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In recent years, an increasing number of genes associated with male and female infertility have been identified. The genetics of infertility is no longer limited to the analysis of karyotypes or specific genes, and it is now possible to analyse several dozen infertility genes simultaneously. Here, we present the diagnostic activity over the past two years including 140 patients (63 women and 77 men). Targeted sequencing revealed causative variants in 17 patients, representing an overall diagnostic rate of 12.1%, with prevalence rates in females and males of 11% and 13%, respectively. The gene-disease relationship (GDR) was re-evaluated for genes due to the addition of new patients and/or variants in the actual study. Five genes changed categories: two female genes (MEIOB and TBPL2) moved from limited to moderate; two male genes (SOHLH1 and GALNTL5) moved from no evidence to strong and from limited to moderate; and SEPTIN12, which was unable to classify male infertility, was reclassified as limited. Many infertility genes have yet to be identified. With the increasing integration of genetics in reproductive medicine, the scope of intervention extends to include other family members, in addition to individual patients or couples. Genetic counselling consultations and appropriate staffing will need to be established in fertility centres. Trial registration number: Not applicable. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Can a genome-wide association study (GWAS) meta-analysis, including a large sample of young premenopausal women from a founder population from Northern Finland, identify novel genetic variants for circulating anti-Müllerian hormone (AMH) levels and provide insights into single-nucleotide polymorphism enrichment in different biological pathways and tissues involved in AMH regulation? SUMMARY ANSWER The meta-analysis identified a total of six loci associated with AMH levels at P  <   5 × 10−8, three of which were novel in or near CHEK2 , BMP4 , and EIF4EBP1 , as well as highlighted significant enrichment in renal system vasculature morphogenesis, and the pituitary gland as the top associated tissue in tissue enrichment analysis. WHAT IS KNOWN ALREADY AMH is expressed by preantral and small antral stage ovarian follicles in women, and variation in age-specific circulating AMH levels has been associated with several health conditions. However, the biological mechanisms underlying the association between health conditions and AMH levels are not yet fully understood. Previous GWAS have identified loci associated with AMH levels in pre-menopausal women, in or near MCM8 , AMH , TEX41 , and CDCA7. STUDY DESIGN, SIZE, DURATION We performed a GWAS meta-analysis for circulating AMH level measurements in 9668 pre-menopausal women. PARTICIPANTS/MATERIALS, SETTING, METHODS We performed a GWAS meta-analysis in which we combined 2619 AMH measurements (at age 31 years) from a prospective founder population cohort (Northern Finland Birth Cohort 1966, NFBC1966) with a previous GWAS meta-analysis that included 7049 pre-menopausal women (age range 15–48 years) (N = 9668). NFBC1966 AMH measurements were quantified using an automated assay. We annotated the genetic variants, combined different data layers to prioritize potential candidate genes, described significant pathways and tissues enriched by the GWAS signals, identified plausible regulatory roles using colocalization analysis, and leveraged publicly available summary statistics to assess genetic and phenotypic correlations with multiple traits. MAIN RESULTS AND THE ROLE OF CHANCE Three novel genome-wide significant loci were identified. One of these is in complete linkage disequilibrium with c.1100delC in CHEK2 , which is found to be 4-fold enriched in the Finnish population compared to other European populations. We propose a plausible regulatory effect of some of the GWAS variants linked to AMH, as they colocalize with GWAS signals associated with gene expression levels of BMP4 , TEX41 , and EIFBP41. Gene set analysis highlighted significant enrichment in renal system vasculature morphogenesis, and tissue enrichment analysis ranked the pituitary gland as the top association. LARGE SCALE DATA The GWAS meta-analysis summary statistics are available for download from the GWAS Catalogue with accession number GCST90428625. LIMITATIONS, REASONS FOR CAUTION This study only included women of European ancestry and the lack of sufficiently sized relevant tissue data in gene expression datasets hinders the assessment of potential regulatory effects in reproductive tissues. WIDER IMPLICATIONS OF THE FINDINGS Our results highlight the increased power of founder populations and larger sample sizes to boost the discovery of novel trait-associated variants underlying variation in AMH levels, which aided the characterization of GWAS signals enrichment in different biological pathways and plausible genetic regulatory effects linked with AMH level variation for the first time. STUDY FUNDING/COMPETING INTEREST(S) This work has received funding from the European Union's Horizon 2020 Research and Innovation Programme under the MATER Marie Sklodowska-Curie Grant Agreement No. 813707 and Oulu University Scholarship Foundation and Paulon Säätiö Foundation. (N.P.-G.), Academy of Finland, Sigrid Jusélius Foundation, Novo Nordisk, University of Oulu, Roche Diagnostics (T.T.P.). This work was supported by the Estonian Research Council Grant 1911 (R.M.). J.R. was supported by the European Union's Horizon 2020 Research and Innovation Program under Grant Agreements No. 874739 (LongITools), 824989 (EUCAN-Connect), 848158 (EarlyCause), and 733206 (LifeCycle). U.V. was supported by the Estonian Research Council grant PRG (PRG1291). The NFBC1966 received financial support from University of Oulu Grant No. 24000692, Oulu University Hospital Grant No. 24301140, and ERDF European Regional Development Fund Grant No. 539/2010 A31592. T.T.P. has received grants from Roche, Perkin Elmer, and honoraria for scientific presentations from Gedeon Richter, Exeltis, Astellas, Roche, Stragen, Astra Zeneca, Merck, MSD, Ferring, Duodecim, and Ajaton Terveys. For all other authors, there are no competing interests. [ABSTRACT FROM AUTHOR]

