficiency results in malformation of intercellular lipid layers in the cornified layers and leads to epidermal lipid barrier disruption. In HI patients, at least one mutation on each allele must be a truncation or deletion mutation to cause serious loss of ABCA12 function. Identification of the gene underlying HI has enabled DNA-based prenatal diagnosis for HI at the earlier stages of pregnancy with low risk. There are no curative treatments for HI. Abca12-deficient mice were created as a model of HI. Treatment of the model mice with retinoid or steroid has not been successful. PMID:25857373

  8. Erythrocytosis due to PHD2 Mutations: A Review of Clinical Presentation, Diagnosis, and Genetics

    PubMed Central

    Wilson, Rachel; Syed, Nausheen; Shah, Prabodh

    2016-01-01

    The association of mutations in the PHD2 protein of the hypoxia-sensing pathway and erythrocytosis has only been established in the last decade. Here we report the case of a novel PHD2 gene mutation in a patient with erythrocytosis and summarize all reported cases to date. Case Report. A 55-year-old man presented with dyspnea and a previous diagnosis of idiopathic erythrocytosis. PHD gene sequencing revealed a mutation on exon 2. The mutation was recognized as p.(Trp334⁎) (c. 1001G>A) resulting in a truncation of a highly conserved amino acid residue in catalytic domain. A diagnosis of erythrocytosis secondary to mutant PHD2 gene was made. Conclusions. Our findings indicate that with PHD2 mutations there is moderate erythrocytosis and erythropoietin (Epo) levels are generally low to normal. Two patients with PHD2 substitution mutations were found to have paraganglioma and one of these patients had a concurrent pheochromocytoma. In addition, one mutation was associated with sagittal sinus thrombosis. Given the severity of some of the clinical features of these mutations, we conclude that clinical guidelines should include the PHD2 mutation in the idiopathic erythrocytosis workup. PMID:27034858

  9. Ethical dilemmas in genetic testing: examples from the Cuban program for predictive diagnosis of hereditary ataxias.

    PubMed

    Mario, Tania Cruz; Armin, Rubn Reynaldo; Cedeo, Humberto Jorge; Mesa, Jos Miguel Laffita; Zaldivar, Yanetza Gonzlez; Rodrguez, Ral Aguilera; Santos, Miguel Velzquez; Mederos, Luis Enrique Almaguer; Herrera, Milena Paneque; Prez, Luis Velzquez

    2011-06-01

    Predictive testing protocols are intended to help patients affected with hereditary conditions understand their condition and make informed reproductive choices. However, predictive protocols may expose clinicians and patients to ethical dilemmas that interfere with genetic counseling and the decision making process. This paper describes ethical dilemmas in a series of five cases involving predictive testing for hereditary ataxias in Cuba. The examples herein present evidence of the deeply controversial situations faced by both individuals at risk and professionals in charge of these predictive studies, suggesting a need for expanded guidelines to address such complexities. PMID:21264501

  10. Inactivation of the wall-associated de-N-acetylase (PgdA) of Listeria monocytogenes results in greater susceptibility of the cells to induced autolysis.

    PubMed

    Popowska, Magdalena; Kusio, Monika; Szymanska, Paulina; Markiewicz, Zdzislaw

    2009-09-01

    Several species of Gram-positive bacteria have cell wall peptidoglycan (syn. murein) in which not all of the sugar moieties are N-acetylated. This has recently been shown to be a secondary effect, caused by the action of a peptidoglycan N-acetylglucosamine deacetylase. We have found that the opportunistic pathogen Listeria monocytogenes is unusual in having three enzymes with such activity, two of which remain in the cytoplasm. Here, we examine the enzyme (PgdA) that crosses the cytoplasmic membrane and is localized in the cell wall. We purified a hexa-His-tagged form of PgdA to study its activity and constructed a mutant devoid of functional Lmo0415 (PgdA) protein. L. monocytogenes PgdA protein exhibited peptidoglycan N-acetylglucosamine deacetylase activity with natural substrates (peptidoglycan) from both L. monocytogenes and Escherichia coli as well as the peptidoglycan sugar chain component N-acetylglucosamine, but not with N-acetylmuramic acid. As was reported recently [6], inactivation of the structural gene was not lethal for L. monocytogenes nor did it affect growth rate or morphology of the cells. However, the pgdA mutant was more prone to autolysis induced by such agents as Triton X-100 and EDTA, and is more susceptible to the cationic antimicrobial peptides (CAMP) lysozyme and mutanolysin, using either peptidoglycan muramidases or autolysis-inducing agents. The pgdA mutant was also slightly more susceptible than the wild-type strain to the action of certain beta-lactam antibiotics. Our results indicate that protein PgdA plays a protective physiological role for listerial cells. PMID:19809250

  11. Legislation on Genetic Diagnosis: Comparison of South Korea and Germany: - With Focus on the Application and Communication Structure.

    PubMed

    Kim, Na-Kyoung

    2015-06-01

    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

  12. Screening and Genetic Diagnosis of Hemoglobinopathies in Southern and Northern Europe: Two Examples

    PubMed Central

    Amato, Antonio; Giordano, Piero C.

    2009-01-01

    Prevention of Hemoglobinopathies has developed around the world based upon the experience done in pioneering endemic countries and is now facing a new phase in non-endemic areas with a recent immigration history. We describe two situations, taking Latium (central Italy) and The Netherlands as two models for endemic and non-endemic countries both confronted with a large multi-ethnic immigrant society. We present prevention results and discuss aspects such as local knowledge and organization. We illustrate the importance of issues like information, carrier diagnostics, screening, counseling and prenatal diagnosis in particular situation of contrasting interest an different ethical opinions. We conclude by underlining the importance of implementing primary prevention at the European level, based upon better information, diagnostics and counseling. PMID:21415989

  13. 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

    2013-01-01

    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 between TNGB and Patients' Associations, has demonstrated how promoting Biobank services can be instrumental in gaining a critical mass of samples essential for research, as well as, raising awareness, trust and interest of the general public in Biobanks. This article focuses on some fundamental aspects of networking and demonstrates how the translational research benefits from a sustained infrastructure. PMID:24004821

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

    PubMed Central

    2013-01-01

    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 between TNGB and Patients’ Associations, has demonstrated how promoting Biobank services can be instrumental in gaining a critical mass of samples essential for research, as well as, raising awareness, trust and interest of the general public in Biobanks. This article focuses on some fundamental aspects of networking and demonstrates how the translational research benefits from a sustained infrastructure. PMID:24004821

  15. 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. PMID:23790482

  16. Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound

    PubMed Central

    Carss, Keren J.; Hillman, Sarah C.; Parthiban, Vijaya; McMullan, Dominic J.; Maher, Eamonn R.; Kilby, Mark D.; Hurles, Matthew E.

    2014-01-01

    The genetic etiology of non-aneuploid fetal structural abnormalities is typically investigated by karyotyping and array-based detection of microscopically detectable rearrangements, and submicroscopic copy-number variants (CNVs), which collectively yield a pathogenic finding in up to 10% of cases. We propose that exome sequencing may substantially increase the identification of underlying etiologies. We performed exome sequencing on a cohort of 30 non-aneuploid fetuses and neonates (along with their parents) with diverse structural abnormalities first identified by prenatal ultrasound. We identified candidate pathogenic variants with a range of inheritance models, and evaluated these in the context of detailed phenotypic information. We identified 35 de novo single-nucleotide variants (SNVs), small indels, deletions or duplications, of which three (accounting for 10% of the cohort) are highly likely to be causative. These are de novo missense variants in FGFR3 and COL2A1, and a de novo 16.8 kb deletion that includes most of OFD1. In five further cases (17%) we identified de novo or inherited recessive or X-linked variants in plausible candidate genes, which require additional validation to determine pathogenicity. Our diagnostic yield of 10% is comparable to, and supplementary to, the diagnostic yield of existing microarray testing for large chromosomal rearrangements and targeted CNV detection. The de novo nature of these events could enable couples to be counseled as to their low recurrence risk. This study outlines the way for a substantial improvement in the diagnostic yield of prenatal genetic abnormalities through the application of next-generation sequencing. PMID:24476948

  17. Direct detection of common and rare inversion mutations in the genetic diagnosis of severe hemophilia A

    SciTech Connect

    Windsor, A.S.; Lillicrap, D.P.; Taylor, S.A.M.

    1994-09-01

    Approximately 50% of the cases of severe hemophilia A (factor VIII:C < 0.01 units/ml) may be due to gross rearrangements of the factor VIII gene. The mutation involves homologous sequences upstream of the factor VIII locus and within intron 22 in an intrachromosomal recombination, inversion, event. The rearrangements can readily be detected on a Southern blot using a probe that is complementary to sequences from within intron 22. We describe here the analysis of this mutation in 71 severe hemophilia A patients. Thirty two of the patients (45%) showed evidence of a rearrangement. Five different patterns of rearrangements were seen, two of which have previously been described and account for the majority of cases (pattern 1, 70% and pattern 2, 16%). Three other abnormal patterns were observed. The inversion mechanism does not usually result in the loss or gain of any genetic material, but in one patient, in whom a unique rearrangement pattern was observed (pattern 3), we have previously documented a gross deletion which removes exons 1-22 of the factor VII gene as well as sequences 5{prime} to the gene. In another individual a fourth pattern in which an extra 19.0 kb band is present was detected. In this case it is unclear as to whether the rearrangement is responsible for the disease or is simply coincident normal variation. A fifth pattern, in which an extra 16.0 kb band was detected, was observed in a family with a new mutation causing hemophilia A. The affected individual and his mother inherited a de novo rearrangement of the factor VIII gene from his unaffected grandfather, implicating it as the cause of the disease. In conclusion, testing for the factor VIII inversion mutation was positive in approximately 45% of severe hemophiliacs, 72% of whom were isolated cases, and as such should constitute the initial stage in the genetic testing protocol for these patients` families.

  18. Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound.

    PubMed

    Carss, Keren J; Hillman, Sarah C; Parthiban, Vijaya; McMullan, Dominic J; Maher, Eamonn R; Kilby, Mark D; Hurles, Matthew E

    2014-06-15

    The genetic etiology of non-aneuploid fetal structural abnormalities is typically investigated by karyotyping and array-based detection of microscopically detectable rearrangements, and submicroscopic copy-number variants (CNVs), which collectively yield a pathogenic finding in up to 10% of cases. We propose that exome sequencing may substantially increase the identification of underlying etiologies. We performed exome sequencing on a cohort of 30 non-aneuploid fetuses and neonates (along with their parents) with diverse structural abnormalities first identified by prenatal ultrasound. We identified candidate pathogenic variants with a range of inheritance models, and evaluated these in the context of detailed phenotypic information. We identified 35 de novo single-nucleotide variants (SNVs), small indels, deletions or duplications, of which three (accounting for 10% of the cohort) are highly likely to be causative. These are de novo missense variants in FGFR3 and COL2A1, and a de novo 16.8 kb deletion that includes most of OFD1. In five further cases (17%) we identified de novo or inherited recessive or X-linked variants in plausible candidate genes, which require additional validation to determine pathogenicity. Our diagnostic yield of 10% is comparable to, and supplementary to, the diagnostic yield of existing microarray testing for large chromosomal rearrangements and targeted CNV detection. The de novo nature of these events could enable couples to be counseled as to their low recurrence risk. This study outlines the way for a substantial improvement in the diagnostic yield of prenatal genetic abnormalities through the application of next-generation sequencing. PMID:24476948

  19. Avoiding pitfalls in molecular genetic testing: case studies of high-resolution array comparative genomic hybridization testing in the definitive diagnosis of Mowat-Wilson syndrome.

    PubMed

    Kluk, Michael Joseph; An, Yu; James, Philip; Coulter, David; Harris, David; Wu, Bai-Lin; Shen, Yiping

    2011-05-01

    The molecular testing options available for the diagnosis of genetic disorders are numerous and include a variety of different assay platforms. The consultative input of molecular pathologists and cytogeneticists, working closely with the ordering clinicians, is often important for definitive diagnosis. Herein, we describe two patients who had long histories of unexplained signs and symptoms with a high clinical suspicion of an underlying genetic etiology. Initial molecular testing in both cases was negative, but the application of high-resolution array comparative genomic hybridization technology lead to definitive diagnosis in both cases. We summarize the clinical findings and molecular testing in each case, discuss the differential diagnoses, and review the clinical and pathological findings of Mowat-Wilson syndrome. This report highlights the importance for those involved in molecular testing to know the nature of the underlying genetic abnormalities associated with the suspected diagnosis, to recognize the limitations of each testing platform, and to persistently pursue repeat testing using high-resolution technologies when indicated. This concept is applicable to both germline and somatic molecular genetic testing. PMID:21497296

  20. Primary effusion lymphoma: cytopathologic diagnosis using in situ molecular genetic analysis for human herpesvirus 8.

    PubMed

    Wakely, Paul E; Menezes, Geetha; Nuovo, Gerard J

    2002-09-01

    Primary effusion lymphoma is a form of diffuse large B-cell lymphoma with neoplastic cells largely limited to proliferation within major body cavities. Human herpes virus-8 is both integral to and required for an unequivocal diagnosis of primary effusion lymphoma. Prior methods for virus identification include DNA extraction with Southern blot analysis or in situ hybridization from paraffin-embedded samples. Our aim is to examine the utility of human herpesvirus-8 identification performed directly on smears from effusion samples by reverse transcriptase in situ polymerase chain reaction in patients with primary effusion lymphoma. Smears and cell block of body cavity fluids from five patients with effusions (three pleural, one peritoneal, and one both pleural and peritoneal) were examined microscopically by conventional Papanicolaou and Romanowsky (Diff-Quik) staining, and by reverse transcriptase in situ polymerase chain reaction for human herpesvirus-8 detection. In situ hybridization was performed also for Epstein-Barr virus (EBER-1, -2), T-cell receptor-beta, and kappa (kappa) and lambda (lambda) mRNA in all cases. Five adults ranged from 40-81 years of age. Three adults were HIV positive, one was a renal transplant recipient, and the oldest patient (Case 3) had the unusual distinction of a normal immune status. Two of three HIV-seropositive patients had concurrent Kaposi sarcoma. All samples were cytologically similar with lymphocytes having large-cell, plasmablastic, and immunoblastic morphology. Malignant cells from effusions were as follows: human herpesvirus-8 positive (all five cases), exhibited kappa monoclonal light chain (five cases), Epstein-Barr virus positive (three cases), and T-cell beta-gene receptor positive (two cases). Diffuse large B-cell lymphoma was evident in one peritoneal nodule (< 10% human herpesvirus-8 positive cells in contrast to > 90% positive in effusions, all kappa positive). Six other tissue specimens (lung, bone marrow, spleen, lymph node) were human herpesvirus-8 negative, and showed no evidence of lymphoma. Reverse transcriptase in situ polymerase chain reaction demonstrated near-complete restriction of human herpesvirus-8-infected malignant lymphoid cells to those in body cavities. Definitive diagnosis of primary effusion lymphoma is possible directly from cytologic smears/cell block by combining cytologic morphology with reverse transcriptase in situ polymerase chain reaction detection of human herpesvirus-8. PMID:12218212

  1. 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.

