Carrier Testing Research Articles

BasePhasing: a highly efficient approach for preimplantation genetic haplotyping in clinical application of balanced translocation carriers

BackgroundPreimplantation genetic testing (PGT) has already been applied in chromosomally balanced translocation carriers to improve the clinical outcome of assisted reproduction. However, traditional methods could not further distinguish embryos carrying a translocation from those with a normal karyotype prior to implantation.MethodsTo solve this problem, we developed a method named “Chromosomal Phasing on Base level” (BasePhasing), which based on Infinium Asian Screening Array-24 v1.0 (ASA) and a specially phasing pipeline. Firstly, by comparing the number of single nucleotide polymorphism (SNP) loci in different minor allele frequencies (MAFs) and in 2Mbp continuous windows of ASA chip and karyomap-12 chip, we verified whether ASA could be adopted for genome-wide haplotype linkage analysis. Besides, the whole gene amplification (WGA) of 3–10 cells of GM16457 cell line was used to verify whether ASA chip could be used for testing of WGA products. Finally, two balanced translocation families were utilized to carry out BasePhasing and to validate the feasibility of its clinical application.ResultsThe average number of SNP loci in each window of ASA (473.2) was twice of that of Karyomap-12 (201.2). The coincidence rate of SNP loci in genomic DNA and WGA products was about 97%. The 5.3Mbp deletion was detected positively in cell line GM16457 of both genomic DNA and WGA products, and haplotype linkage analysis was performed in genome wide successfully. In the two balanced translocation families, 18 blastocysts were analyzed, in which 8 were unbalanced and the other 10 were balanced or normal chromosomes. Two embryos were transferred back to the patients successfully, and prenatal cytogenetic analysis of amniotic fluid was performed in the second trimester. The results predicted by BasePhasing and prenatal diagnosis were totally consistent.ConclusionsInfinium ASA bead chip based BasePhasing pipeline shows good performance in balanced translocation carrier testing. With the characteristics of simple operation procedure and accurate results, we demonstrate that BasePhasing is one of the most suitable methods to distinguish between balanced and structurally normal chromosome embryos from translocation carriers in PGT at present.

Balancing uncertainty with patient autonomy in precision medicine.

By the nature of their unknown pathogenicity, variants of unknown significance (VUS) should not inform clinical decisions for genetic carrier testing; nevertheless, VUS are increasingly returned to patients. We argue that the benefits of returning VUS to patients are outweighed by the potential for individual and health-care system-level harm. Variants of unknown significance (VUS) are genetic variants whose association with disease risk is unknown. The authors posit that VUS should not inform clinical decision-making as the benefits of returning this genetic information to patients undergoing genetic testing are outweighed by the potential for harm.

Assessment of Sexual Reproductive Health Knowledge Amongst Patients with Cystic Fibrosis

This study is concerned with evaluating cystic fibrosis (CF) annual review practice. More precisely, we wanted to know if we are utilizing genetic counseling services and identifying poor knowledge of sexual reproductive health at annual review. We conducted short interviews with 21 CF patients at annual review regarding genetic counseling knowledge and perception. Patient responses were documented, analyzed and coded using a simple thematic analysis to precis the content. Immediately post-interview, patients were asked to complete a CF questionnaire comprised of nine questions, testing knowledge of the science of Mendelian genetics, contraceptive needs and fertility. Knowledge was then compared to responses documented at annual review. Emerging themes from interviews included: poor knowledge and a need for more information regarding what genetic counseling involves, a positive perception and experience of genetic counseling for those who had attended, and partner anxiety related to carrier testing. The percentage of patients who reported they were aware of the CF fertility and genetic issues was 95%, however, questionnaire scores ranged from 0 to 9/9 (mean 4.8 SD [2.2]). 57% of patients had received genetic counseling. These patients had a statistically significantly higher score 6.2 (1.5) versus those who had not 2.9 (1.3) p < 0.001. The All Wales Adult CF Centre annual review practice is insufficient to identify patients who may benefit from further education on reproductive health. Traditionally these domains have been granted less significance. However, as life expectancy, quality of life and reproductive assistive techniques improve, ensuring appropriate patient knowledge is of greater importance.

Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma.

Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first-degree relatives (and second-degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy-catecholamines and bi-annual rapid whole-body magnetic resonance imaging and clinical examination. Surveillance should start 5years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre-symptomatic genetic testing. The surveillance of children younger than 15years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow-up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.

Medical care for carriers of hemophilia —carrier testing, carrier check-up and perinatal management

Medical care for carriers of hemophilia —carrier testing, carrier check-up and perinatal management

Challenging the Current Recommendations for Carrier Testing in Children.

The authors of current professional guidelines generally do not support the return of information about genetic carrier status for infants and children because of a perceived lack of immediate benefit and an abundance of caution regarding potential harm and desire to protect the children's future autonomy. The advent of genomic sequencing, used either as a diagnostic or a screening tool, and the increasing use of this technology in childhood creates the potential for the identification of carrier status in the pediatric period. As part of the BabySeq Project, researchers are exploring the implications of genomic sequencing in both newborns who are healthy and newborns who are sick and developing policies and procedures for the return of carrier status information to the parents and physicians of newborns. In this commentary, we review the history of carrier testing in children and explore the potential benefits, risks, and challenges of returning such results both for the children, their parents, and potential future siblings.

Stein-Rule Estimation in Genetic Carrier Testing

In this paper, we apply the fully correlated random parameters logit (FCRPL) model to the genetic carrier testing data using shrinkage estimation. We show that shrinkage estimates with higher shrinkage constant improve the percentages of correct predicted choices by 2% and 10% respectively with Jewish and general population samples. The mean estimates of elasticity based on the shrinkage estimates are closer to those with the FCRPL model estimates and have smaller standard errors than the corresponding results based on the uncorrelated random parameters logit model estimates.

NEED OF GENETIC COUNSELING SERVICES AT DISTRICT D.I.KHAN

Genetic counseling is an advocating strategy based on family history and genetic testing results, in order to avoid inherited disorders and their transmission to next generation.1 For the first time Sarah Lawrence College at New York offered the first master’s level training course of genetic counseling in 1969. According to a recent estimate, seven thousand genetic counsellors in 28 different countries are offering their services in the field of medical genetics.4 Now-a-days, in the era of advance genomics, the genetic counseling services became more specialized as cancer genetics, cardiogenetics, neurogenetics, infertility genetics and other speciality areas. The clinical implementation of genetic counseling services in US, Canada, and European countries is well established. However, in Asia these only exist in India, Indonesia, Japan, Malaysia, Philippines, Singapore, South Korea, Taiwan and few Middle Eastern countries.4 As far as Pakistan is concerned, it is still in infancy in Pakistan, requiring great improvements to be done. Genetic counseling services are the dire need of those countries where consanguineous marriages are highly prevalent so as to reduce the burden of genetic disorders and improve the quality of life.2 Pakistan is one among those countries which has alarming rate of consanguineous marriages, especially first cousin unions.3 However, within Pakistan, Khyber-Pukhtunkhwa, including D.I.Khan division has comparatively high ratio of close familial marriages. Currently, D.I.Khan is inhabited by multi-ethnic population of local as well as those migrated from South Waziristan and other adjoining tribal areas. According to a non-documented evidence, it is observed that cancer, type-2 diabetes, thalassemia, cataract, and certain neurological disorders have high occurrence in these people. World Health Organization (WHO), in its report, has observed that genetic counseling services in developing countries are inadequate, and advised the governments to ensure, their availability as part of their healthcare systems.3,4 Keeping in view this scenario, D.I.Khan requires to establish a genetic counseling centre. It is proposed to set up genetic counseling centre with the mutual collaboration of Gomal University and Gomal Medical College, D.I.Khan that should advise the people regarding disease carrier testing, pharmacogenetics testing, pre-natal testing and pre-symptomatic testing. We also propose that each tertiary care hospital should engage a genetic counsellor to prevent the incidence of genetic disorders, select the best personalized medicine and pre-symptomatic management of disease.

