The ethics of preconception expanded carrier screening in patients seeking assisted reproduction.
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SUBMITTER: de Wert G
PROVIDER: S-EPMC7880037 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundExpanded carrier screening (ECS) has emerged as an effective approach to identify at-risk couples (ARCs)-before they initiate attempts at reproduction-who possess a high probability of having a child affected by severe recessive diseases. The objective of this study was to evaluate the clinical utility of ECS in Chinese patients seeking the help of assisted reproductive technology (ART).MethodsAn ECS test, which covers 201 genes implicated in 135 recessive (autosomal or X-linked) diseases, was routinely offered to all ART patients in a single genetics and in vitro fertilization clinic. Additional options for preimplantation or prenatal genetic diagnosis were discussed and offered to all ARCs. All ECS results were aggregated and the clinical decisions of the ARCs were surveyed.ResultsA total of 2,923 ART patients, representing 1,462 couples, were screened. Overall, 46.73% of the individuals were found to be the carriers for at least 1 of the 135 diseases. Of the tested couples, 2.26% (n = 33) were identified as ARCs. As of the completion of this study, 21 (63.6%) ARCs have decided to avert an affected pregnancy with the help of preimplantation genetic testing for monogenetic conditions. The cumulative carrier rate of the 187 autosomal recessive genes in the ECS panel for the 2,836 Han Chinese individuals without a family history was estimated to be 45.91%. The estimated at-risk couple rate indicates that the screening for only the top 31 genes with gene carrier rates >0.5% would identify more than 94% of the ARCs identified by screening all 187 genes.ConclusionOur study demonstrates that ESC yields a significant clinical value for ART patients in China. In addition, by estimating the yields of the ECS panel, we identify genes that are appropriate for screening the Han population.
| S-EPMC7507411 | biostudies-literature
Project description:Purpose: Expanded carrier screening (ECS) is an effective method to identify at-risk couples (ARCs) and avoid birth defects. This study aimed to reveal the carrier spectrum in the Chinese population and to delineate an expanded carrier gene panel suitable in China. Methods: Medical exome sequencing (MES), including 4,158 disease-causing genes, was offered to couples at two reproductive centers. It was initially used as a diagnostic yield for potential patients and then used for ECS. Clinical information and ECS results were retrospectively collected. Results: A total of 2,234 couples, representing 4,468 individuals, underwent MES. In total, 254 individuals showed genetic disease symptoms, and 56 of them were diagnosed with genetic diseases by MES. Overall, 94.5% of them were carriers of at least one disease-causing variant. The most prevalent genes were GJB2 for autosomal recessive disorders and G6PD for X-linked diseases. The ARC rate was 9.80%, and couples were inclined to undergo preimplantation genetic testing when diseases were classified as "profound" or "severe." Conclusion: This study provided insight to establish a suitable ECS gene panel for the Chinese population. Disease severity significantly influenced reproductive decision-making. The results highlighted the importance of conducting ECS for couples before undergoing assisted reproductive technology.
| S-EPMC9441495 | biostudies-literature
Project description:Preconception expanded carrier screening (ECS) aims to detect carrier couples of autosomal recessive (AR) disorders before pregnancy in order to increase reproductive autonomy of prospective parents. Genetic knowledge and knowledge gained from experience influence decision making on participation in genetic testing and understanding carrier test results. In this study we assessed whether parents and relatives of patients with the severe AR condition mucopolysaccharidosis type III (MPS III), who are expected to have genetic and experiential knowledge, have more positive attitudes toward ECS than the Dutch reference group. Parents of all MPS III patients known to the Dutch expert center were invited to participate and asked to invite first and second degree relatives. The online questionnaire started with an educational text, and assessed attitudes toward ECS, genetic knowledge and perceived MPS III severity. Results were compared with the Dutch population. Parents and relatives of MPS III patients (n = 159) scored higher on the genetic knowledge test and perceived MPS III as more severe compared with the general Dutch population (n = 781). Parents and relatives reported to be more likely to participate in ECS (84.3% and 62.5%, respectively) compared with the public (31%) (p < 0.001). Being a relative of a MPS III patient was the strongest variable in the regression analyses for intended ECS participation. Our results show that genetic knowledge influences ECS decision making. Therefore, appropriate information on ECS and genetic counseling is needed to enable prospective parents from the general population, including relatives of patients with severe hereditary disorders, to make informed decisions.