  2. 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

  3. 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

  4. Integrative functional genetic-epigenetic approach for selecting genes as urine biomarkers for bladder cancer diagnosis.

    PubMed

    Eissa, Sanaa; Matboli, Marwa; Essawy, Nada O E; Kotb, Youssef M

    2015-12-01

    Early screening for bladder cancer (BC) holds the key to combat and control the increasing global burden of BC mortality. We presented a simple approach to characterize, analyze, and validate a panel of biomarkers in BC and their relationship to bilharziasis. We investigated voided urine and blood samples from patients with bladder cancer (n = 94), benign bladder lesions (n = 60), and age-matched normal controls (n = 56). This study was divided into the following phases. (1) We analyzed the expression of urinary Hyaluronoglucosaminidase 1 (HYAL1) protein in BC and control samples by zymography. (2) We performed bioinformatics analysis to retrieve a set of epigenetic regulators of HYAL1. (3) This set of three selected genes [long non-coding RNA-urothelial cancer associated 1(lncRNA-UCA1), microRNA-210, and microRNA-96] was then analyzed in the same urine samples used in phase I by quantitative real-time PCR. (4) A high reproducibility of gene selection results was also determined from statistical validation. The urinary expression of HYAL1 protein and its epigenetic regulators were higher in BC patients (P < .001). The receiver-operating characteristic curve analyses demonstrated that each one had good sensitivity and specificity for distinguishing BC patients from non-BC ones (HYAL1, 89.4 and 91.2 %; miR-210, 76.6 and 93 %; miR-96, 76.6 and 89.4 %; and lncRNA-UCA1, 91.5 and 96.5 %). There was a significant positive correlation between HYAL1 and the selected epigenetic biomarkers. The performance of this urine biomarker panel reached 100 % sensitivity and 89.5 % specificity for bladder cancer diagnosis. PMID:26138586

  5. CEP3 and CEP17 DNA probe potential in the genetic diagnosis and prognostic prediction of esophageal squamous cell cancer

    PubMed Central

    NIYAZ, MADINIYAT; ABDURAHMAN, ABLAJAN; TURGHUN, ABDUGHENI; AWUT, IDIRIS

    2016-01-01

    The aim of the present study was to investigate the clinical application of molecular pathological diagnosis for the prognosis of Kazakh patients with esophageal squamous cell carcinoma (ESCC) using centromere enumeration probes (CEPs) for chromosomes 3 and 17. A total of 40 patients with ESCC that had received radical surgical treatment and 10 healthy control participants were enrolled in the present study. Touch preparations of fresh cancerous and normal tissues were completed and fluorescence in situ hybridization (FISH) was performed to count the copy numbers of CEP 3 and 17, and abnormalities were analyzed, in comparison with routine pathological diagnoses. FISH analysis demonstrated that abnormal copy numbers of CEP 3 and 17 (aneuploidy) were detected in all 40 patients with ESCC. CEP 3 and 17 polyploidy rates differed significantly between poorly differentiated, moderately differentiated and well-differentiated ESCC groups (P<0.05): Well-differentiated, 35.38 and 30.92%; moderately differentiated, 55.81 and 44.43%; and poorly differentiated, 76.26 and 71.90%, respectively. Furthermore, polyploidy rates were significantly increased in the group with lymph node metastasis, as compared with the group without (CEP 3, P=0.0001; CEP 17, P=0.012). Variations in the copy numbers of CEP 3 and 17 were demonstrated to be correlated with the level of differentiation and lymph node metastasis in patients with ESCC. Therefore, the present results indicate that DNA probes may be used to predict prognostic factors in patients with ESCC. Furthermore, FISH technology is an objective and qualitative method that is capable of detecting variations in CEP 3 and 17; therefore, FISH may be used in the genetic diagnosis of ESCC in Kazakh patients. PMID:27073452

  6. Automated analysis of fluorescent in situ hybridization (FISH) labeled genetic biomarkers in assisting cervical cancer diagnosis.

    PubMed

    Wang, Xingwei; Zheng, Bin; Zhang, Roy R; Li, Shibo; Chen, Xiaodong; Mulvihill, John J; Lu, Xianglan; Pang, Hui; Liu, Hong

    2010-06-01

    The numerical and/or structural deviation of some chromosomes (i.e., monosomy and _polysomy of chromosomes 3 and X) are routinely used as positive genetic biomarkers to diagnose cervical cancer and predict the disease progression. Among the available diagnostic methods to analyze the aneusomy of chromosomes 3 and X, fluorescence in situ hybridization (FISH) technology has demonstrated significant advantages in assisting clinicians to more accurately detect and diagnose cervical carcinoma at an early stage, in particular for the women at a high risk for progression of low-grade and high-grade squamous intra-epithelium lesions (LSIL and HSIL). In order to increase the diagnostic accuracy, consistency, and efficiency from that of manual FISH analysis, this study aims to develop and test an automated FISH analysis method that includes a two-stage scheme. In the first stage, an interactive multiple-threshold algorithm is utilized to segment potential interphase nuclei candidates distributed in different intensity levels and a rule-based classifier is implemented to identify analyzable interphase cells. In the second stage, FISH labeled biomarker spots of chromosomes 3 and X are segmented by a top-hat transform. The independent FISH spots are then detected by a knowledge-based classifier, which enables recognition of the splitting and stringy FISH signals. Finally, the ratio of abnormal interphase cells with numerical changes of chromosomes 3 and X is calculated to detect positive cases. The experimental results of four test cases showed high agreement of FISH analysis results between the automated scheme and the cytogeneticist's analysis including 92.7% to 98.7% agreement in cell segmentation and 4.4% to 11.0% difference in cell classification. This preliminary study demonstrates the feasibility of potentially applying the automatic FISH analysis method to expedite the screening and detecting cervical cancer at an early stage. PMID:20441233

  7. Circulating trophoblastic cells provide genetic diagnosis in 63 fetuses at risk for cystic fibrosis or spinal muscular atrophy.

    PubMed

    Mouawia, Hussein; Saker, Ali; Jais, Jean-Philippe; Benachi, Alexandra; Bussières, Laurence; Lacour, Bernard; Bonnefont, Jean-Paul; Frydman, René; Simpson, Joe Leigh; Paterlini-Brechot, Patrizia

    2012-11-01

    This study sought to determine whether a reliable non-invasive prenatal diagnosis (NI-PND) of cystic fibrosis (CF) or spinal muscular atrophy (SMA) can be achieved through analysis of circulating fetal trophoblastic cells (CFTC). The kinetics of CFTC circulation were also studied. CFTC were isolated by isolation by size of epithelial tumour/trophoblastic cells at 9-11 weeks of gestation, before chorionic villus sampling (CVS), from the blood of 63 pregnant women at 25% risk for having a child affected by either CF (n=32) or SMA (n=31). Collected cells were laser-microdissected, short tandem repeat-genotyped to determine fetal origin and blindly assessed for mutation analysis. CFTC were independently analysed weekly (4-12 weeks of gestation) in 14 women who achieved pregnancy following IVF. Diagnostic results were compared with those obtained by CVS. All seven CF and seven SMA pregnancies carrying an affected fetus were correctly identified as well as non-affected pregnancies. CFTC provided 100% diagnostic sensitivity (95% CI 76.8-100%) and specificity (95% CI 92.7-100%) in these 63 consecutive pregnancies at risk for CF or SMA. CFTC were found to circulate from 5 weeks of gestation and can be used to develop an early and reliable approach for NI-PND. We sought to determine whether a reliable non-invasive prenatal diagnosis (NI-PND) of two rare genetic diseases - cystic fibrosis (CF) and spinal muscular atrophy (SMA) - can be achieved through analysis of circulating fetal trophoblastic cells (CFTC) in blood of pregnant women. We also studied the time of appearance and circulation of CFTC in maternal blood. CFTC were isolated from maternal blood by isolation by size of epithelial tumour/trophoblastic cells (ISET; an approach for cell isolation from blood) at 9-11 weeks of gestation before chorionic villus sampling (CVS) from the blood of 63 pregnant women at 25% risk for having a child affected by either CF (n=32) or SMA (n=31). Collected cells were analysed by genetic test to determine fetal origin and blindly assessed for mutation analysis. We independently analysed CFTC in maternal blood samples taken weekly (4-12 weeks of gestation) from 14 women who achieved pregnancy following IVF. Diagnostic results were compared with those obtained by CVS. All seven CF and seven SMA pregnancies carrying an affected fetus were correctly identified as well as non-affected pregnancies. CFTC provided 100% diagnostic sensitivity and specificity in these 63 consecutive pregnancies at risk for CF or SMA. CFTC were found to circulate from 5 weeks of gestation and can be used to develop an early and reliable approach for NI-PND. PMID:23000084

  8. [Report on 8 years' experience in prenatal diagnosis of genetic defects. I. Indications and methods].

    PubMed

    Weise, W; Düker, D

    1983-01-01

    Prenatal diagnostic procedures were done following 1231 transabdominal amniocenteses in 1113 patients of a gestational age of 17.4 +/- 0.5 weeks. Partly parallel the following methods were used: 1218 estimations of alpha-fetoprotein, 903 chromosomal analyses, 89 amniofetographies, 40 fetoscopies and 7 estaminations of hormones, immunoglobulins and enzymes. Amniotic fluid could be obtained in 91.8 per cent with the first insertion of the needle, using the free-hand-needle-technique. In 8 per cent amniotic fluid samples were bloody. The amniocentesis had to be repeated in 7.6 per cent because of no growth of cells (6.3 per cent), or no amniotic fluid could be obtained (1.3 percent). In the average 14.9 +/- 8.1 metaphases were analysed and 2.9 +/- 1.1 karyogram were made. The organisation of prenatal diagnostics was explained. The indication was in 39.6 per cent the age, in 20.3 per cent the repeated risk of the birth of a fetus with trisomy 21. In 13.7 per cent there was an indication to estimate alpha-fetoprotein which was done nearly without exception for exclusion of neural tube defects. The prenatal determination of the fetal sex was necessary in 7.3 per cent in cases of X-chromosomal inheritable diseases. Previous deliveries of infants with malformation-syndrome or chromosomal trisomies like Edwards-or Patau-syndrome and radiation or chemotherapy of one of the parents were summarized under other indications (7.3 per cent). Balanced parental translocations were the indication in 1.7 per cent. Amniofetography was used in 8 per cent of the patients to exclude malformations caused by prevalent multiple factors. It was in 35 per cent the prevailing diagnostic method. The set of problems of its use was discussed. Fetoscopy (3.6 per cent) partly was an additional diagnostic procedure partly a leading method. By means of a catalogue of indications it was referred to the use of fetoscopy to visualization in prenatal diagnostics. The exclusion of genetic metabolic defects was the motive to prenatal biochemic investigations in 0.5 per cent. The prerequisites of devices and technique to prenatal diagnostics were discussed. PMID:6198822

  9. Genetic parameters for somatic cell score according to udder infection status in Valle del Belice dairy sheep and impact of imperfect diagnosis of infection

    PubMed Central

    2010-01-01

    Background Somatic cell score (SCS) has been promoted as a selection criterion to improve mastitis resistance. However, SCS from healthy and infected animals may be considered as separate traits. Moreover, imperfect sensitivity and specificity could influence animals' classification and impact on estimated variance components. This study was aimed at: (1) estimating the heritability of bacteria negative SCS, bacteria positive SCS, and infection status, (2) estimating phenotypic and genetic correlations between bacteria negative and bacteria positive SCS, and the genetic correlation between bacteria negative SCS and infection status, and (3) evaluating the impact of imperfect diagnosis of infection on variance component estimates. Methods Data on SCS and udder infection status for 1,120 ewes were collected from four Valle del Belice flocks. The pedigree file included 1,603 animals. The SCS dataset was split according to whether animals were infected or not at the time of sampling. A repeatability test-day animal model was used to estimate genetic parameters for SCS traits and the heritability of infection status. The genetic correlation between bacteria negative SCS and infection status was estimated using an MCMC threshold model, implemented by Gibbs Sampling. Results The heritability was 0.10 for bacteria negative SCS, 0.03 for bacteria positive SCS, and 0.09 for infection status, on the liability scale. The genetic correlation between bacteria negative and bacteria positive SCS was 0.62, suggesting that they may be genetically different traits. The genetic correlation between bacteria negative SCS and infection status was 0.51. We demonstrate that imperfect diagnosis of infection leads to underestimation of differences between bacteria negative and bacteria positive SCS, and we derive formulae to predict impacts on estimated genetic parameters. Conclusions The results suggest that bacteria negative and bacteria positive SCS are genetically different traits. A positive genetic correlation between bacteria negative SCS and liability to infection was found, suggesting that the approach of selecting animals for decreased SCS should help to reduce mastitis prevalence. However, the results show that imperfect diagnosis of infection has an impact on estimated genetic parameters, which may reduce the efficiency of selection strategies aiming at distinguishing between bacteria negative and bacteria positive SCS. PMID:20659318

  10. Geoelectrical investigation of old/abandoned, covered landfill sites in urban areas: model development with a genetic diagnosis approach

    NASA Astrophysics Data System (ADS)

    Meju, Maxwell A.

    2000-05-01

    Geoelectrical methods have an important, albeit difficult role to play in landfill investigations. In the present economic conditions, with the environmentally sensitive regime, adequate desk-study and model development are essential ingredients for a successful site investigation of landfills. This paper attempts to develop a genetic investigative model for old/abandoned landfill sites where the records of operations are not available. The main elements of the model are the site boundaries, age and nature of anthropogenic deposits, depth and dip of the layers of refuse and sealing materials, the integrity and shape of the capping zones or separating walls and basal floor slopes, the position of concealed access roads in the site, the water table (or perched water bodies within the refuse) and the presence of leachate. The attendant geotechnical, hydrogeological, and bio-geochemical constraints at such sites are also incorporated in the model for consistency of practical solutions to landfill problems. The nature of anthropogenic deposits and the spatial-temporal characteristics of leachates are reviewed in a geoelectrical context. The analogy between waste degradation and leaching, and the well-known weathering processes of supergene mineral enrichment and saprolite formation in crystalline rocks is explored, and used to develop a conceptual resistivity-vs.-depth model for landfill sites. The main tenet of the model is that vertical conductivity profiles will attain maximum values in the zone of mineral enrichment near the water table and tail-off away from it. This conceptual resistivity model is shown to be consistent with non-invasive observations in landfill sites in different geographical environments. Power-law relationships are found to exist between some geoelectrically important hydrochemical parameters (fluid conductivity, chloride content and total dissolved solids) in leachates and leachate-contaminated groundwater from some landfill sites. Since some chemical parameters of fill are known to vary consistently with time, a plausible hydrochemical and age-deductive scheme for saturated fill is proposed for geoelectrical models of landfills without significant amounts of metal. Practical suggestions are made for a consistent approach in geoelectrical investigation and diagnosis of old landfill sites. A few field examples are used to illustrate the diagnosis approach.