A generic wake analysis tool and its application to the Japan Bulk Carrier test case

Economic pressures and regulatory obligations have brought about a great interest in improving ship propulsion efficiency. This has motivated and directed research to improve the hydrodynamic performance of a vessel thus seeking the development and generation of optimised designs. When analysing flow characteristics of a vessel, particular attention is given to analysing its wake field and stern flow characteristics. For the detailed analysis of the wake flow field, a Wake Analysis Tool (WAT) was developed within the programming environment of a commercial CAE tool. The WAT is based on a framework that enables easy interaction to an external CFD solver reading flow field properties from a generic csv file. The wake flow field is visualised and analysed in schematic form according to the standard and customized (i.e. the British Ship Research Association criteria) wake analyses. By coupling the CAE tool with a commercial flow solver, an example was given how to use the wake tool in a fully automated simulation process. Finally, the wake tool was used to analyse the nominal propeller wake flow of the Japan Bulk Carrier (JBC) thus showing how it can be efficiently applied to a set of numerical results.

User Acceptability of Whole Exome Reproductive Carrier Testing for Consanguineous Couples in Australia.

The study aimed to explore with consanguineous couples in Australia the acceptability and perceived utility of whole exome reproductive carrier screening for autosomal recessive and X-linked recessive conditions. Semi-structured interviews with 21 consanguineous couples were conducted prior to the offer of screening. Interviews were coded, and thematic analysis was informed by an inductive approach. Three major themes were identified: experiences and attitudes of Australian consanguineous couples, childhood genetic conditions and beliefs, and the perceived utility of genomic screening. All but one couple had previously sought genetic advice, and a large majority of couples were aware of childhood conditions within their family or community. Thirteen couples perceived consanguinity as increasing the risk of having affected children. Nine spoke of premarital screening programs routinely conducted in their countries of origin. All supported the concept and availability of genomic reproductive carrier screening. Hypothetically, if found to be carriers of a severe childhood disorder, 13 couples reported they would test a pregnancy, and 12 of whom would consider termination of pregnancy or pre-implantation genetic diagnosis. Four couples would not test a pregnancy and two were unsure. A majority of couples would communicate potential at-risk status to family members, although there were some caveats. Fourteen couples chose to have exome screening and reported that they would utilize the results with the goal of preventing childhood conditions. Of these couples, nine (64%) had an affected child but were aware that testing may reveal they were at risk for a child with a different condition and five (71%) without an affected child. While from diverse ethnic and backgrounds, all couples practiced a religion and all but one couple were recruited from the same clinical genetics unit, with a likely higher genetic literacy and bias towards accepting genetic testing. However, the choice made by all couples was reportedly made with consideration of their personal values, their current family situation, and exome testing issues, including fear of incidental findings and concerns about test reliability.

Hereditary Colorectal Cancer: Clinics, Diagnostics and Management

Hereditary Colorectal Cancer: Clinics, Diagnostics and Management Abstract. About five percent of all colorectal cancers are caused by highly penetrant, autosomal dominantly or recessively inherited tumour predispositions. Current molecular genetic diagnostics, making use of high-throughput sequencing technologies, allow a cost-efficient, prompt and comprehensive investigation. In contrast to sporadic colorectal cancer hereditary forms are often associated with an elevated lifetime risk for additional, extracolonic tumours which necessitate specific long-term interdisciplinary prevention measures and surveillance. Moreover, the genetic confirmation of an underlying cancer predisposition allows family members at risk, following genetic counselling, the possibility of predictive carrier testing. This article aims at providing a concise overview of clinics, diagnostics and management for some of the best researched colorectal cancer predispositions.

1226. Can Universal Decolonization Obviate the Need for Screening and Contact Precautions for Carriers of Methicillin-Resistant Staphylococcus aureus in a Medical Intensive Care Unit With MRSA Endemicity? An Interrupted Time Series Study