| S-EPMC7609293 | biostudies-literature
Project description:BackgroundExpanded carrier screening can provide risk information for numerous conditions. Understanding how individuals undergoing preconception expanded carrier screening value this information is important. The NextGen study evaluated the use of genome sequencing for expanded carrier screening and reporting secondary findings, and we measured participants' willingness to pay for this approach to understand how it is valued by women and couples planning a pregnancy.MethodsWe assessed 277 participants' willingness to pay for genome sequencing reporting carrier results for 728 gene/condition pairs and results for 121 secondary findings. We explored the association between attitudes and demographic factors and willingness to pay for expanded carrier screening using genome sequencing and conducted interviews with 58 of these participants to probe the reasoning behind their preferences.ResultsMost participants were willing to pay for expanded carrier screening using genome sequencing. Willingness to pay was associated with income level and religiosity, but not risk status for a condition in the carrier panel. Participants willing to pay nothing or a small amount cited issues around financial resources, whereas those willing to pay higher amounts were motivated by "peace of mind" from carrier results.ConclusionWomen and couples planning a pregnancy value genome sequencing. The potentially high out-of-pocket cost of this service could result in healthcare disparities, since maximum amounts that participants were willing to pay were higher than a typical copay and related to income.
| S-EPMC6051630 | biostudies-literature
Project description:Preconception expanded carrier screening (ECS) aims to identify couples with an increased risk of having a child with an autosomal recessive (AR) disorder before pregnancy, thereby enabling reproductive choices. Genetic knowledge and experiential knowledge both influence the uptake of ECS. As people in the general public often lack such knowledge, it is essential to provide appropriate and understandable information when offering ECS. This study investigated the effect of an educational video, compared to an educational text, on the knowledge and attitudes toward preconception ECS in the general population. Both the text and video consisted of a brief educational summary on AR inheritance and on the type of disorders included in ECS, with the progressive neurodegenerative condition mucopolysaccharidosis type III (MPS III) as an example. Participants in the reproductive age were invited in collaboration with a research agency. Respondents (N = 789) were offered an educational video prior to completing an online questionnaire that examined genetic knowledge, the perceived severity of MPS III, perceived risk, and attitudes toward ECS. Outcomes were compared to reference data collected previously in which respondents had been offered an educational text (N = 781). We first again studied the attitudes toward ECS in a smaller educational text group (N = 266) in order to assess whether attitudes had changed over time due to increased media coverage on ECS, which did not reveal any significant changes. Respondents who were offered the video had a better genetic knowledge, perceived MPS III as more severe, perceived their risks higher and were more likely to participate in ECS compared to those who were offered text. Online video may well be used as supportive tool to the genetic counseling process, creating more knowledge on ECS and severe genetic disorders included in preconception screening panels.
| S-EPMC8048558 | biostudies-literature
Project description:IntroductionPreconception carrier screening (PCS) identifies couples at risk of having children with recessive genetic conditions. New technologies have enabled affordable sequencing for multiple disorders simultaneously, including identifying carrier status for many recessive diseases. The aim of the study was to identify the most effective way of delivering PCS in Western Australia (WA) through the public health system.Methods and analysisThis is a multicentre cohort pilot study of 250 couples who have used PCS, conducted at three sites: (1) Genetic Services of Western Australia, (2) a private genetic counselling practice in Perth and (3) participating general practice group practices in the Busselton region of WA. The primary outcome of the pilot study was to evaluate the feasibility of implementing the comprehensive PCS programme in the WA healthcare system. Secondary outcome measures included evaluation of the psychosocial impact of couples, such as reproductive autonomy; identification of areas within the health system that had difficulties in implementing the programme and evaluation of tools developed during the study.Ethics and disseminationApproval was provided by the Women and Newborn Health Service Human Research Ethics Committee (HREC) at King Edward Memorial Hospital for Women (RGS0000000946) and the University of Western Australia (UWA) HREC (RA/4/20/4258). Participants may choose to withdraw at any time. Withdrawal will in no way affect participating couples' medical care. Study couples will be redirected to another participating health professional for consultation or counselling in the event of a health professional withdrawing. All evaluation data will be deidentified and stored in a password-protected database in UWA. In addition, all hard copy data collected will be kept in a locked cabinet within a secure building. All electronic data will be stored in a password-protected, backed-up location in the UWA Institutional Research Data Store. All evaluative results will be published as separate manuscripts, and selected results will be presented at conferences.
| S-EPMC6589024 | biostudies-literature
Project description:Advances in sequencing technologies permit the analysis of a larger selection of genes for preconception carrier screening. The study was designed as a sequential carrier screen using genome sequencing to analyze 728 gene-disorder pairs for carrier and medically actionable conditions in 131 women and their partners (n = 71) who were planning a pregnancy. We report here on the clinical laboratory results from this expanded carrier screening program. Variants were filtered and classified using the latest American College of Medical Genetics and Genomics (ACMG) guideline; only pathogenic and likely pathogenic variants were confirmed by orthologous methods before being reported. Novel missense variants were classified as variants of uncertain significance. We reported 304 variants in 202 participants. Twelve carrier couples (12/71 couples tested) were identified for common conditions; eight were carriers for hereditary hemochromatosis. Although both known and novel variants were reported, 48% of all reported variants were missense. For novel splice-site variants, RNA-splicing assays were performed to aid in classification. We reported ten copy-number variants and five variants in non-coding regions. One novel variant was reported in F8, associated with hemophilia A; prenatal testing showed that the male fetus harbored this variant and the neonate suffered a life-threatening hemorrhage which was anticipated and appropriately managed. Moreover, 3% of participants had variants that were medically actionable. Compared with targeted mutation screening, genome sequencing improves the sensitivity of detecting clinically significant variants. While certain novel variant interpretation remains challenging, the ACMG guidelines are useful to classify variants in a healthy population.