  11. Preimplantation diagnosis.

    PubMed Central

    Goldberg, J D; Martin, M C; Lebo, R V; Pedersen, R A

    1993-01-01

    Preimplantation embryonic biopsy and analysis offer couples at increased risk of having offspring affected with a genetic disorder the possibility of an early prenatal diagnosis. For many couples, this approach would avoid the issue of the selective termination of affected fetuses. Substantial advances have been made in the area of preimplantation diagnosis, but the possible difficulties with this approach cannot be ignored. Images PMID:8236971

  12. 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.

  13. 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.

  14. 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

  15. Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström Syndromes

    PubMed Central

    Redin, Claire; Le Gras, Stéphanie; Mhamdi, Oussema; Geoffroy, Véronique; Stoetzel, Corinne; Vincent, Marie-Claire; Chiurazzi, Pietro; Lacombe, Didier; Ouertani, Ines; Petit, Florence; Till, Marianne; Verloes, Alain; Jost, Bernard; Chaabouni, Habiba Bouhamed; Dollfus, Helene; Mandel, Jean-Louis; Muller, Jean

    2012-01-01

    Background Bardet-Biedl syndrome (BBS) is a pleiotropic recessive disorder that belongs to the rapidly growing family of ciliopathies. It shares phenotypic traits with other ciliopathies, such as Alström syndrome (ALMS), nephronophthisis (NPHP) or Joubert syndrome. BBS mutations have been detected in 16 different genes (BBS1-BBS16) without clear genotype-to-phenotype correlation. This extensive genetic heterogeneity is a major concern for molecular diagnosis and genetic counselling. While various strategies have been recently proposed to optimise mutation detection, they either fail to detect mutations in a majority of patients or are time consuming and costly. Method We tested a targeted exon-capture strategy coupled with multiplexing and high-throughput sequencing on 52 patients: 14 with known mutations as proof-of-principle and 38 with no previously detected mutation. Thirty genes were targeted in total including the 16 BBS genes, the 12 known NPHP genes, the single ALMS gene ALMS1 and the proposed modifier CCDC28B. Results This strategy allowed the reliable detection of causative mutations (including homozygous/heterozygous exon deletions) in 68% of BBS patients without previous molecular diagnosis and in all proof-of-principle samples. Three probands carried homozygous truncating mutations in ALMS1 confirming the major phenotypic overlap between both disorders. The efficiency of detecting mutations in patients was positively correlated with their compliance with the classical BBS phenotype (mutations were identified in 81% of ‘classical’ BBS patients) suggesting that only a few true BBS genes remain to be identified. We illustrate some interpretation problems encountered due to the multiplicity of identified variants. Conclusion This strategy is highly efficient and cost effective for diseases with high genetic heterogeneity, and guarantees a quality of coverage in coding sequences of target genes suited for diagnosis purposes. PMID:22773737

  16. 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 ...

  17. 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 ...

  18. 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...

  19. 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. PMID:26394185

  20. A comparison of the caffeine halothane muscle contracture test with the molecular genetic diagnosis of malignant hyperthermia.

    PubMed

    MacKenzie, A E; Allen, G; Lahey, D; Crossan, M L; Nolan, K; Mettler, G; Worton, R G; MacLennan, D H; Korneluk, R

    1991-07-01

    Malignant hyperthermia (MH) is currently diagnosed by the caffeine-halothane contracture (CHC) test. In a previous study, this test was used to establish linkage between the human gene for MH susceptibility and the ryanodine receptor (RYR) gene. The current study extends the genetic linkage analysis to a large French-Canadian kindred. In this family, genetic linkage between RYR and MH genes was not demonstrable using the currently recommended limits of normal for the CHC test in the identification of MH-susceptible individuals. With CHC test threshold limits below those currently recommended, however, complete linkage between the RYR and MH genes was seen. Comparisons of CHC test results with genetic linkage studies will increase the diagnostic accuracy of both tests as well as generate new insights into the biology of MH. PMID:2064058

  1. 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

  2. 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…

  3. European guidance for the molecular diagnosis of pseudohypoparathyroidism not caused by point genetic variants at GNAS: an EQA study.

    PubMed

    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

    2015-04-01

    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

  4. 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…

  5. 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

  6. 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. PMID:26173767

  7. 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.

  8. Karyotypic and Molecular Genetic Changes Associated With Fetal Cardiovascular Abnormalities: Results of a Retrospective 4-Year Ultrasonic Diagnosis Study

    PubMed Central

    Bao, Bihui; Wang, Yu; Hu, Hua; Yao, Hong; Li, Yuyan; Tang, Shuai; Zheng, Lihong; Xu, Yan; Liang, Zhiqing

    2013-01-01

    Objective: To investigate the incidence of aneuploidy in fetuses with congenital heart defects (CHDs) and to further identify submicroscopic changes and global DNA methylation levels as potential biomarkers in complex CHD cases. Methods: Fetuses at high risk for birth defects or with obvious sonographic anomalies were recruited at the Prenatal Diagnosis Center and Ultrasonic Diagnosis Center. Elective fetal karyotyping and DNA copy number and promoter methylation analyses were carried out following parental consent. G-banded karyotyping was performed to detect fetal aneuploidy. Copy number variations (CNVs) were detected using the Affymetrix SNP Array 6.0 and validated by real time PCR. Global DNA methylation analyses were conducted using a Roche NimbleGen Human DNA Methylation 3x720K Array, and DNA methylation differences were assayed by a Sequenom MassARRAY EpiTYPER. Results: Conventional karyotyping identified 30 cases with aneuploidy in 179 CHD fetuses. Various CNVs were found in two aneuploid fetuses and in five euploid CHD fetuses. Verified segmental deletion or duplications were not directly associated with cardiovascular malformations except in DAAM1 and GATA6. Verifiable aberrant DNA methylation could not be identified in three complex CHD fetuses. Conclusions: In this study, Trisomy 18, Trisomy 21 and 45,XO were the most common aneuploidies identified in CHD fetuses. In the affected samples, only DAAM1 deletion and GATA6 amplification could be associated with cardiovascular biological processes. PMID:23678296

  9. Clinical and genetic characterization of Bardet-Biedl syndrome in Tunisia: defining a strategy for molecular diagnosis.

    PubMed

    M'hamdi, O; Redin, C; Stoetzel, C; Ouertani, I; Chaabouni, M; Maazoul, F; M'rad, R; Mandel, J L; Dollfus, H; Muller, J; Chaabouni, H

    2014-02-01

    Bardet-Biedl syndrome (BBS, OMIM 209900) is a rare genetic disorder characterized by obesity, retinitis pigmentosa, post axial polydactyly, cognitive impairment, renal anomalies and hypogonadism. The aim of this study is to provide a comprehensive clinical and molecular analysis of a cohort of 11 Tunisian BBS consanguineous families in order to give insight into clinical and genetic spectrum and the genotype-phenotype correlations. Molecular analysis using combined sequence capture and high-throughput sequencing of 30 ciliopathies genes revealed 11 mutations in 11 studied families. Five mutations were novel and six were previously described. Novel mutations included c.1110G>A and c.39delA (p.G13fs*41) in BBS1, c.115+5G>A in BBS2, c.1272+1G>A in BBS6, c.1181_1182insGCATTTATACC in BBS10 (p.S396Lfs*6). Described mutations included c.436C>T (p.R146*) and c.1473+4A>G in BBS1, c.565C> (p.R189*) in BBS2, deletion of exons 4-6 in BBS4, c.149T>G (p.L50R) in BBS5, and c.459+1G>A in BBS8; most frequent mutations were described in BBS1 (4/11, 37%) and BBS2 (2/11, 18%) genes. No phenotype-genotype correlation was evidenced. This data expands the mutations profile of BBS genes in Tunisia and suggests a divergence of the genetic spectrum comparing Tunisian and other populations. PMID:23432027

  10. Glucocorticoid protects rodent hearts from ischemia/reperfusion injury by activating lipocalin-type prostaglandin D synthase–derived PGD2 biosynthesis

    PubMed Central

    Tokudome, Satori; Sano, Motoaki; Shinmura, Ken; Matsuhashi, Tomohiro; Morizane, Shintaro; Moriyama, Hidenori; Tamaki, Kayoko; Hayashida, Kentaro; Nakanishi, Hiroki; Yoshikawa, Noritada; Shimizu, Noriaki; Endo, Jin; Katayama, Takaharu; Murata, Mitsushige; Yuasa, Shinsuke; Kaneda, Ruri; Tomita, Kengo; Eguchi, Naomi; Urade, Yoshihiro; Asano, Koichiro; Utsunomiya, Yasunori; Suzuki, Takeshi; Taguchi, Ryo; Tanaka, Hirotoshi; Fukuda, Keiichi

    2009-01-01

    Lipocalin-type prostaglandin D synthase (L-PGDS), which was originally identified as an enzyme responsible for PGD2 biosynthesis in the brain, is highly expressed in the myocardium, including in cardiomyocytes. However, the factors that control expression of the gene encoding L-PGDS and the pathophysiologic role of L-PGDS in cardiomyocytes are poorly understood. In the present study, we demonstrate that glucocorticoids, which act as repressors of prostaglandin biosynthesis in most cell types, upregulated the expression of L-PGDS together with cytosolic calcium-dependent phospholipase A2 and COX2 via the glucocorticoid receptor (GR) in rat cardiomyocytes. Accordingly, PGD2 was the most prominently induced prostaglandin in vivo in mouse hearts and in vitro in cultured rat cardiomyocytes after exposure to GR-selective agonists. In isolated Langendorff-perfused mouse hearts, dexamethasone alleviated ischemia/reperfusion injury. This cardioprotective effect was completely abrogated by either pharmacologic inhibition of COX2 or disruption of the gene encoding L-PGDS. In in vivo ischemia/reperfusion experiments, dexamethasone reduced infarct size in wild-type mice. This cardioprotective effect of dexamethasone was markedly reduced in L-PGDS–deficient mice. In cultured rat cardiomyocytes, PGD2 protected against cell death induced by anoxia/reoxygenation via the D-type prostanoid receptor and the ERK1/2-mediated pathway. Taken together, these results suggest what we believe to be a novel interaction between glucocorticoid-GR signaling and the cardiomyocyte survival pathway mediated by the arachidonic acid cascade. PMID:19451694

  11. Effects of Genetic Susceptibility for Type 2 Diabetes on the Evolution of Glucose Homeostasis Traits Before and After Diabetes Diagnosis

    PubMed Central

    Gautier, Alain; Roussel, Ronan; Lange, Céline; Piguel, Xavier; Cauchi, Stéphane; Vol, Sylviane; Froguel, Philippe; Balkau, Beverley; Bonnet, Fabrice

    2011-01-01

    OBJECTIVE To assess the impact of genetic susceptibility on evolution toward type 2 diabetes (T2D) by analyzing time trajectories of fasting glucose, glycated hemoglobin (HbA1c), insulin sensitivity (homeostasis model assessment [HOMA2%S]), and β-cell secretion (HOMA2%B) in a large nondiabetic cohort. We also examined whether baseline HbA1c modified the effect of genetic predisposition on the time trajectories. RESEARCH DESIGN AND METHODS Time trajectories were drawn in 4,744 participants from the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.) cohort based on samples collected every 3 years over a 9-year follow-up. Trajectories were analyzed according to the TCF7L2 common variant, a family history of T2D, and a combination of at-risk alleles from nine T2D-associated genes. RESULTS There was a marked decrease in HOMA2%B in parallel to a steep increase in HbA1c over the 3 years before incident diabetes, which was not influenced by genetic predisposition when considered alone. However, after the onset of T2D, the TCF7L2 at-risk variant was associated with a greater decrease in HOMA2%B. There was a joint effect of a family history of T2D with the presence of the TCF7L2 risk allele with a greater rise in HbA1c conferred by the coexistence of a family history and the T risk allele. An HbA1c ≥5.7% at baseline was associated with a greater increase in both glycemia and HbA1c levels in the presence of a combination of diabetes at-risk alleles. CONCLUSIONS After incident T2D, TCF7L2 at-risk variants were associated with a faster decrease in β-cell function compared with those with the CC genotype. There was a joint effect of family history of T2D and TCF7L2 risk variant on the rise in glycemia and the decrease in insulin secretion at the end of follow-up, suggesting the joint influence of the combination of diabetes genetic predisposition with familial factors on the evolution of glycemia over time. PMID:21911746

  12. 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. Citation: Kugathas S, Audouze K, Ermler S, Orton F, Rosivatz E, Scholze M, Kortenkamp A. 2016. 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. Environ Health Perspect 124:452–459; http://dx.doi.org/10.1289/ehp.1409544 PMID:26359731

  13. 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. PMID:24989832

  14. 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

  15. A rare genetic disorder in the differential diagnosis of the entrapment neuropathies: hereditary neuropathy with liability to pressure palsies.

    PubMed

    Koc, Filiz; Güzel, Rengin; Benlidayi, Ilke Coskun; Yerdelen, Deniz; Güzel, Irfan; Sarica, Yakup

    2006-04-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal-dominant, slowly progressive neuromuscular disorder, which is characterized by recurrent acute peripheral nerve palsies. Electrophysiological studies show decreased motor and sensory conduction velocities in both clinically affected and unaffected nerves. Focal thickening of myelin sheath with sausage-like formation, also called tomacula, is seen in nerve biopsies. In genetic studies, 1.5-Mb deletion on chromosome 17p11.2 is detected in approximately 85% of HNPP cases and point mutations are determined in some cases. We describe a 26-year-old man who had a 6-month history of paresthesia in the little fingers of his hands. He was diagnosed with HNPP by neurologic examination, and electrophysiological and histopathologic studies. Studies in his mother and one brother also showed entrapment neuropathy. However, no deletions or point mutations were determined in this family. Other genetic defects apart from the known ones might be present in this disease. The most frequent entrapment syndrome, carpal tunnel syndrome, is also seen in this disease, so physicians dealing with musculoskeletal problems should be alert about this subject. Awareness of HNPP may help avoid unnecessary operative interventions. PMID:16601541

  16. [Molecular-Genetic Diagnosis and Molecular-Targeted Therapy in Cancer: Challenges in the Era of Precision Medicine].