While unequally resourced partners from the so-called global South are often considered 'mere sample providers' in larger international genomics collaborations, in this paper, we show how they strategically work to mobilize their role in a global system of tissue exchange to deliver services for local communities. We unpack how a prenatal diagnostic service for thalassemia in Pakistan emerged out of the maneuvering efforts of internationally connected Pakistani researchers. By tracing the distributed capacities that emerged and circulated as they set about improving medical genetics in Pakistan, we outline some key conditions that led to the establishment of the service: first, the scale of unmet needs that geneticists faced when collecting data as part of their research that made medical genomics a relevant field; secondly, joint efforts between researchers and physicians that were engaged with the challenge of decreasing disease prevalence through diagnostics and abortion; and finally, the ways in which international research collaborations helped generate resources to improve medical genetics in Pakistan. To understand how genetic research and medicine is currently being developed in Pakistan, we need to ethnographically re-center our analyses in ways that allow us to identify the resourceful ways in which researchers maneuvre to secure locally relevant outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND As in other domains of medicine, high-throughput sequencing methods have led to the identification of an ever-increasing number of gene variants in the fields of both male and female infertility. The increasing number of recently identified genes allows an accurate diagnosis for previously idiopathic cases of female infertility and more appropriate patient care. However, robust evidence of the gene–disease relationships (GDR) allowing the proper translation to clinical application is still missing in many cases. OBJECTIVE AND RATIONALE An evidence-based curation of currently identified genes involved in female infertility and differences in sex development (DSD) would significantly improve both diagnostic performance and genetic research. We therefore performed a systematic review to summarize current knowledge and assess the available GDR. SEARCH METHODS PRISMA guidelines were applied to curate all available information from PubMed and Web of Science on genetics of human female infertility and DSD leading to infertility, from 1 January 1988 to 1 November 2021. The reviewed pathologies include non-syndromic as well as syndromic female infertility, and endocrine and reproductive system disorders. The evidence that an identified phenotype is caused by pathogenic variants in a specific gene was assessed according to a standardized scoring system. A final score (no evidence, limited, moderate, strong, or definitive) was assigned to every GDR. OUTCOMES A total of 45 271 publications were identified and screened for inclusion of which 1078 were selected for gene and variant extraction. We have identified 395 genes and validated 466 GDRs covering all reported monogenic causes of female infertility and DSD. Furthermore, we present a genetic diagnostic flowchart including 105 genes with at least moderate evidence for female infertility and suggest recommendations for future research. The study did not take into account associated genetic risk factor(s) or oligogenic/polygenic causes of female infertility. WIDER IMPLICATIONS We have comprehensively reviewed the existing research on the genetics of female infertility and DSD, which will enable the development of diagnostic panels using validated genes. Whole genome analysis is shifting from predominantly research to clinical application, increasing its diagnostic potential. These new diagnostic possibilities will not only decrease the number of idiopathic cases but will also render genetic counselling more effective for infertile patients and their families. [ABSTRACT FROM AUTHOR]

Couples at risk of transmitting a genetic disease to their offspring may experience doubts about their reproductive options. This study examines the effects of an online decision aid (DA) on the (joint) reproductive decision‐making process of couples (not pregnant at time of inclusion) at risk of transmitting a genetic disease to their offspring. The primary outcome is decisional conflict, and secondary outcomes are knowledge, realistic expectations, deliberation, joint informed decision‐making, and decisional self‐efficacy. These outcomes were measured with a pretest–posttest design: before use (T0), after use (T1), and 2 weeks after use (T2) of the decision aid (DA). Usability of the DA was assessed at T1. Paired sample t‐tests were used to compute differences between baseline and subsequent measurements. The comparisons of T0‐T1 and T0‐T2 indicate a significant reduction in mean decisional conflict scores with stronger effects for participants with high baseline decisional conflict scores. Furthermore, use of the DA led to increased knowledge, improved realistic expectations, and increased levels of deliberation, with higher increase in participants with low baseline scores. Decision self‐efficacy only improved for participants with lower baseline scores. Participants indicated that the information in the DA was comprehensible and clearly organized. These first results indicate that this online DA is an appropriate tool to support couples at risk of transmitting a genetic disease and a desire to have (a) child(ren) in their reproductive decision‐making process. [ABSTRACT FROM AUTHOR]