BackgroundUniversal decolonization of patients in intensive care units (ICUs) has been identified to be an effective infection control strategy of methicillin-resistant Staphylococcus aureus (MRSA). However, it remains uncertain whether universal decolonization can obviate the need for active surveillance testing (AST) and contact precautions (CPs) for MRSA carriers.MethodsWe conducted an interrupted time series study to evaluate whether universal decolonization (daily chlorhexidine bathing plus twice-daily intranasal mupirocin ointment for 5 days) without AST and CPs did affect the incidence of MRSA acquisition on clinical specimen and MRSA bacteremia (the first positive blood culture obtained more than 48 hours after ICU admission) in a medical ICU. There was a 12-month control period of universal decolonization combined with AST and CPs, followed by a 12-month intervention period of universal decolonization without AST and CPs for MRSA carriers. Changes in incidence density (new cases of MRSA acquisition on clinical specimen per 1,000 eligible patient-days) of MRSA were evaluated by segmented Poisson regression, and the cox proportional-hazards regression model was used to compare the differences in incidence of MRSA bacteremia between the two periods.ResultsThe median overall prevalence of MRSA did not differ between the two periods (25.3% vs. 23.4%, P = 0.55), and the segmented Poisson regression analysis revealed that there were no significant differences in both level and trend of MRSA prevalence (P = 0.43 and P = 0.27, respectively). The incidence density of MRSA acquisition on clinical specimen was lower during the intervention period (5.7 vs. 4.5, P = 0.039). However, both level and trend of MRSA incidence density did not differ significantly whether to perform active surveillance and contact precaution or not (P = 0.94 and P = 0.81, respectively). No patient developed MRSA bacteremia during the control period and there were only two patients of MRSA bacteremia during the intervention period, which showed no significant difference (Log rank test, P = 0.21).ConclusionUniversal decolonization without AST and CPs for MRSA carriers do not increase the incidence of MRSA acquisition on clinical specimen and ICU-attributable MRSA bacteremia in ICU with high prevalence rate of MRSA.Disclosures All authors: No reported disclosures.

First reported adult patient with TARP syndrome: A case report

TARP syndrome (talipes equinovarus, atrial septal defect, Robin sequence, and persistence of the left superior vena cava) is a rare X‐linked syndrome often resulting in pre‐ or post‐natal lethality in affected males. In 2010, RBM10 was identified as the disease‐causing gene, and we describe the first adult patient with TARP syndrome at age 28 years, hereby expanding the phenotypic spectrum. Our patient had Robin sequence, atrial septal defect, intellectual disability, scoliosis, and other findings previously associated with TARP syndrome. In addition, he had a prominent nose and nasal bridge, esotropia, displacement of lacrimal points in the cranial direction, small teeth, and chin dimple, which are the findings that have not previously been associated with TARP syndrome. Our patient was found to carry a hemizygous c.273_283delinsA RBM10 mutation in exon 4, an exon skipped in three of five protein‐coding transcripts, suggesting a possible explanation for our patient surviving to adulthood. Direct sequencing of maternal DNA indicated possible mosaicism, which was confirmed by massive parallel sequencing. One of two sisters were heterozygous for the mutation. Therefore, we recommend sisters of patients with TARP syndrome be carrier tested before family planning regardless of carrier testing results of the mother. Based on our patient and previously reported patients, we suggest TARP syndrome be considered as a possible diagnosis in males with severe or profound intellectual disability combined with septal heart defect, and Robin sequence, micrognathia, or cleft palate.

Effect of inbreeding on intellectual disability revisited by trio sequencing.

In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. Because of the high rate of parental consanguinity, which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in near- and middle-east countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but because of the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown. This prompted us to perform whole-exome sequencing in 100 sporadic ID patients from Iran and their healthy consanguineous parents. In 61 patients, we identified apparently causative changes in known ID genes. Of these, 44 were homozygous recessive and 17 dominant DNMs. Assuming that the DNM rate is stable, these results suggest that parental consanguinity raises the ID risk about 3.6-fold, and about 4.1 to 4.25-fold for children of first-cousin unions. These results do not rhyme with recent opinions that consanguinity-related health risks are generally small and have been "overstated" in the past.