    PubMed

    Miyachi, Hayato

    2015-10-01

    Elucidation of the molecular pathogenesis of neoplasms and application of emerging technologies for testing and therapy have resulted in a series of paradigm shifts in patient care, from conventional to personalized medicine. This has been promoted by companion diagnostics and molecular targeted therapy, tailoring the treatment to the individual characteristics of each patient. Precision oncology has been accelerated by integrating the enhanced resolution of molecular analysis, mechanism clarity, and therapeutic relevance through genomic knowledge. In its clinical implementation, there are laboratory challenges concerning accurate measurement using stored samples, differentiation between driver and passenger mutations as well as between germline and somatic mutations, bioinformatics availability, practical decision-making algorithms, and ethical issues regarding incidental findings. The medical laboratory has a new role in providing not only testing services but also an instructive approach to users to ensure the sample quality and privacy protection of personal genome information, supporting the quality of patient practice based on laboratory diagnosis. PMID:26897855

  17. [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. PMID:25270337

  18. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis

    PubMed Central

    Dong, Yi; Ni, Wang; Chen, Wan-Jin; Wan, Bo; Zhao, Gui-Xian; Shi, Zhu-Qing; Zhang, Yue; Wang, Ning; Yu, Long; Xu, Jian-Feng; Wu, Zhi-Ying

    2016-01-01

    Background: Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B pathogenic mutations. The symptoms of WD can be effectively prevented if the affected individuals are identified and intervened early. However, clinical utility of this molecular analysis is challenging due to hundreds of variants with various clinical effects in the gene. Here, we aim to describe the spectrum of ATP7B variants and assess their clinical effects in the Han Chinese population. Methods: The ATP7B gene was directly sequenced in 632 unrelated WD patients and 503 unrelated healthy individuals. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Different frequency of variants observed in both cases and controls were tested using Chi-square or Fisher's exact tests. Results: We detected 161 non-synonymous variants in these 632 WD patients, 58 of which were novel. Among these variants, 78, 64, 8, 4, and 7 were classified as 'pathogenic variants', 'likely pathogenic variants', 'variants with uncertain significance', 'likely benign variants', and 'benign variants', respectively. Ninety percent (569/632) of these WD patients can be genetically diagnosed with two or more 'pathogenic' or 'likely pathogenic' variants. The 14 most common disease-causing variants were found at least once in 94% (537/569) of genetically diagnosed patients. Conclusions: These data expand the spectrum of ATP7B variants and facilitate effective screening for ATP7B variants for early diagnosis of WD and development of individualized treatment regimens. PMID:27022412

  19. [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. PMID:26764295

  20. Pap smear diagnosis using a hybrid intelligent scheme focusing on genetic algorithm based feature selection and nearest neighbor classification.

    TOXLINE Toxicology Bibliographic Information

    Marinakis Y; Dounias G; Jantzen J

    2009-01-01

    The term pap-smear refers to samples of human cells stained by the so-called Papanicolaou method. The purpose of the Papanicolaou method is to diagnose pre-cancerous cell changes before they progress to invasive carcinoma. In this paper a metaheuristic algorithm is proposed in order to classify the cells. Two databases are used, constructed in different times by expert MDs, consisting of 917 and 500 images of pap smear cells, respectively. Each cell is described by 20 numerical features, and the cells fall into 7 classes but a minimal requirement is to separate normal from abnormal cells, which is a 2 class problem. For finding the best possible performing feature subset selection problem, an effective genetic algorithm scheme is proposed. This algorithmic scheme is combined with a number of nearest neighbor based classifiers. Results show that classification accuracy generally outperforms other previously applied intelligent approaches.

  1. 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

  2. Visna/Maedi virus genetic characterization and serological diagnosis of infection in sheep from a neurological outbreak.

    PubMed

    Glaria, I; Reina, R; Ramrez, H; de Andrs, X; Crespo, H; Jauregui, P; Salazar, E; Lujn, L; Prez, M M; Benavides, J; Prez, V; Polledo, L; Garca-Marn, J F; Riezu, J I; Borrs, F; Amorena, B; de Andrs, D

    2012-03-23

    An extensive outbreak characterized by the appearance of neurological symptoms in small ruminant lentivirus (SRLV) infected sheep has been identified in Spain, but the genetic characteristics of the strain involved and differential diagnostic tools for this outbreak remain unexplored. In this work, 23 Visna-affected naturally infected animals from the outbreak, 11 arthritic animals (both groups presenting anti-Visna/Maedi virus serum antibodies), and 100 seronegative animals were used. Eight of the Visna-affected animals were further studied post-mortem by immunohistochemistry. All had lesions in spinal cord, being the most affected part of the central nervous system in six of them. A representative strain of the outbreak was isolated. Together with other proviral sequences from the outbreak the virus was assigned to genotype A2/A3. In vitro culture of the isolate revealed that viral production was slow/low in fibroblast-like cells but it was high in blood monocyte-derived macrophages. The long terminal repeat (LTR) of the viral genome of this isolate lacked an U3-duplication, but its promoter activity in fibroblast-like cells was normal compared to other strains. Thus, viral production could not be inferred from the LTR promoter activity in this isolate. Analysis of the viral immunodominant epitopes among SRLV sequences of the outbreak and other known sequences allowed the design of a synthetic SU peptide ELISA that detected the Visna affected animals, representing a tool of epidemiological interest to control viral spread of this highly pathogenic strain. PMID:21940116

  3. 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

  4. 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. PMID:25758664

  5. 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. PMID:25205505

  6. 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. PMID:26811500

  7. 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. The pros and cons of the basic and advanced statistical tools available for measuring genetic diversity are briefly discussed and their source links (mostly) were provided to get easy access; thus, it improves the understanding of tools and its practical applicability to the researchers. PMID:25874132

  8. 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. The pros and cons of the basic and advanced statistical tools available for measuring genetic diversity are briefly discussed and their source links (mostly) were provided to get easy access; thus, it improves the understanding of tools and its practical applicability to the researchers. PMID:25874132

  9. Genetic testing in Marfan syndrome.

    PubMed

    Child, Anne H; Aragon-Martin, Jose A; Sage, Karen

    2016-01-01

    Genetic testing is aiding rapid diagnosis of Marfan syndrome as a basis for management of eye, heart and skeletal disease. The affected patient's mutation can be used as a basis for prenatal or postnatal diagnosis of offspring. Preimplantation genetic diagnosis, the technique of choice, can ensure an unaffected pregnancy. PMID:26903455

  10. [Dysphagia. Diagnosis, differential diagnosis].

    PubMed

    Collo, D

    1976-11-11

    The wide scope of differential diagnosis in dysphagia makes interdisplinary team-work essential. The aim of this review therefore is to show the various specialties of medicine dealing with dysphagia and to point out possible causes and therapeutic measures. PMID:992550

  11. 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

  12. Preconception and preimplantation diagnosis for cystic fibrosis.

    PubMed

    Verlinsky, Y; Rechitsky, S; Evsikov, S; White, M; Cieslak, J; Lifchez, A; Valle, J; Moise, J; Strom, C M

    1992-02-01

    Preimplantation diagnosis provides couples at high genetic risk the possibility of avoiding genetic disease without the need for prenatal diagnosis and selective abortion of the affected pregnancy. Following extensive background work on the reliability of genetic diagnosis in a single cell, we offered on a research basis preimplantation diagnosis to five couples at risk for offspring with the delta-F508 mutation (the major mutation causing cystic fibrosis). There was no detrimental effect from polar body removal on either fertilization or preimplantation development. Genetic analysis, undertaken in 22 polar bodies and 15 corresponding blastomeres, identified 21 embryos of which ten were transferred. PMID:1553355

  13. Genetic screening of a pedigree with osteogenesis imperfecta type Ⅰ and identification of a novel mutation in COL1A2 pathogenic gene.

    PubMed

    Rong, Li; Yuanping, Guo; Jingxin, Pan; Yibin, Guo

    2015-01-01

    To uncover the molecular pathogenic mechanism of congenital osteogenesis imperfecta (OI) type I, all the 103 exons of the COL1A1 (Collagen, type Ⅰ, alpha 1) and COL1A2 (Collagen, type Ⅰ, alpha 2) genes in a child with OI type Ⅰ were screened using PCR-DNA direct sequencing. The results showed no pathological mutation in COL1A1 gene, but a novel mutation c.946G>T/p.G316C in the exon 19 of COL1A2 gene, which was inherited from her father. This mutation was not found in her mother and other six phenotypically normal relatives. By denaturing high performance liquid chromatography (DHPLC) screening, the abnormal double-peak was visualized in PCR products of exon 19 of COL1A2 gene in the proband and her father, while the normal single-peak was shown in those of her mother and all the healthy controls. Using allele specific amplification (ASA) screening, a specific band of 391 bp in COL1A2 exon 19 was amplified only in the proband and her father, but not in other samples. The amino acid encoded by the mutation site is evolutionarily highly conserved, and this mutation was a "damaging" or "probably damaging" factor to OI type Ⅰ, based on the predicting results using SIFT and Polyphen-2 softwares. In conclusion, the novel c.946G>T/p.G316C mutation in COL1A2 gene is a pathogenic mutation that could result in OI type Ⅰ. If the couple wants to get pregnant again, it is necessary to screen the mutation site in COL1A2 gene through the prenatal genetic diagnosis in the first trimester or through preimplantation genetic diagnosis (PGD) in the progestation. PMID:25608812

  14. Genetics of familial hypercholesterolemia.

    PubMed

    Brautbar, Ariel; Leary, Emili; Rasmussen, Kristen; Wilson, Don P; Steiner, Robert D; Virani, Salim

    2015-04-01

    Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol and premature cardiovascular disease, with a prevalence of approximately 1 in 200-500 for heterozygotes in North America and Europe. Monogenic FH is largely attributed to mutations in the LDLR, APOB, and PCSK9 genes. Differential diagnosis is critical to distinguish FH from conditions with phenotypically similar presentations to ensure appropriate therapeutic management and genetic counseling. Accurate diagnosis requires careful phenotyping based on clinical and biochemical presentation, validated by genetic testing. Recent investigations to discover additional genetic loci associated with extreme hypercholesterolemia using known FH families and population studies have met with limited success. Here, we provide a brief overview of the genetic determinants, differential diagnosis, genetic testing, and counseling of FH genetics. PMID:25712136

  15. Neurofibromatoses: part 1 - diagnosis and differential diagnosis.

    PubMed

    Rodrigues, Luiz Oswaldo Carneiro; Batista, Pollyanna Barros; Goloni-Bertollo, Eny Maria; de Souza-Costa, Danielle; Eliam, Lucas; Eliam, Miguel; Cunha, Karin Soares Gonçalves; Darrigo-Junior, Luiz Guilherme; Ferraz-Filho, José Roberto Lopes; Geller, Mauro; Gianordoli-Nascimento, Ingrid F; Madeira, Luciana Gonçalves; Malloy-Diniz, Leandro Fernandes; Mendes, Hérika Martins; de Miranda, Débora Marques; Pavarino, Erika Cristina; Baptista-Pereira, Luciana; Rezende, Nilton A; Rodrigues, Luíza de Oliveira; da Silva, Carla Menezes; de Souza, Juliana Ferreira; de Souza, Márcio Leandro Ribeiro; Stangherlin, Aline; Valadares, Eugênia Ribeiro; Vidigal, Paula Vieira Teixeira

    2014-03-01

    Neurofibromatoses (NF) are a group of genetic multiple tumor growing predisposition diseases: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH), which have in common the neural origin of tumors and cutaneous signs. They affect nearly 80 thousand of Brazilians. In recent years, the increased scientific knowledge on NF has allowed better clinical management and reduced complication morbidity, resulting in higher quality of life for NF patients. In most cases, neurology, psychiatry, dermatology, clinical geneticists, oncology and internal medicine specialists are able to make the differential diagnosis between NF and other diseases and to identify major NF complications. Nevertheless, due to its great variability in phenotype expression, progressive course, multiple organs involvement and unpredictable natural evolution, NF often requires the support of neurofibromatoses specialists for proper treatment and genetic counseling. This Part 1 offers step-by-step guidelines for NF differential diagnosis. Part 2 will present the NF clinical management. PMID:24676443

  16. Increasing Live Birth Rate by Preimplantation Genetic Screening of Pooled Polar Bodies Using Array Comparative Genomic Hybridization

    PubMed Central

    Feichtinger, Michael; Stopp, Tina; Göbl, Christian; Feichtinger, Elisabeth; Vaccari, Enrico; Mädel, Ulrike; Laccone, Franco; Stroh-Weigert, Monika; Hengstschläger, Markus; Feichtinger, Wilfried; Neesen, Jürgen

    2015-01-01

    Meiotic errors during oocyte maturation are considered the major contributors to embryonic aneuploidy and failures in human IVF treatment. Various technologies have been developed to screen polar bodies, blastomeres and trophectoderm cells for chromosomal aberrations. Array-CGH analysis using bacterial artificial chromosome (BAC) arrays is widely applied for preimplantation genetic diagnosis (PGD) using single cells. Recently, an increase in the pregnancy rate has been demonstrated using array-CGH to evaluate trophectoderm cells. However, in some countries, the analysis of embryonic cells is restricted by law. Therefore, we used BAC array-CGH to assess the impact of polar body analysis on the live birth rate. A disadvantage of polar body aneuploidy screening is the necessity of the analysis of both the first and second polar bodies, resulting in increases in costs for the patient and complex data interpretation. Aneuploidy screening results may sometimes be ambiguous if the first and second polar bodies show reciprocal chromosomal aberrations. To overcome this disadvantage, we tested a strategy involving the pooling of DNA from both polar bodies before DNA amplification. We retrospectively studied 351 patients, of whom 111 underwent polar body array-CGH before embryo transfer. In the group receiving pooled polar body array-CGH (aCGH) analysis, 110 embryos were transferred, and 29 babies were born, corresponding to live birth rates of 26.4% per embryo and 35.7% per patient. In contrast, in the control group, the IVF treatment was performed without preimplantation genetic screening (PGS). For this group, 403 embryos were transferred, and 60 babies were born, resulting in live birth rates of 14.9% per embryo and 22.7% per patient. In conclusion, our data show that in the aCGH group, the use of aneuploidy screening resulted in a significantly higher live birth rate compared with the control group, supporting the benefit of PGS for IVF couples in addition to the suitability and effectiveness of our polar body pooling strategy. PMID:26024488

  17. 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

  18. 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

  19. Noninvasive prenatal diagnosis.

    PubMed

    Cheng, Wei-Lun; Hsiao, Ching-Hua; Tseng, Hua-Wei; Lee, Tai-Ping

    2015-08-01

    Prenatal examination plays an important role in present medical diagnosis. It provides information on fetal health status as well as the diagnosis of fetal treatment feasibility. The diagnosis can provide peace of mind for the perspective mother. Timely pregnancy termination diagnosis can also be determined if required. Amniocentesis and chorionic villus sampling are two widely used invasive prenatal diagnostic procedures. To obtain complete fetal genetic information and avoid endangering the fetus, noninvasive prenatal diagnosis has become the vital goal of prenatal diagnosis. However, the development of a high-efficiency separation technology is required to obtain the scarce fetal cells from maternal circulation. In recent years, the rapid development of microfluidic systems has provided an effective method for fetal cell separation. Advantages such as rapid analysis of small samples, low cost, and various designs, greatly enhance the efficiency and convenience of using microfluidic systems for cell separation. In addition, microfluidic disks can be fully automated for high throughput of rare cell selection from blood samples. Therefore, the development of microfluidic applications in noninvasive prenatal diagnosis is unlimited. PMID:26384048