| S-EPMC5992121 | biostudies-literature
Project description:PurposeThe recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.MethodsGuided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered serious by a systematic classification scheme. We evaluated this method retrospectively using results from 474,644 de-identified carrier screens. We then constructed several idealized panels to highlight strengths and limitations of different ECS methodologies.ResultsBased on modeled fetal risks for "severe" and "profound" diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screen's sensitivity is greatly impacted by two factors: (i) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping) and (ii) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome).ConclusionThe described approaches enable principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.
| S-EPMC5763154 | biostudies-literature
Project description:Study questionWhat are the sperm and egg donor rejection rates after expanded carrier screening (ECS)?Summary answerUsing an ECS panel looking at 46/47 genes, 17.6% of donors were rejected.What is known alreadyThe use of ECS is becoming commonplace in assisted reproductive technology, including testing of egg and sperm donors. Most national guidelines recommend rejection of donors if they are carriers of a genetic disease. If the use of ECS increases, there will be a decline in the number of donors available.Study design, size, durationA review of the current preconception ECS panels available to donors was carried out through an online search. The genetic testing results of donors from Cryos International were analysed to determine how many were rejected on the basis of the ECS.Participants/materials, setting, methodsData on gamete donors and their carrier status was provided by Cryos International, who screen donors using their own bespoke ECS panel. The ECS panels identified through the review were compared to the Cryos International panel and data.Main results and the role of chanceA total of 16 companies and 42 associated ECS panels were reviewed. There were a total of 2673 unique disorders covered by the panels examined, with a mean of 329 disorders screened. None of these disorders were common to all panels. Cryos International screen 46 disorders in males and 47 in females. From 883 candidate donors, 17.6% (155/883) were rejected based on their ECS result. Carriers of alpha-thalassaemia represented the largest proportion of those rejected (19.4%, 30/155), then spinal muscular atrophy (15.5%, 24/155) and cystic fibrosis (14.8%, 23/155).Limitations, reasons for cautionPanel information was found on company websites and may not have been accurate.Wider implications of the findingsThis study highlights the need for consistent EU regulations and guidelines that allow genetic matching of gamete donors to their recipients, preventing the need to reject donors who are known carriers. A larger ECS panel would be most beneficial; however, this would not be viable without matching of donors and recipients.Study funding/competing interest(s)No specific funding was obtained. J.C.H. is the founder of Global Women Connected, a platform to discuss women's health issues and the Embryology and PGD Academy, who deliver education in clinical embryology. She has been paid to give a lecture by Cryos in 2019. A-B.S. is an employee of Cryos International.Trial registration numberN/A.
| S-EPMC8129592 | biostudies-literature
Project description:Technological developments have enabled carrier screening for multiple disorders. This study evaluated experiences with a preconception carrier screening offer for four recessive disorders in a Dutch founder population. Questionnaires were completed by 182 attendees pretesting and posttesting and by 137 non-attendees. Semistructured interviews were conducted with seven of the eight carrier couples. Attendees were mainly informed about the existence of screening by friends/colleagues (49%) and family members (44%). Familiarity with the genetic disorders was high. Knowledge after counseling increased (p < 0.001); however, still 9%, compared to 29% before counseling, wrongly mentioned an increased risk of having an affected child if both parents are carriers of different disorders. Most attendees (97%) recalled their test results correctly, but two couples reported being carrier of another disorder than reported. Overall, 63% felt worried while waiting for results but anxiety levels returned to normal afterwards. In all, 2/39 (5%) carriers felt less healthy. Screened individuals were very satisfied; they did not regret testing (97%) and would recommend testing to others (97%). The majority (94%) stated that couples should always have a pretest consultation, preferably by a genetic counselor rather than their general practitioner (83%). All carrier couples made reproductive decisions based on their results. Main reason for non-attendance was unawareness of the screening offer. With expanded carrier screening, adequately informing couples pretest and posttesting is of foremost importance. Close influencers (family/friends) can be used to raise awareness of a screening offer. Our findings provide lessons for the implementation of expanded carrier screening panels in other communities and other settings.
| S-EPMC5838981 | biostudies-literature