Australians’ perspectives on support around use of personal genomic testing: Findings from the Genioz study

Personal genomic testing using direct-to-consumer and consumer-directed models, with or without involvement of healthcare providers, is increasing internationally, including in Australia. This study forms a sub-set of the Genioz study – Genomics: National Insights of Australians. We aimed to explore Australians’ experiences with these types of tests, especially online DNA tests, and their views regarding whom they would seek support from around understanding test results. The study used a mixed methods approach, employing an exploratory quantitative online survey and follow-up qualitative semi-structured interviews. Between May 2016 and May 2017, 2841 Australians responded to the survey. Interviews were conducted with 63 purposively sampled respondents, including 45 who had a genetic test and 18 who had not. Of 571 respondents who had any type of genetic test, 322 had a personal genomic test using criteria defined by the researchers. Testing for ancestry/genealogy was the most common, reported by 267 participants, reflecting the increased advertising of these tests in Australia. Some respondents described downloading their raw data for further interpretation through third party websites for genealogical as well as health related information. Carrier testing, testing for serious and preventable conditions and nutrition and/or wellness were the most common health related tests reported by respondents. Participants generally preferred to seek support from general practitioners (GPs), medical specialists with relevant expertise and independent genetics specialists, although another important preference for non-health information was online forums and networks. There was less preference for seeking support from employees associated with the testing companies. Generally, of those who had a health related PGT, the most common actions were seeking medical advice or doing nothing with the information, while more of those who had a personal genomic test for nutrition and/or wellness sought advice from complementary/alternative health practitioners (eg naturopaths) and integrative GPs, and 60% reported they had changed their diet. As awareness of personal genomic testing increases, publicly funded clinical genetics services may be less inclined to discuss results from personal genomic testing. Genetic counsellors could play an important role in providing this support, both pre-test and post-test, through opportunities for private practice but independent from testing companies.

College students’ knowledge about Sickle Cell Disease

ABSTRACTSickle Cell Disease (SCD) is a serious health problem affecting millions around the world. Key to prevention is knowledge about the disease and the reproductive implications. This study explored college students’ knowledge about SCD. Participants included 416 college students at a North Texas campus between October and December 2014. A cross-sectional survey design using an 18-question survey was used. Although most participants had heard of SCD, 21% had never heard of the disease. Furthermore, participants lacked knowledge regarding the differences between the disease and carrier status, prevalence, reproductive implications, prevention, and testing. Findings showed that couples had more knowledge about SCD compared to singles and there were no significant differences between those with children and those without indicating a need for education before they start dating. Most participants had not undergone SCD carrier screening and had no interest in screening. The Universal Prevention approach would be a suitable approach and should be utilized in improving knowledge about SCD.

Mutation analysis of Phenylalanine hydroxylase gene in Iranian patients with Phenylketonuria.

Background: Phenylketonuria as the most common genetic metabolic disorder is the result of disruption of the phenylalanine hydroxylase gene. This study was carried out to explore the phenylalanine hydroxylase gene mutation status of Iranian phenylketonuria patients. Methods: Blood samples were collected from 30 patients, and hot spot areas of the phenylalanine hydroxylase gene, including exons 6, 7, 8, 11, and 12 were studied through polymerase chain reaction and sequencing techniques. Results: Eight different mutations, including 5 missense mutations, 1 splice mutation, 1 nonsense mutation, and 1 Silent/Splice mutation were detected. These mutations were R243X, R261Q, R261X, P281L, R241C, V399V, E280K, and IVS11+1G>C. V399V and R241C were reported for the first time in Iranian population. Three polymorphisms including Q232Q, V245V and L385L and 3 novel intronic variants including IVS10-15A>C, IVS6+44T>G, and IVS6+36 T>G were also detected in this study. Conclusion: The results of this study prove the heterogeneous status of phenylalanine hydroxylase gene mutations in the Iranian population, which can be useful in carrier testing and genetic counseling.