  20. A fetus with mitochondrial trifunctional protein deficiency: Elevation of 3-OH-acylcarnitines in amniotic fluid functionally assured the genetic diagnosis

    PubMed Central

    Bo, Ryosuke; Hasegawa, Yuki; Yamada, Kenji; Kobayashi, Hironori; Taketani, Takeshi; Fukuda, Seiji; Yamaguchi, Seiji

    2015-01-01

    Mitochondrial trifunctional protein (TFP) is a multienzyme complex that catalyzes the last three steps of the β-oxidation cycle of long-chain fatty acids. In the prenatal diagnosis of TFP deficiency, acylcarnitine (AC) analysis has been considered difficult because of limited excretion of long-chain ACs into the fetal urine and hence into the amniotic fluid. Here, we report our experience with prenatally diagnosing TFP deficiency using AC analysis of amniotic fluid. The index case was a boy born at 38 weeks gestation and weighing 2588 g. He suddenly became unconscious and hypoglycemic and died on day 6 of life. Postmortem blood AC analysis and gene sequencing revealed TFP deficiency. Therefore, the parents underwent prenatal diagnoses for their subsequent 2 pregnancies. Mutation analysis suggested that one (Case 1) was affected and the other (Case 2) was not. AC analysis also demonstrated identical results, with significantly elevated 3-hydroxy-AC levels in the amniotic fluid of the affected pregnancy compared with those of heterozygotes and normal controls (n = 2 for heterozygotes and n = 8 for normal controls). Our findings suggest that AC analysis can functionally confirm results even in families with unidentified mutations, without raising issues related to maternal cell contamination. During prenatal diagnosis, misdiagnosis has to be avoided, and combining AC analysis with gene sequencing may result in more accurate prenatal diagnosis of TFP deficiency. PMID:27014569

  1. Genetics Home Reference: sialuria

    MedlinePlus

    ... the diagnosis and management of various health conditions: Diagnostic Tests Drug ... Simpel H, Van Coster RN, Orvisky E, Krasnewich DM, Gahl WA. Dominant inheritance of sialuria, an inborn error of feedback inhibition. Am J Hum Genet. 2001 ...

  2. Genetic Screening

    PubMed Central

    Burke, Wylie; Tarini, Beth; Press, Nancy A.; Evans, James P.

    2011-01-01

    Current approaches to genetic screening include newborn screening to identify infants who would benefit from early treatment, reproductive genetic screening to assist reproductive decision making, and family history assessment to identify individuals who would benefit from additional prevention measures. Although the traditional goal of screening is to identify early disease or risk in order to implement preventive therapy, genetic screening has always included an atypical element—information relevant to reproductive decisions. New technologies offer increasingly comprehensive identification of genetic conditions and susceptibilities. Tests based on these technologies are generating a different approach to screening that seeks to inform individuals about all of their genetic traits and susceptibilities for purposes that incorporate rapid diagnosis, family planning, and expediting of research, as well as the traditional screening goal of improving prevention. Use of these tests in population screening will increase the challenges already encountered in genetic screening programs, including false-positive and ambiguous test results, overdiagnosis, and incidental findings. Whether this approach is desirable requires further empiric research, but it also requires careful deliberation on the part of all concerned, including genomic researchers, clinicians, public health officials, health care payers, and especially those who will be the recipients of this novel screening approach. PMID:21709145

  3. Scabies Diagnosis

    MedlinePlus

    ... Monday-Friday Closed Holidays Contact CDC-INFO Scabies General Information Scabies FAQs Workplace FAQs Epidemiology & Risk Factors Biology Disease Diagnosis Treatment Prevention & Control Resources for Health ...

  4. [Genetic counseling in dystrophinopathies].

    PubMed

    Coubes, C

    2015-12-01

    Genetic counseling in dystrophinopathies makes it possible to diagnose carriers, assess the risk for descendents, and discuss the different possibilities for having a boy without the disease: prenatal diagnosis, preimplantation diagnosis, ovocyte donation, and adoption. The different stages of each proposal are detailed. Prenatal diagnosis and preimplantation diagnosis can occur only within a highly defined legal framework. Invasive prenatal diagnosis in particular brings up the risk of miscarriage or termination of pregnancy for medical reasons. Preimplantation diagnosis is the study of the genetic characteristics of a 3-day-old embryo. It is proposed to couples who risk transmitting a particularly serious genetic disease to their child as an alternative to prenatal diagnosis. It requires turning to medically assisted reproduction for couples who do not necessarily present sterility problems. Preimplantation diagnosis requires a highly committed clinical and biological multidisciplinary team. It is very stressful for couples, both physically and psychologically. Technological advances (new-generation sequencing) suggests that noninvasive prenatal diagnosis may be possible in the years to come. PMID:26773580

  5. 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. PMID:12452146

  6. [Genetic variability in Scotch pine in the southeastern part of its range].

    PubMed

    Larionova, A Ia

    2002-12-01

    The main parameters of genetic variability have been determined in an isolated natural Scotch pine population from Chita oblast' (Tsasuchei Forest) by analysis of 19 genes coding for nine enzymes: GDH, IDH, LAP, PGM, AAT, ADH, MDH, 6-PGD, and DIA. Polymorphic genes constituted 63.2% of all structural genes studied in the population at the 99% polymorphism criterion. The mean number of alleles per locus was 1.63. The observed and expected heterozygosities were 0.237 and 0.251, respectively. These estimates are close to the corresponding mean values for Scotch pine according to the data on 18 or more structural genes. PMID:12575449

  7. Diagnosis of genetic defects through parallel assessment of PLCζ and CAPZA3 in infertile men with history of failed oocyte activation

    PubMed Central

    Javadian-Elyaderani, Soudabeh; Ghaedi, Kamran; Tavalaee, Marziyeh; Rabiee, Farzaneh; Deemeh, Mohammad Reza; Nasr-Esfahani, Mohammad Hossein

    2016-01-01

    Objective(s): Phospholipase C ζ (PLCζ) is considered as a nominee for sperm associated oocyte activating factors and is located back-to-back with CAPZA3, an actin-capping protein controlling actin polymerization during spermiogenesis. They contain a common bidirectional promoter. The objective of this study was to identify individuals with parallel low expression of PLCζ and CAPZA3 mRNA, in hope of detecting genetic defects in this bidirectional promoter. Materials and Methods: Semen samples were collected from 24 fertile and 59 infertile individuals with total failed, low and high fertilization rate post intra-cytoplasmic sperm injection (ICSI), as well as globozoospermic individuals. Expression of PLCζ and CAPZA3 were assessed by Real time PCR. In addition, PLCζ was assessed by Western blot. Results: Significant correlations between PLCζ with CAPZA3 and also between these two genes with fertilization were observed. Individuals with low fertilization presented significantly lower expression of these two genes. Low expression of PLCζ was also verified by Western analysis. Sequence analysis of bidirectional promoter of these two genes in an individual with parallel low expression of both PLCζ and CAPZA3, revealed a mutation within the CAPZA3 predicted promoter, known as human regulatory factor X4 which is a testis-specific dimeric DNA-binding protein. In the opposite stand, in the same location, the mutation appears to be outside but in the vicinity of PLCζ, in a binding region predicate by Genomatix. Conclusion: Parallel assessment of CAPZA3 with PLCζ at mRNA level in individuals with inability to induce oocyte activation may help researcher to identify genetic defects associated with failed fertilization. PMID:27114798

  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. 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

  11. The importance of analysis of long-range rearrangement of BRCA1 and BRCA2 in genetic diagnosis of familial breast cancer.

    PubMed

    Kwong, Ava; Chen, Jiawei; Shin, Vivian Y; Ho, John C W; Law, Fian B F; Au, Chun Hang; Chan, Tsun-Leung; Ma, Edmond S K; Ford, James M

    2015-09-01

    Germline BRCA gene mutations are reportedly associated with hereditary breast and ovarian cancers. Identification of BRCA mutations greatly improves the preventive strategies and management of breast cancer. Sanger sequencing has been the gold standard in identifying these mutations. However, 4-28% of inherited BRCA mutations may be due to large genomic rearrangements (LGRs), which could be missed by using Sanger sequencing alone. Our aim is to evaluate the pick-up rate of LGRs in our cohort. A total of 1,236 clinically high-risk patients with breast and/or ovarian cancers were recruited through The Hong Kong Hereditary Breast Cancer Family Registry from 2007 to 2014. Full gene sequencing (either Sanger or next generation sequencing) and multiplex ligation-dependent probe amplification (MLPA) were performed. We identified 120 deleterious BRCA mutations: 57 (4.61%) were in BRCA1 and 63 (5.10%) were in BRCA2. LGRs accounted for 6.67% (8 of 120) of all BRCA mutations, whereas 8.77 % (5 of 57) were BRCA1 mutations and 4.76% (3 of 63) were BRCA2 mutations. Through this integrated approach, both small nucleotide variations and LGRs could be detected. We suggest that MLPA should be incorporated into the standard practice for genetic testing to avoid false-negative results, which would greatly affect the management of these high-risk families. PMID:26271414

  12. Diagnostic exome sequencing identifies two novel IQSEC2 mutations associated with X-linked intellectual disability with seizures: implications for genetic counseling and clinical diagnosis.

    PubMed

    Gandomi, Stephanie K; Farwell Gonzalez, K D; Parra, M; Shahmirzadi, L; Mancuso, J; Pichurin, P; Temme, R; Dugan, S; Zeng, W; Tang, Sha

    2014-06-01

    Intellectual disability is a heterogeneous disorder with a wide phenotypic spectrum. Over 1,700 OMIM genes have been associated with this condition, many of which reside on the X-chromosome. The IQSEC2 gene is located on chromosome Xp11.22 and is known to play a significant role in the maintenance and homeostasis of the brain. Mutations in IQSEC2 have been historically associated with nonsyndromic X-linked intellectual disability. Case reports of affected probands show phenotypic overlap with conditions associated with pathogenic MECP2, FOXG1, CDKL5, and MEF2C gene mutations. Affected individuals, however, have also been identified as presenting with additional clinical features including seizures, autistic-behavior, psychiatric problems, and delayed language skills. To our knowledge, only 5 deleterious mutations and 2 intragenic duplications have been previously reported in IQSEC2. Here we report two novel IQSEC2 de novo truncating mutations identified through diagnostic exome sequencing in two severely affected unrelated male probands manifesting developmental delay, seizures, hypotonia, plagiocephaly, and abnormal MRI findings. Overall, diagnostic exome sequencing established a molecular diagnosis for two patients in whom traditional testing methods were uninformative while expanding on the mutational and phenotypic spectrum. In addition, our data suggests that IQSEC2 may be more common than previously appreciated, accounting for approximately 9 % (2/22) of positive findings among patients with seizures referred for diagnostic exome sequencing. Further, these data supports recently published data suggesting that IQSEC2 plays a more significant role in the development of X-linked intellectual disability with seizures than previously anticipated. PMID:24306141

  13. [Asthma diagnosis].

    PubMed

    Ortega Martell, José Antonio; Fernández Vega, Margarita

    2009-01-01

    The diagnosis of asthma is based primarily on patient history, conducting the interrogation to the search for risk factors for developing it and the triggers of their symptoms. This chapter will detail some laboratory tests and cabinet that can support this clinical diagnosis. Respiratory function tests help to show the degree of airway obstruction and its reversibility with treatment. Allergy tests help prove the existence of cells sensitized to a specific allergen and once identified, implement environmental control measures or if necessary to control this immunomodulation exaggerated immune response. The exhaled nitric oxide test has been most useful in assessing the course of asthma during treatment, rather than for diagnosis. Sometimes the confirmatory diagnosis of asthma is achieved after excluding other diseases that may present a similar clinical picture, and especially after knowing the response to standard treatment with bronchodilators and anti-inflammatory drugs. PMID:20873051

  14. Genetics Home Reference: Erdheim-Chester disease

    MedlinePlus

    ... are slightly more likely to develop the disease, accounting for about 60 percent of cases. Related Information ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  15. Genetics Home Reference: sick sinus syndrome

    MedlinePlus

    ... instructions for making proteins called ion channels that transport positively charged atoms (ions) into cardiac cells, including ... More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of sick sinus ...

  16. Genetics Home Reference: multiple endocrine neoplasia

    MedlinePlus

    ... followed by FMTC. Type 2B is relatively uncommon, accounting for about 5 percent of all cases of ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  17. Comparisons of eccrine sweat gland anatomy in genetic, chromosomal, and other diseases, and a suggested procedure for use of sweat gland measurements in differential diagnosis.

    PubMed

    Shankle, W R; Azen, S P; Landing, B H

    1982-04-01

    Statistical analysis of the dimensions of microdissected eccrine sweat glands (duct length, coil volume, ratio of coil volume to duct length, and axis ratio of coil) was performed for several diseases (cystic fibrosis of the pancreas, Werdnig-Hoffmann disease, tetralogy of Fallot, chronic renal disease, and trisomies 13, 18, and 21) using both individual and grouped age-matched control patients. Duct length, coil volume, and the ratio of the two all rise with age. Eccrine gland duct length was found to be significantly large in tetralogy of Fallot and Werdnig-Hoffmann disease and small in chronic renal disease (less so in males than in females, trisomy 13 and trisomy 18). Secretory coil volume was significantly smaller than normal in trisomy 21 (Down syndrome) and in chronic renal disease, and the ratio of coil volume to duct length was low in trisomy 21 and chronic renal disease. The shape of the secretory coil (axis ratio) was possibly abnormal in trisomy 13. Gland dimensions were normal for cystic fibrosis. Using the multivariate procedure of discriminant analysis, it was found that sweat gland measures significantly contributed to the differentiation of diseases, after adjustments were made for variations in age-at-death. This suggested the possibility that criteria for distinction of clinically similar genetic, metabolic, or chromosomal diseases by study of the anatomic properties of eccrine glands obtained by skin biopsy could be developed. A procedure of analysis comparing the "percentage of normal" of gland dimensions for each disease to control values, and thereby differentiating disease categories on the basis of the "percentage of normal" values, is presented. PMID:6213065

  18. 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

  19. [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

  20. 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 examine pilot mental models of the aircraft subsystems and their use in diagnosis tasks. Future research plans include piloted simulation evaluation of the diagnosis decision aiding concepts and crew interface issues. Information is given in viewgraph form.