Purpose: To describe the association between geographic location of residence and use of aneuploidy screening or prenatal genetic counseling and how it is modified by maternal race and ethnicity., Methods: Retrospective cohort of individuals at a tertiary care center between 2017-2019. County of residence was classified as rural or metropolitan based in US Office of Management and Budget 2019 definitions. Maternal race and ethnicity were self-identified. Our composite outcome was defined as use of aneuploidy screening or genetic counseling visit. The composite outcome was compared by geographic location and ethnicity. Logistic regression was used to model the relationship between geographic location and the composite outcome., Results: A total of 8774 pregnancies were included. Of these, 4770 (54%) had genetic screening, and 3781 (43%) had at least 1 genetic counseling visit. Rural patients were significantly less likely to have the composite outcome compared with metropolitan peers (37.1% vs 47.2%, P < .001). In addition, we identified differences in the composite outcome between White rural patients and LatinX rural patients (37.7% vs 35.6%, P < .001) and between Asian rural patients and LatinX and Black rural patients (41.0% vs 35.6%, P < .001; 41.0% vs 36.8%, P < .001). Logistic regression demonstrated that rural patients were significantly less likely to have the composite outcome compared with metropolitan peers, after adjusting for LatinX ethnicity and gestational age at first prenatal visit (OR 0.72, [0.55, 0.95], P = .002)., Conclusion: Rural, minority patients were significantly less likely to receive reproductive genetic services compared with metropolitan peers extending our knowledge of disparities in maternity care., Competing Interests: Conflict of Interest Asha N. Talati receives research support from the National Institutes of Health, Billion to One, and The Greenwall Foundation. Divya P. Mallampati receives salary support from the Department of Health and Human Services. Neeta L. Vora receives research support from National Institutes of Health and received supplies in kind from Illumina unrelated to this research., (Copyright © 2024. Published by Elsevier Inc.)

Thanks to advances in technology, genetic testing is now available to explore the causes of infertility and to assess the risk of a given couple passing on a genetic disorder to their offspring. This allows at-risk couples to make an informed decision when opting for assisted reproduction and allows professionals to offer pre-implantation diagnosis when appropriate. Genetic screening of an infertile couple has thus become standard practice for an appropriate diagnosis, treatment, and prognostic assessment. This review aims to highlight the conditions under which genetic screening plays a role in improving reproductive outcomes for infertile couples., Competing Interests: Conflict of Interest The authors declare no competing interests., (Copyright © 2024 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved.)

Background: Due to the highly variable clinical phenotype, Klinefelter Syndrome is underdiagnosed. Objective: Assessment of supervised machine learning based prediction models for identification of Klinefelter Syndrome among azoospermic patients, and comparison to expert clinical evaluation. Materials and methods: Retrospective patient data (karyotype, age, height, weight, testis volume, follicle‐stimulating hormone, luteinizing hormone, testosterone, estradiol, prolactin, semen pH and semen volume) collected between January 2005 and June 2019 were retrieved from a patient data bank of a University Centre. Models were trained, validated and benchmarked based on different supervised machine learning algorithms. Models were then tested on an independent, prospectively acquired set of patient data (between July 2019 and July 2020). Benchmarking against physicians was performed in addition. Results: Based on average performance, support vector machines and CatBoost were particularly well‐suited models, with 100% sensitivity and >93% specificity on the test dataset. Compared to a group of 18 expert clinicians, the machine learning models had significantly better median sensitivity (100% vs. 87.5%, p = 0.0455) and fared comparably with regards to specificity (90% vs. 89.9%, p = 0.4795), thereby possibly improving diagnosis rate. A Klinefelter Syndrome Score Calculator based on the prediction models is available on http://klinefelter‐score‐calculator.uni‐muenster.de. Discussion: Differentiating Klinefelter Syndrome patients from azoospermic patients with normal karyotype (46,XY) is a problem that can be solved with supervised machine learning techniques, improving patient care. Conclusions: Machine learning could improve the diagnostic rate of Klinefelter Syndrome among azoospermic patients, even more for less‐experienced physicians. [ABSTRACT FROM AUTHOR]