DUCHENNE MUSCULAR DYSTROPHY - GENETICS: P.216Genetic carrier screening for Duchenne muscular dystrophy: the outcome of over forty years of genetic counselling on disease incidence in New South Wales Australia

Duchenne muscular dystrophy (DMD), an X-linked recessive genetic disorder results in progressive muscle weakness, causing significant morbidity and mortality. Its incidence is approximately 1 in 5000 live male births. DMD is caused by mutations in the dystrophin gene, maternally inherited in approximately two thirds of affected boys. Female relatives have carrier risk. Clinical genetics services offer carrier testing ('cascade screening') and genetic counselling for relatives of DMD patients, enabling identification of carrier status and provision of reproductive options. In selected countries, reduced disease incidence is observed, possibly due to genetic counselling, cascade testing and prenatal diagnosis. To estimate changes in DMD incidence in NSW over 40 years and determine whether cascade screening and genetic counselling has led to this change. A retrospective study of 'probands' (live male and prenatal genetically diagnosed DMD) cases born within NSW from 2002-2012 will be conducted. Female carriers/mosaic cases are excluded from analysis. A retrospective clinical review of confounding factors potentially associated with DMD diagnosis will also be conducted, using clinical data sourced from all the major NSW paediatric hospitals. Data will be collated with results from a previous study reporting DMD incidence over a 25-year period from 1975 to 2001 inclusive. The combined results of these studies will be presented in the final analysis. Birth rate statistics will be sourced from the Australian Bureau of Statistics. The denominator for incidence will be live male birth rates. Data analysis is pending. However, we hypothesize that DMD incidence in NSW has reduced over the last 40 years owing to improvements in the methodology of genetic screening. This study will demonstrate the impact of robust genetic screening and counselling services, thus serving as a model for other health care systems globally.

ACOG Technology Assessment in Obstetrics and Gynecology No. 14 Summary: Modern Genetics in Obstetrics and Gynecology.

Knowledge of human genetics has increased dramatically, and obstetrician-gynecologists and other health care providers are increasingly called on to incorporate genetics and genetic testing into medical practice. Advances in our understanding of the molecular basis of inherited disorders have led to the development of DNA-based tests that can be used for prenatal and postnatal diagnosis, carrier testing, and aneuploidy screening. These techniques have allowed for diagnosis of a wide variety of genetic diseases ranging from aneuploidies to single-gene disorders. Once a specific pathogenic variant in a gene has been identified, direct testing for that specific variant is possible; this is the most accurate molecular diagnostic method. Counseling patients about genetic testing and results can be challenging and obstetrician-gynecologists and women's health care providers are encouraged to make use of and refer to genetics professionals when necessary. The correct interpretation of molecular genetic diagnostic testing is highly dependent on an accurate clinical diagnosis, test sensitivity, ethnic variability in variants and disease prevalence, genetic heterogeneity, reduced penetrance, and phenotypical variability. As genetics becomes a more integral part of routine medical practice, it is essential that obstetrician-gynecologists and other health care providers be aware of advances in the understanding of genetic disease and the fundamental principles of genetic screening and molecular testing. This technology assessment has been revised to reflect advances in clinical genetics related to obstetrics and gynecology, including epigenetics, sequencing, and testing.

ACOG Technology Assessment in Obstetrics and Gynecology No. 14: Modern Genetics in Obstetrics and Gynecology.

Knowledge of human genetics has increased dramatically, and obstetrician-gynecologists and other health care providers are increasingly called on to incorporate genetics and genetic testing into medical practice. Advances in our understanding of the molecular basis of inherited disorders have led to the development of DNA-based tests that can be used for prenatal and postnatal diagnosis, carrier testing, and aneuploidy screening. These techniques have allowed for diagnosis of a wide variety of genetic diseases ranging from aneuploidies to single-gene disorders. Once a specific pathogenic variant in a gene has been identified, direct testing for that specific variant is possible; this is the most accurate molecular diagnostic method. Counseling patients about genetic testing and results can be challenging and obstetrician-gynecologists and women's health care providers are encouraged to make use of and refer to genetics professionals when necessary. The correct interpretation of molecular genetic diagnostic testing is highly dependent on an accurate clinical diagnosis, test sensitivity, ethnic variability in variants and disease prevalence, genetic heterogeneity, reduced penetrance, and phenotypical variability. As genetics becomes a more integral part of routine medical practice, it is essential that obstetrician-gynecologists and other health care providers be aware of advances in the understanding of genetic disease and the fundamental principles of genetic screening and molecular testing. This technology assessment has been revised to reflect advances in clinical genetics related to obstetrics and gynecology, including epigenetics, sequencing, and testing.