  1. Genetics and Medicine: An Evolving Relationship

    ERIC Educational Resources Information Center

    Scriver, Charles R.; And Others

    1978-01-01

    Described is the importance of genetic factors in health and disease and calls for the development of services for genetic screening, diagnosis, and counseling. Such services presently available in Canada are described. (BB)

  2. Autism: definition, neurobiology, screening, diagnosis.

    PubMed

    Rapin, Isabelle; Tuchman, Roberto F

    2008-10-01

    Autism (ie, the autism spectrum disorders) is now recognized in 1 in 150 children. This article highlights the definition, neurobiology, screening, and diagnosis of autism. The genetics, immunology, imaging, and neurophysiology of autism are reviewed, with particular emphasis on areas that impact pediatricians. Early recognition of the social deficits that characterize autism is key to maximizing the potential of these children. PMID:18929056

  3. 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.

  4. Outcomes of trophectoderm biopsy on cryopreserved blastocysts: a case series.

    PubMed

    Lathi, Ruth B; Massie, Jamie A M; Gilani, Morgan; Milki, Amin A; Westphal, Lynn M; Baker, Valerie L; Behr, Barry

    2012-11-01

    Preimplantation genetic diagnosis (PGD) is an increasingly common adjunct to IVF. The information gained from PGD may be used to reduce the incidence of chromosomally abnormal pregnancies and augment the current selection process of embryos. As such, patients may choose to utilize PGD in either fresh or cryopreserved IVF cycles. It is a common practice to cryopreserve excess embryos at the blastocyst stage. In these cases, trophectoderm biopsy is the only technique available for PGD. This articles reports this study centre's experience with trophectoderm biopsies of cryopreserved blastocysts in 12 patients who underwent 13 cycles of PGD. The implantation rate per embryo transferred was 46% and the ongoing pregnancy rate per embryo transfer was 63%. The results from this case series demonstrate that trophectoderm biopsy on cryopreserved blastocysts to perform PGD is logistically feasible. In addition, the rate of implantation and ongoing pregnancy were maintained within a reasonable range to justify the procedure. Preimplantation genetic diagnosis (PGD) is an increasingly common adjunct to IVF and is used to evaluate the genetic makeup of the embryo prior to transfer of the embryo into the uterus. The information gained from PGD may be used to identify single-gene disorders that result in genetic disease, reduce the incidence of chromosomally abnormal pregnancies and/or augment the selection process of embryos to be transferred. In order to perform PGD, a biopsy of the embryo is the performed and cells are removed for testing. PGD may be performed in either fresh or frozen (cryopreserved) IVF cycles. Patients who have cryopreserved embryos remaining in storage from a previous fresh cycle may wish to have these embryos tested with PGD. Many embryos are frozen on day 5 of development, referred to as the blastocyst stage. At this stage of development, embryo biopsy is performed via a technique known as 'trophectoderm biopsy', in which 1-3 of the cells destined to become the placenta are removed from the embryo for chromosomal testing. We report our experience with trophectoderm biopsy of frozen blastocysts in 12 patients who underwent 13 cycles of PGD. The implantation rate per embryo transferred was 46% and the ongoing pregnancy rate per embryo transfer was 63%. The results from this case series demonstrate that trophectoderm biopsy on cryopreserved blastocysts to perform PGD is logistically feasible. In addition, the rate of implantation and ongoing pregnancy were maintained within a reasonable range to justify the procedure. PMID:22985500

  5. Laser desorption mass spectrometry for molecular diagnosis

    NASA Astrophysics Data System (ADS)

    Chen, C. H. Winston; Taranenko, N. I.; Zhu, Y. F.; Allman, S. L.; Tang, K.; Matteson, K. J.; Chang, L. Y.; Chung, C. N.; Martin, Steve; Haff, Lawrence

    1996-04-01

    Laser desorption mass spectrometry has been used for molecular diagnosis of cystic fibrosis. Both 3-base deletion and single-base point mutation have been successfully detected by clinical samples. This new detection method can possibly speed up the diagnosis by one order of magnitude in the future. It may become a new biotechnology technique for population screening of genetic disease.

  6. Eugenics and genetic testing.

    PubMed

    Holtzman, N A

    1998-01-01

    Pressures to lower health-care costs remain an important stimulus to eugenic approaches. Prenatal diagnosis followed by abortion of affected fetuses has replaced sterilization as the major eugenic technique. Voluntary acceptance has replaced coercion, but subtle pressures undermine personal autonomy. The failure of the old eugenics to accurately predict who will have affected offspring virtually disappears when prenatal diagnosis is used to predict Mendelian disorders. However, when prenatal diagnosis is used to detect inherited susceptibilities to adult-onset, common, complex disorders, considerable uncertainty is inherent in the prediction. Intolerance and the resurgence of genetic determinism are current pressures for a eugenic approach. The increasing use of carrier screening (to identify those at risk of having affected offspring) and of prenatal diagnosis could itself generate intolerance for those who refuse the procedures. Genetic determinism deflects society from social action that would reduce the burden of disease far more than even the maximum use of eugenics. PMID:15168670

  7. Dual Diagnosis

    MedlinePlus

    ... that make them feel better temporarily. Sometimes the substance abuse occurs first. Over time, that can lead to emotional and mental problems. Someone with a dual diagnosis must treat both conditions. For the treatment to be effective, the person needs to stop ...

  8. Genetic Analysis of Isozyme Loci in Tetraploid Potatoes ( SOLANUM TUBEROSUM L.)

    PubMed Central

    Martinez-Zapater, J. M.; Oliver, Jose L.

    1984-01-01

    The genetic control of eight isozyme loci revealed by starch gel electrophoresis was studied through the analysis of three progenies derived from four tetraploid cultivars of Solanum tuberosum (groups Andigena and Tuberosum). Duplicate gene expression was found in seven (Got-A, Got-B, Pgd-C, Pgi-B, Pgm-A, Pgm-B and Pox-C) isozyme loci. In another isozyme gene (Adh-A), the parental genotypes were not adequate to distinguish between a monogenic or a digenic model of genetic control. Tetrasomic inheritance was demonstrated in four (Got-A, Got-B, Pgd-C and Pgi-B) isozyme loci. In the remaining duplicate genes, the parental genotypes precluded discrimination between disomic or tetrasomic models. Tetrasomic segregations of the chromosomal type were generally found; however, the isozyme phenotypes shown by three descendants from selfing cv. Katahdin indicate the occurrence of chromatid segregations, although aneuploidy cannot be ruled out. Either autoploidy or amphidiploidy with lack of chromosome differentiation between the two diploid ancestors can account for the existence of tetrasomic inheritance in the common potato. PMID:17246238

  9. 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

  10. Genetics Home Reference: Gillespie syndrome

    MedlinePlus

    ... Kennedy Shriver National Institute of Child Health and Human Development: What Are Treatments for Intellectual and Developmental Disabilities? Genetic Testing Registry: Aniridia, cerebellar ataxia, and mental retardation These resources from MedlinePlus offer information about the diagnosis and ...

  11. 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. PMID:26893002

  12. 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.

  13. 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. PMID:16956347

  14. 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

  15. 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. PMID:26345167

  16. 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.

  17. [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

  18. 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. PMID:26724724

  19. 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

  20. Diagnostic recognition of genetic disease

    SciTech Connect

    Nyhan, W.L.; Sakati, N.A.

    1987-01-01

    This book discusses the diagnosis and management of genetically determined diseases. Genetics are also discussed, but the major focus is on diagnosis. Patients with genetically determined disorders have clinical pictures that cross most of the boundaries of subspecialty practice, and are frequently seen by a variety of physicians. The pediatrician will often be the first to come in contact with these patients, but internists are increasingly concerned with these patients, especially those with inborn errors of metabolism. The hematologist may be the first to see a patient with Fanconi anemia, and the gynecologist, the patient with Turner's syndrome. In brief this book emphasizes the diagnosis of various genetic diseases in relation to different medical specialties.

  1. Prenatal Diagnosis of WAGR Syndrome

    PubMed Central

    Tezcan, Berrin; Rich, Philip; Bhide, Amarnath

    2015-01-01

    Wilm's tumour, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome is a rare genetic disorder with an estimated prevalence of 1 in 500,000 to 1 million. It is a contiguous gene syndrome due to deletion at chromosome 11p13 in a region containing WT1 and PAX6 genes. Children with WAGR syndrome mostly present in the newborn/infancy period with sporadic aniridia. The genotypic defects in WAGR syndrome have been well established. However, antenatal ultrasonographic presentation of this syndrome has never been reported. Prenatal diagnosis of this condition is possible in some cases with careful ultrasound examination of classical and nonclassical manifestations of this syndrome. The key point for this rare diagnosis was the decision to perform chromosomal microarray analysis after antenatal diagnosis of absent corpus callosum and absent cavum septum pellucidum, as this finding mandates search for potentially associated genetic disorders. We report a case of WAGR syndrome diagnosed prenatally at 29-week gestation. The diagnosis of the anomaly was based on two- and three-dimensional ultrasound as well as fetal MRI scan and microarray analysis. The ultrasonographic findings included borderline ventriculomegaly, absent corpus callosum, and absent cavum septum pellucidum. Cytogenetic results from the amniotic fluid confirmed WAGR syndrome. Parental karyotype was normal, with no evidence of copy number change, deletion, or rearrangement of this region of chromosome 11. PMID:26605098

  2. 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. PMID:25066489

  3. QUALITATIVE GENETICS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Qualitative genetics, also known as Mendelian genetics or transmission genetics refers to those genetic traits that have a distinct phenotype, and are controlled by one or several genes. More than 300 qualitative genetic traits are known and are maintained in the USDA soybean Genetic Type Collectio...

  4. 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.

  5. [Diagnosis and therapy of mitochondrial diseases].

    PubMed

    Pál, Endre

    2012-07-30

    Mitochondrial diseases are a significant part of neuromuscular diseases. Majority of them is multisystemic disorder. The diagnosis can be established in more and more cases. Beyond the routine neurological examination imaging methods (MRI and MR-spectroscopy) and electrophysiology (EMG, ENG, EEG, evoked potential tests) might be helpful in setting the diagnosis. Raised blood lactate level supports the diagnosis. Muscle biopsy demonstrates mitochondrial abnormalities in the majority of cases. The positivity of genetic tests is low, because the amount of mitochondrial DNA alterations is different in tissues. Therefore other tissue than blood (mainly muscle) is necessary for genetic tests. The other reason is that the respiratory chain is under double -mitochondrial and nuclear - genetic control, and testing the nuclear genes are available only in selected laboratories. The treatment is limited, mainly symptomatic. PMID:23074842

  6. Osteoarthritis: diagnosis and treatment.

    PubMed

    Sinusas, Keith

    2012-01-01

    Osteoarthritis is a common degenerative disorder of the articular cartilage associated with hypertrophic bone changes. Risk factors include genetics, female sex, past trauma, advancing age, and obesity. The diagnosis is based on a history of joint pain worsened by movement, which can lead to disability in activities of daily living. Plain radiography may help in the diagnosis, but laboratory testing usually does not. Pharmacologic treatment should begin with acetaminophen and step up to nonsteroidal anti-inflammatory drugs. Exercise is a useful adjunct to treatment and has been shown to reduce pain and disability. The supplements glucosamine and chondroitin can be used for moderate to severe osteoarthritis when taken in combination. Corticosteroid injections provide inexpensive, short-term (four to eight weeks) relief of osteoarthritic flare-ups of the knee, whereas hyaluronic acid injections are more expensive but can maintain symptom improvement for longer periods. Total joint replacement of the hip, knee, or shoulder is recommended for patients with chronic pain and disability despite maximal medical therapy. PMID:22230308

  7. 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

  8. Genetics Home Reference: age-related macular degeneration

    MedlinePlus

    ... form. The dry form is much more common, accounting for 85 to 90 percent of all cases ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  9. [Molecular diagnosis of primary immunodeficiencies].

    PubMed

    García Rodríguez, M C; López Granados, E; Cambronero Martínez, R; Ferreira Cerdán, A; Fontán Casariego, G

    2001-01-01

    Knowledge of the molecular defects responsible for some primary immunodeficiency diseases (PIDs) offers undoubted advantages in establishing a reliable diagnosis. Such knowledge would allow us not only to establish a prognosis but also to instigate the most appropriate therapy. After molecular diagnosis, some patients could benefit from gene therapy. However, apart from the diagnosis of the disease, molecular biological techniques also enable more reliable identification of carriers and, when suggested by the family history and when the familial defect is already known, prenatal diagnosis will also be possible, thus establishing the earliest possible treatment. Using the single-stranded conformational polymorphism technique followed by direct sequencing, we found 22 different mutations in 22 patients from unrelated families and with a phenotype compatible with x-linked agammaglobulinemia. Fourteen of these are new, previously undescribed mutations and the remaining eight are already included in the data base (http://www.uta.fi/imt/bioinfo/Btkbase). Analysis of the female carrier was performed in all the mothers and the mutation was de novo in only one patient. Study of the BtK gene enabled differential diagnosis with common variable immunodeficiency disease in some patients who showed absent or very low lymphocyte B counts as well as forms of autosomal recessive agammaglobulinemia. Using the same techniques, we were able to identify mutations in the CD40 ligand gene in three families in which one of the members had clinical and biological phenotype compatible with X-linked hyper-IgM. Molecular diagnosis was very useful in identifying carriers in these families as well as in making the differential diagnosis among patients with common variable immunodeficiency disease. Purely on this were we able to provide appropriate genetic counseling. PMID:11434883

  10. Genetics for the ophthalmologist

    PubMed Central

    Sadagopan, Karthikeyan A.; Capasso, Jenina; Levin, Alex V.

    2012-01-01

    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

  11. 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.

  12. 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. PMID:23615969

  13. [Genetic differentiation in plants of the genus Cypripedium from Russia inferred from allozyme data].

    PubMed

    Filippov, E G; Andronova, E V

    2011-05-01

    Ten gene loci of nine enzyme systems (PGI, 6-PGD, NADHD, SKDH, GDH, PGM, DIA, ADH, GOT-1, and GOT-2) were analyzed in Cypripedium calceolus, C. macranthon, C. shanxiense, and C. ventricosum plants from the south of the Russian Far East. Alleles of loci 6-PGD, NADHD, GDH, ADH, GOT-1, and PGIproved to be diagnostic for C. calceolus and C. macranthon. Plants of C. shanxiense from Primorye and Sakhalin Island were monomorphic at all of the loci examined, and their allelic structure can be regarded as diagnostic for the species. The allelic structure for fragments of the C. calceolus population from the western and eastern parts of the species range differed in two loci, PGl and SKDH: alleles absent in C. calceolus plants from the western part of the range occurred at a high frequency in the plants of this species from the eastern part of the range (28 and 55 plants or 41% and 68%, respectively). These alleles were found in C. shanxiense. The genetic structure of C. shanxiense was similar to that of C. calceolus from the eastern part of the range, i.e., the region when these species are sympartic. The additional alleles in C. calceolus from the eastern part of the range might have appeared as a result of hybridization with C. shanxiense. Our results indicate that C. calceolus plants occuring on the territory of Russia form two groups that represent two different units of genetic diversity preservation. We suggest that C. x ventricosum plants in southern Primorye were formed by hybridization between C. macranthon and C. calceolus x C. shanxiense hybrids. Thus, they differ from plants inhabiting the Urals and West Siberia, which originated by hybridization between C. macranthon and C. calceolus. The population of C. x ventricosum presumably also consists of two plant groups differing in genetic structure, which should be regarded as two different units of preservation of this taxon. PMID:21786667

  14. 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 ...

  15. New Genetics

    MedlinePlus

    ... Occasion of Darwin's Birthday Computing Genetics Model Organisms RNA Interference The New Genetics is a science education ... the basics of DNA and its molecular cousin RNA, and new directions in genetic research. The New ...

  16. 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. ...

  17. [Genetics of hypophosphatasia].

    PubMed

    Mornet, E; Simon-Bouy, B

    2004-05-01

    Hypophosphatasia is a rare inherited disorder characterized by defective bone and teeth mineralization and deficiency of serum and bone alkaline phosphatase activity. The symptoms are highly variable in their clinical expression, which ranges from stillbirth without mineralized bone to early loss of teeth without bone symptoms. Currently, there is no treatment for the disease. Recent developments in molecular biology allow to better understand the genetics of the disease, especially its transmission that may be recessive or dominant, to improve genetic counseling and molecular diagnosis, and offer new perspectives of treatment. PMID:15135429

  18. The genetics of lissencephaly.

    PubMed

    Fry, Andrew E; Cushion, Thomas D; Pilz, Daniela T

    2014-06-01

    Lissencephaly is a spectrum of severe brain malformations caused by the failure of migrating neurons to reach optimal positions in the developing cerebral cortex. Several syndromes associated with lissencephaly have been characterized in recent years. Identification of the genetic basis of these disorders has brought fascinating insights into the mechanisms of brain development, as well as benefits to patients through improved molecular diagnosis and genetic counseling. This review explores the clinical presentation, radiological features, histological findings and molecular basis of lissencephaly with the aim of facilitating the selection and interpretation of gene tests in patients with 'smooth brain' phenotypes. PMID:24862549

  19. Genetic structure of the human population in the Po delta

    PubMed Central

    Beretta, M.; Mazzetti, P.; Mamolini, E.; Gavina, R.; Barale, R.; Vullo, C.; Ravani, A.; Franze, A.; Sapigni, T.; Soracco, E.; Davi, D.; Ricci, N.; Cappello, N.; Rendine, S.; Piazza, A.; Barrai, I.

    1989-01-01

    The genetic structure of the population of Ferrara Province in the Po delta in Italy was investigated using χ2 analysis, kinship analysis, analysis of correspondences, and geographical mapping of principal components of gene frequencies, χ2 Analysis tests for Hardy-Weinberg equilibrium and for heterogeneity of gene and phenotype frequencies; kinship analysis tests for association between indicators of genetic and geographic proximity; analysis of correspondences relates localities and genetic systems in an eigenvectorial space; and geographic mapping displays the principal components of gene frequencies in the real space. In 1,364 adults in 26 residential units, seven presumably neutral isoenzyme systems were typed; ACP1 ESD, GLO I, GPT, PGD, PGM1 and PGP. It was found that average kinship for these neutral systems is correlated with geographic distance in this small area, but not as strongly as kinship for beta-thalassemia. A north-south gradient was observed for ESD. Analysis of correspondences indicated GPT, PGM1, and GLO I as the systems contributing most to differentiation within the province. The maps obtained from principal components of gene frequencies were consistent with the migrational history of the area. ImagesFigure 4Figure 5Figure 6Figure 7Figure 8 PMID:2741951

  20. 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. PMID:22809468

  1. Tuberous sclerosis: diagnosis and prenatal diagnosis by MLPA.

    PubMed

    Padma Priya, T; Dalal, Ashwin B

    2012-10-01

    Tuberous sclerosis complex (TSC) is an autosomal dominant disorder, caused due to mutations in the TSC1 and TSC2 genes. Mutations in TSC2 gene are more common than in TSC1 gene and mostly they are in the form of large genomic deletions or duplications. The authors report on a novel deletion in TSC2 gene, prenatal diagnosis and genetic counseling in a family with a 3- year- old affected male child. This is the first report on MLPA based mutation analysis of TSC1 and TSC2 genes from India. PMID:21541650

  2. An improved CHC algorithm for damage diagnosis of offshore platforms

    NASA Astrophysics Data System (ADS)

    Huang, Weiping; Wang, Xiaoyan

    2007-01-01

    An improved CHC algorithm is proposed in the paper and it could be used for the damage diagnosis of structures. It breaks the bottle neck of genetic algorithm in the damage diagnosis of large structures and takes a shorter time than the SGA (Standard Genetic Algorithm) in diagnosing structural damage with the same level of error. The case studies show that the algorithm is rapid in convergence and produces satisfactory results in diagnosing both fixed-end beams and jacket offshore platforms.

  3. Bacteriophage: laboratorial diagnosis and phage therapy

    PubMed Central

    Silva, Joas L. Da; Hirata, Rosario D.C.; Hirata, Mario H.

    2009-01-01

    Bacteriophages have been researched as a new alternative to antibiotics. These viruses inject their genetic material into bacteria and use their host machinery to multiply themselves. The research of bacteriophages in Brazil will certainly provide low-cost treatment of multidrug resistant bacteria, new microbiological diagnosis and advantages for the Brazilian food industry. PMID:24031398

  4. 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.

  5. [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

  6. Craniosynostosis genetics: The mystery unfolds

    PubMed Central

    Panigrahi, Inusha

    2011-01-01

    Craniosynsostosis syndromes exhibit considerable phenotypic and genetic heterogeneity. Sagittal synostosis is common form of isolated craniosynostosis. The sutures involved, the shape of the skull and associated malformations give a clue to the specific diagnosis. Crouzon syndrome is one of the most common of the craniosynostosis syndromes. Apert syndrome accounts for 4.5% of all craniosynostoses and is one of the most serious of these syndromes. Most syndromic craniosynostosis require multidisciplinary management. The following review provides a brief appraisal of the various genes involved in craniosynostosis syndromes, and an approach to diagnosis and genetic counseling. PMID:22090712

  7. Celiac disease: advances in diagnosis.

    PubMed

    Snyder, Melissa R; Murray, Joseph A

    2016-04-01

    Celiac disease (CD) is characterized by small intestinal damage, which is mediated by a gluten-driven inflammatory response. Establishing a robust diagnosis is critical for improved quality of life and prevention of co-morbidities, although treatment is associated with a substantial life-long burden of care for patients and families. Unfortunately, CD remains a challenging diagnosis. As awareness of the disease increases, more diagnoses of CD are being made by primary care physicians. In fact, many patients may not present to a gastroenterologist because their symptoms are not clearly linked to a gastrointestinal pathology. Also, many patients are starting a gluten-free diet without prior testing, a circumstance that leads to even more confusion. Lastly, the number of serologic and genetic tests, and the role of endoscopy, can be confusing. The purpose of this review is to examine diagnostic testing strategies, focusing on published guidelines, for the evaluation of patients with suspected CD. PMID:26654883

  8. 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. PMID:7721278

  9. Genetic technologies and ethics.

    PubMed

    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

  10. Rhabdomyolysis: a genetic perspective.

    PubMed

    Scalco, Renata Siciliani; Gardiner, Alice R; Pitceathly, Robert Ds; Zanoteli, Edmar; Becker, Jefferson; Holton, Janice L; Houlden, Henry; Jungbluth, Heinz; Quinlivan, Ros

    2015-01-01

    Rhabdomyolysis (RM) is a clinical emergency characterized by fulminant skeletal muscle damage and release of intracellular muscle components into the blood stream leading to myoglobinuria and, in severe cases, acute renal failure. Apart from trauma, a wide range of causes have been reported including drug abuse and infections. Underlying genetic disorders are also a cause of RM and can often pose a diagnostic challenge, considering their marked heterogeneity and comparative rarity.In this paper we review the range of rare genetic defects known to be associated with RM. Each gene has been reviewed for the following: clinical phenotype, typical triggers for RM and recommended diagnostic approach. The purpose of this review is to highlight the most important features associated with specific genetic defects in order to aid the diagnosis of patients presenting with hereditary causes of recurrent RM. PMID:25929793

  11. [Genetics in osteoarthritis].

    PubMed

    Fernández-Moreno, Mercedes; Rego, Ignacio; Blanco, Francisco J

    2007-10-01

    Osteoarthritis is a degenerative articular pathology with complex pathogeny because diverse factors interact causing a process of deterioration of the cartilage. In spite of the multifactorial nature of this pathology, from years 50 one knows 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 candidates 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 pathology are not known, however, which seems clear is that levels of expression of several genes are altered, and that the inheritance will become a substantial factor in future considerations of diagnosis and treatment of the osteoarthitis. PMID:21794474

  12. 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

  13. Automated genotyping in diagnosis.

    PubMed

    Noble, J S; Leach, K J; Ellis, L A; Taylor, G R

    1996-01-01

    At present automated genotyping in diagnosis involves the detection, digitrzation, and analysis of labeled DNA using computer software. This chapter describes the use of the Applied Biosystems (Foster City, CA) 373 DNA Sequencer and Genescan 672 software for sizing fluorescently labeled PCR products in a diagnostic molecular genetics laboratory. The Applied Biosystems Genotyper software is not covered since this is not used at present in this laboratory. An outline of the steps involved in automated genotyping, from polymerase chain reaction (PCR) to archiving data, is shown in Fig. 1. Fig. 1. Overview of the procedure. Labeled PCR products are produced by either incorporation of fluorescent dNTPs or labeled primers. A polyacrylamide gel is cast, scanned, and prerun, and the Genescan collection and analysis files are set up. The PCR products are mixed with a size standard, denatured, and loaded onto the prerun gel. After electrophoresrs the collected data is transferred to another Macintosh for analysis. A results file is generated and the PCR products are scored and checked. The results file is then archived. PMID:21374518

  14. 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

  15. 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. PMID:27089755

  16. [Pediatric neurological disorders and genetic counseling].

    PubMed

    Fukushima, Yoshimitsu

    2003-07-01

    Genetic counseling provides medical and genetic information of the disease including its natural history, recurrence risk, availability and usefulness of genetic testing, as well as psycho-social support. In the field of pediatric neurology, the majority of genetic counseling seems to be a simple risk estimation of the next child and unrelated to ethical issues. However, in some cases requiring prenatal diagnosis or presymptomatic testing, we have to address serious ethical issues. Genetic counseling should be provided by an educated medical doctor at a suitable genetics clinic. In Japan, we have "Japanese Board of Medical Genetics, Clinical Geneticist" as an education system of clinical genetics for medical doctors. Pediatric neurologists should know the special issues of genetic information and contact with clinical geneticists in selected cases. PMID:12875203

  17. Microcomputer based differential diagnosis of dysmorphic syndromes.

    PubMed

    Veloso, M L; Feijóo, M J

    1989-03-01

    Dysmorphic syndromes are characterized by associations of physical abnormalities depending in its diagnosis on the recognition of a particular pattern. Because of their multiplicity, the rarity of some of them, and the frequency of new reports, computerized data bases have proved useful as powerful tools assisting in the differential diagnosis. The role of artificial intelligence methods, in particular Expert Systems, as promising tools in helping physicians to perform a clinical diagnosis is underlined. Using a high level computer language presently used in the artificial intelligence field (Prolog), a microcomputer based system for the differential diagnosis of dysmorphic syndromes is described. Its capabilities and simplicity of use, derived from an efficient and attractive computer interface, are underlined. The need of performance assessment by evaluating its accuracy and usefulness before its introduction into genetic clinical practice is stressed. Finally, for the completeness of the knowledge base, the need of cooperation between international centers is emphasized. PMID:2662096

  18. Genetics of Canine Primary Glaucomas.

    PubMed

    Komromy, Andrs M; Petersen-Jones, Simon M

    2015-11-01

    Primary glaucomas are a leading cause of incurable vision loss in dogs. Based on their specific breed predilection, a genetic cause is suspected to be responsible, and affected dogs should be excluded from breeding. Despite the high prevalence of primary glaucomas in dogs, their genetics have been studied in only a small number of breeds. The identification of canine glaucoma disease genes, and the development of genetic tests, will help to avoid the breeding of affected dogs in the future and will allow for earlier diagnosis and potentially more effective therapy. PMID:26277300

  19. Celiac disease: diagnosis and management.

    PubMed

    Pelkowski, Timothy D; Viera, Anthony J

    2014-01-15

    Celiac disease is an autoimmune disorder of the gastrointestinal tract. It is triggered by exposure to dietary gluten in genetically susceptible individuals. Gluten is a storage protein in wheat, rye, and barley, which are staples in many American diets. Celiac disease is characterized by chronic inflammation of the small intestinal mucosa, which leads to atrophy of the small intestinal villi and subsequent malabsorption. The condition may develop at any age. Intestinal manifestations include diarrhea and weight loss. Common extraintestinal manifestations include iron deficiency anemia, decreased bone mineral density, and neuropathy. Most cases of celiac disease are diagnosed in persons with extraintestinal manifestations. The presence of dermatitis herpetiformis is pathognomonic for celiac disease. Diagnosis is supported by a positive tissue transglutaminase serologic test but, in general, should be confirmed by a small bowel biopsy showing the characteristic histology associated with celiac disease. The presence of human leukocyte antigen alleles DQ2, DQ8, or both is essential for the development of celiac disease, and can be a useful genetic test in select instances. Treatment of celiac disease is a gluten-free diet. Dietary education should focus on identifying hidden sources of gluten, planning balanced meals, reading labels, food shopping, dining out, and dining during travel. About 5% of patients with celiac disease are refractory to a gluten-free diet. These patients should be referred to a gastroenterologist for reconsideration of the diagnosis or for aggressive treatment of refractory celiac disease, which may involve corticosteroids and immunomodulators. PMID:24444577

  20. 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),…

  1. [Is preimplantation diagnosis legal?--on the need for harmonizing legislation].

    PubMed

    Ratzel, Rudolf

    2002-07-01

    Whether PGD is already legally permitted in Germany today is a moot point. A guidelines draft of the Germany's Federal General Medical Council, the Bundesärztekammer, on pre-implantation genetic diagnostics that--like the earlier findings of the ethics commission of the German federal state of the Rhineland-Palatinate--assumed that the method is admissible, if certain clearly-defined indications are present and a rigorous testing procedure has been established, has given the discussion a new impetus. The discussion is in full swing, with calls by politicians for the legislator to pass a regulation mounting. Of late, though, constitutional objections have been raised against a positive-law regulation. Such a simple legal move to regulate PGD, it is claimed, would violate the constitutionally-guaranteed right to inviolable human dignity. Critics, however, point out that such an absolute inviolability does not exist. According to them, not only the verdicts by the German Federal Constitutional Court, the Bundesverfassungsgericht, on the reform of section 218 of the German Federal Penal Code (StGB)--the paragraph that specifies the conditions under which an abortion is not punished--that relativize (in terms of the indication model) one claim to existence with respect to another, but also the approval in terms of pharmaceutical and medicine-products law of nidation-blocking agents, serve to show this. If the condition of being a human being were made to coincide with the completion of the genetic code upon the completion of the process of fertilisation, then one tended to forget, the critics noted, that this attendant dignity was not properly "infused with life" unless nidation had been successful. Without nidation everything were fragmentary, the total protection of human dignity according to Article 1 Section 1 of the Federal Republic's Basic Law, Germany's constitution, notwithstanding. During every in vitro fertilisation embryo transfer is conditional upon a variety of factors the presence of which is not noted until after fertilisation has taken place. On the part of the embryos, too, certain conditions have to be met whose presence at the moment of fertilisation is not assured. Thus an embryo with, for instance, defects that can be visually detected will not be transferred. With regard to these facts too the opponents of pre-implantation genetic diagnostics must be challenged to answer the question of why an embryo with visually-detectable defects should undoubtedly be allowed to be discarded, but the act of searching for "internal" defects be banned. Thus the fact remains that the mere acceptance of the loss of created embryos does not make artificial insemination a punishable offense, as long as the motive for the act is to bring about pregnancy. To achieve legal security for the couples and the physicians involved the law on the protection of embryos should be changed. The new regulations should determine under which conditions PGD is permissible. As is already the case for other norms that apply to reproductive medicine, but also for the practice of abortion, these regulations should contain an analogous right of refusal for the professionals involved. The laws relating to the healing professions, to the professional chambers, as well as the regulations of the various German federal states (which together constitute the Federal Republic of Germany) that apply to the professions should be amended accordingly. PMID:12219494

  2. 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 ...

  3. 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 ...

  4. 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 ...

  5. Food Allergy Diagnosis

    MedlinePlus

    ... Skip Content Marketing Share this: Main Content Area Food Allergy Diagnosis © iStockphoto On this page Detailed History ... diagnosis of food allergy. back to top Oral food challenge Caution Because oral food challenges can cause ...

  6. Plague Diagnosis and Treatment

    MedlinePlus

    ... this page: About CDC.gov . Plague Home Ecology & Transmission Symptoms Diagnosis & Treatment Maps & Statistics Info for Healthcare Professionals Clinicians Public Health Officials Veterinarians Prevention History of Plague Resources FAQ Diagnosis and Treatment Recommend ...

  7. 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…

  8. Genetic counseling

    MedlinePlus

    Genetics is the study of heredity, the process of a parent passing certain genes on to their ... certain diseases are also often determined by genes. Genetic counseling is the process where parents can learn ...

  9. 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 ...

  10. Genetic Mapping

    MedlinePlus

    ... for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for Teachers ... Education Kit Online Genetics Education Resources Smithsonian NHGRI Genome Exhibition Talking Glossary: English Talking Glossary: Español Issues ...

  11. Genetic Discrimination

    MedlinePlus

    ... See these resources for additional information on the law: Genetic Information Nondiscrimination Act of 2008 GINA & You ... cfm Top of page Genetic Discrimination and Other Laws Bill Clinton's Executive Order Prohibiting the Use of ...

  12. Genetics (image)

    MedlinePlus

    Genetics is the study of heredity and how traits are passed along from parents to offspring. Genes ... chromosome. The inheritance of genetic diseases, abnormalities, or traits is described by both the type of chromosome ...

  13. Genetic Mapping

    MedlinePlus

    ... Links for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for Teachers ... genetic mapping? Among the main goals of the Human Genome Project (HGP) was to develop new, better and ...

  14. 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 ...

  15. Genetic determinants of cardiac hypertrophy

    PubMed Central

    Marian, Ali J.

    2009-01-01

    Purpose of review Cardiac hypertrophy is a common phenotypic response of the heart to stimulants. It is associated with increased morbidity and mortality in various cardiovascular disorders. Genetic factors are important determinants of phenotypic expression of cardiac hypertrophy, whether in single-gene disorders or in complex traits. We focus on the molecular genetics of cardiac hypertrophy in various conditions with an emphasis on hypertrophic cardiomyopathy, a genetic paradigm of cardiac hypertrophic response. Recent findings The molecular genetic basis of cardiac hypertrophy in single-gene disorders has been partially elucidated. Likewise, the impact of genetics on the expression of cardiac hypertrophy in the general population has been demonstrated. Identification of mutations in the Z disk proteins has expanded the spectrum of causal mutations beyond the thin and thick filaments of the sarcomeres. In addition, modifier loci have been mapped and shown to impart considerable effects on the expression of cardiac hypertrophy in hypertrophic cardiomyopathy. Elucidation of the molecular genetics of sarcomeric hypertrophic cardiomyopathy and many of the phenocopies has highlighted the limitations of clinical diagnosis as a determinant of management and prognostic advice. The findings have raised the importance of diagnosis and treatment algorithms, which are based on both genotype and phenotype information. Summary Cardiac hypertrophy, regardless of the cause, is the phenotypic consequence of complex interactions between genetic and nongenetic factors. PMID:18382207

  16. Preimplantation genetics: a case for prospective action.

    PubMed

    Pergament, E; Bonnicksen, A

    1994-08-15

    Preimplantation genetics describes a newly-emerging field in medical genetics, the consequence of the implementation of clinical preimplantation diagnosis and the likely future development of germ-line gene therapy. Given the existing clinical and laboratory difficulties already demonstrated in preimplantation diagnosis and the sensitive ethical issues surrounding genetic manipulation of human embryos, there is a need for 1) critical and objective evaluation of developments in this field by human and medical geneticists and 2) development of guidelines for research and clinical practice in the years ahead. We propose a course of prospective action for preimplantation genetics implemented through the newly-formed American College of Medical Genetics in order to address the ethics, safety, accuracy, cost, and overall merit of preimplantation genetics. PMID:7802000

  17. Parental Choices and Ethical Dilemmas Involving Disabilities: Special Education and the Problem of Deliberately Chosen Disabilities

    ERIC Educational Resources Information Center

    Kauffman, James M.; Hallahan, Daniel P.

    2009-01-01

    Ethical issues regarding children with disabilities have long involved their treatment after they are born. These issues remain important, but children may be deliberately created with or without characteristics that are usually thought of as disabilities. Preimplantation genetic diagnosis (PGD) and related technologies that involve human…

  18. Genetic modification and genetic determinism.

    PubMed

    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

  19. 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

  20. 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.

  1. 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.

  2. SOYBEAN GENETICS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soybean genetics is a broad area encompassing all aspects, such as qualitative genetics, molecular genetics, etc. The objective of this book chapter, a revision of a 1998 book on soybean, was to include information that could be used for soybean improvement, and to summarize the current status of s...

  3. 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 symptoms Making ...

  4. Soybean Genetics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soybean genetics is a broad area encompassing all aspects, such as qualitative genetics, molecular genetics, etc. The objective of this book chapter was to include information that could be used for soybean improvement, and to summarize the current status of soybean genomics. Soybean germplasm is ...

  5. Exostoses, enchondromatosis and metachondromatosis; diagnosis and management.

    PubMed

    McFarlane, J; Knight, T; Sinha, A; Cole, T; Kiely, N; Freeman, R

    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

  6. [Is systemic diagnosis possible?].

    PubMed

    Siewierska, Anna; Sliwczyńska, Jadwiga; Namysłowska, Irena

    2008-01-01

    The authors discuss the concept of systemic diagnosis and its logical and scientific validity. A diagnosis is the result of the "diagnostic process", with the presence of the acting object (the person making the diagnosis) and the subject (the individual or group patient, such as family), between whom there is a skew relation. They also wonder, to which part of this diagnostic process is the term "systemic" applied--to the clinician or to the subject of the diagnosis, their relation or the effect of the process. The authors also stress the crucial effect of the constructivism and social constructionism on the process of the systemic diagnosis. PMID:18567400

  7. Genetic evaluation of male infertility

    PubMed Central

    2014-01-01

    Men with severe oligospermia (<5 million sperm/mL ejaculate fluid) or azoospermia should receive genetic testing to clarify etiology of male infertility prior to treatment. Categorization by obstructive azoospermia (OA) or non-obstructive azoospermia (NOA) is critical since genetic testing differs for the former with normal testicular function, testicular volume (~20 mL), and follicle-stimulating hormone (FSH) (1-8 IU/mL) when compared to the latter with small, soft testes and increased FSH. History and physician examination along with laboratory testing (following appropriate genetic counseling) is critical to accurate selection of genetic testing appropriate for azoospermia due to primary testicular failure as compared with congenital hypogonadotropic hypogonadism (HH). Genetic testing options include cystic fibrosis transmembrane conductance regulator (CFTR) testing for men with congenital absence of the vas, while karyotype, Y chromosome microdeletions (YCMD), and other specific genetic tests may be warranted depending on the clinical context of severe oligospermia or NOA. The results of genetic testing guide management options. The most recent techniques for genetic analysis, including sperm microRNA (miRNA) and epigenetics, are forming the foundation for future genetic diagnosis and therapeutic targets in male infertility. PMID:26813518

  8. Genetic testing.

    PubMed

    Petersen, G M

    2000-08-01

    New research developments in the molecular genetics of cancer have led to the feasibility of cancer genetic testing. At present, genetic test results can better inform individuals at risk about appropriately tailored strategies for cancer screening and prevention. In the future, more persons will be eligible for genetic evaluation; in particular, if it is shown that patients with cancer who are carriers of germline mutations respond differently to treatments, genetic testing may be warranted. Consideration needs to be given to the appropriate delivery of genetic risk assessment and testing. There is a great potential for misinterpretation of gene test results and for adverse psychosocial consequences for patients. Genetic counseling is an important component in cancer risk assessment and management, particularly in helping persons at risk understand the implications of gene test results in the context of their experience with cancer and surveillance. PMID:10949782

  9. 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. PMID:25454304

  10. 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

  11. Mitochondrial genetics and disease.

    PubMed

    Area-Gomez, Estela; Schon, Eric A

    2014-09-01

    Mitochondrial disease resulting in reduced bioenergetic output can be due to mutations in either nuclear DNA-encoded or mitochondrial DNA-encoded gene products. We summarize some of the underlying principles of mitochondrial genetics that impact the diagnosis and pathogenesis of mitochondrial disorders. In addition, we present a brief overview of a new frontier in the field, namely, mitochondrial "dynamics," which controls organellar fusion, fission, trafficking, and positioning, and exerts mitochondrial "quality control" by maintaining organellar integrity and viability. Analysis of mutations in gene products associated with this latter area has opened up new vistas in the study of disorders associated with compromised energy production. PMID:25028417

  12. Genetics Home Reference: STING-associated vasculopathy with onset in infancy

    MedlinePlus

    ... Diagnosis & Management These resources address the diagnosis or management of SAVI: Beth Israel Deaconess Medical Center: Autoinflammatory Disease Center Eurofever Project Genetic Testing Registry: Sting-associated vasculopathy, infantile-onset ...

  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. The SHOX gene and the short stature. Roundtable on diagnosis and treatment of short stature due to SHOX haploinsufficiency: how genetics, radiology and anthropometry can help the pediatrician in the diagnostic process Padova (April 20th, 2011).

    PubMed

    De Sanctis, Vincenzo; Tosetto, Ilaria; Iughetti, Lorenzo; Antoniazzi, Franco; Clementi, Maurizio; Toffolutti, Tiziana; Facchin, Paola; Monti, Elena; Pisanello, Lorena; Tonini, Giorgio; Greggio, Nella A

    2012-08-01

    The growth of the human body depends from a complex interaction between nutritional, environmental and hormonal factors and by a large number of different genes. One of these genes, short stature homeobox (SHOX), is believed to play a major role in growth. SHOX haploinsufficiency is associated with a wide spectrum of conditions, all characterized growth failure such as Leri-Weill dyschondrosteosis, Turner syndrome, short stature with subtle auxological and radiological findings and the so called "idiopathic short stature" (short stature with no specific findings other than growth failure). The document was prepared by a multidisciplinary team (paediatric endocrinologists, paediatrician, radiologist, geneticist and epidemiologist) to focus on the investigation of children with suspected SHOX- deficiency (SHOX-D) for an early identification and a correct diagnostic work - up of this genetic disorder. On the basis of a number of screening studies, SHOX-D appears to be a relatively frequent cause of short stature. The following recommendations were suggested by our multidisciplinary team: (i) a careful family history, measurements of body proportions and detection of any dysmorphic features are important for the suspect of a genetic disorder ,(ii)the presence of any combination of the following physical findings, such as reduced arm span/height ratio, increased sitting height/height ratio, above average BMI, Madelung deformity, cubitus valgus, short or bowed forearm, dislocation of the ulna at the elbow, or the appearance of muscular hypertrophy, should prompt the clinician to obtain a molecular analysis of the SHOX region, (iii) it is of practical importance to recognise early or mild signs of Madelung deformity on hand and wrist radiographs, (iv) growth hormone ,after stimulation test, is usually normal. However, treatment with rhGH may improve final adult height; the efficacy of treatment is similar to that observed in those treated for Turner syndrome. PMID:23304810

  15. 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.

  16. 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. PMID:26498608

  17. [Update on genetic predisposition to prostate cancer].

    PubMed

    Cussenot, Olivier; Cancel-Tassin, Graldine

    2015-01-01

    Genetic predisposition to prostate cancer rarely corresponds to a high penetrance Mendelian pattern of inheritance. These hereditary forms are specific entities for which mutations in the BRCA2gene, the HOXB13gene (variant G84E) or, to a lesser extent BRCA1gene, must be researched. In contrast, the genetic component of the majority of prostate cancer is polygenic, involving an unfavorable combination of common genetic variants, resulting from a mixture of the genetic inheritance of the father and the mother. One hundred of these genetic susceptibility variants have now been identified and validated. The main phenotypic trait associated with hereditary predisposition is the younger age at onset, which warrants special monitoring in order to stay in the window of curability at diagnosis. The psychological impact of a family history of prostate cancer or breast cancer favors the establishment of a dedicated monitoring and procedures for early diagnosis. PMID:25609482

  18. Genetic Evaluation of Short Stature

    PubMed Central

    Rosenfeld, Ron G.

    2014-01-01

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

  19. Diagnosis of Leishmaniasis

    MedlinePlus

    ... Monday-Friday Closed Holidays Contact CDC-INFO Leishmaniasis General Information Leishmaniasis FAQs Epidemiology & Risk Factors Biology Disease Diagnosis Treatment Prevention & Control Resources for Health ...

  20. Enterobiasis (Pinworm Infection): Diagnosis

    MedlinePlus

    ... Contact CDC-INFO Pinworm Infection General Information Pinworm Infection FAQs Epidemiology & Risk Factors Biology Disease Diagnosis Treatment Prevention & Control Resources for Health Professionals Publications Information For: Travelers ...