Increased demand for in vitro fertilization (IVF) due to socio-demographic trends, and supply facilitated by new technologies, converged to transform the way a substantial proportion of humans reproduce. The purpose of this article is to describe the societal and demographic trends driving increased worldwide demand for IVF, as well as to provide an overview of emerging technologies that promise to greatly expand IVF utilization and lower its cost. [ABSTRACT FROM AUTHOR]

Copyright of Ethik in der Medizin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: To better understand the needs and experiences of the X-linked carrier community to improve future recognition, diagnosis, and treatment by bringing X-linked carrier voices together. Methods: An anonymous survey link was distributed to members of Remember the Girls, a non-profit organization for female (XX) carriers of X-linked conditions, through its website, Facebook group, Instagram, and Twitter. The survey was developed to gather data on XX carriers of numerous X-linked conditions. Results: One hundred and fifty individuals participated in the study. The majority (81/150) of individuals learned about their carrier status by giving birth to a son diagnosed with an X-linked condition. However, over 80% (120/145) believed that they should learn this information before the age of 18. Over 80% of participants (124/148) felt that they either have or may have symptoms attributable to their X-linked condition. Yet, only 10.1% (15/148) felt that they had sufficient access to knowledgeable healthcare providers and/or medical information. Additionally, 46.7% (70/150) of participants reported that healthcare providers did not discuss reproductive options with them. Improving carrier access to medical information, research studies, new treatments, and reproductive methods was found to be the top priority. Conclusion: Limited information exists on X-linked carriers' risk for symptoms and there is a lack of available treatments. This study demonstrates the need for more knowledgeable healthcare providers and medical information within the X-linked carrier community. [ABSTRACT FROM AUTHOR]

Aim: Despite a considerable interest in expanded carrier screening (ECS) in the general population, actual uptake of ECS remains low. More insights are needed to better understand the perspectives of reproductive-aged individuals. Materials & methods: Nonpregnant women of reproductive age recruited through public pharmacies throughout Flanders (Belgium) were invited to participate in an online survey. Results: Most participants (63.6%) indicated they would consider ECS for themselves in the future. About one in two participants showed a positive attitude toward ECS. Conclusion: This study reports valuable insights in the perspectives of nonpregnant reproductive-aged women in Flanders (Belgium) regarding ECS that can be used in the ongoing debate on the responsible implementation of ECS. Previous studies have reported a considerable interest in carrier screening for hereditary conditions among individuals in the general population, but actual uptake remains low. This study examines the perspectives of nonpregnant reproductive-aged women in Flanders (Belgium) regarding expanded carrier screening (ECS) for hereditary conditions to gain more insights in factors that possibly influence the opinions of reproductive-aged women. These insights are crucial to ensure a responsible implementation of ECS within healthcare services and to make sure that future parents are making informed choices when they are presented with the choice to accept or decline ECS. The results of this study can be used by healthcare providers interacting with couples planning a pregnancy to improve pre-/post-test counseling services. Which in turn can help to manage expectations and reduce misconceptions among potential users of ECS. [ABSTRACT FROM AUTHOR]

Purpose: When undergoing expanded carrier screening (ECS), couples are often screened sequentially to reduce need for a second individual's test. It is unknown how often partners of individuals found to be carriers complete the recommended testing with a sequential approach and what factors contribute to decision-making regarding partner testing. Additionally, the economic burden placed on individuals by ECS testing and its effect on partner testing has not been evaluated. Methods: In part 1, all individuals at a university-affiliated reproductive endocrinology and infertility practice identified to be carriers of a recessively inherited mutation using the Counsyl/Foresight ECS were included. Conditions were categorized by severity according to a previously described classification system. In part 2, all individuals who underwent ECS with a single test provider between September 1, 2013 and February 1, 2020 were contacted via email to complete a confidential and anonymized online survey. Results: In part 1, a total of 2061 patients were screened. 36.9% were carriers of one or more recessively inherited disorders. Twenty-seven percent of positively screened individuals did not have their partner screened. Carriers of a moderate condition had a trend towards a reduced odds for having their partner screened compared to a profound condition (OR 0.36, 95% CI 0.12–1.05, p = 0.06). Number of conditions was not predictive of subsequent partner screening (OR 0.95, 95% CI 0.72–1.25, p = 0.72). In part 2, the cost of ECS was not covered by insurance for 54.5% (103/189) and most paid over $300 out-of-pocket for testing (47.6%). The most common reason for not completing partner testing was that the results would not alter their course when seeking conception (33.3%). 73.5% of patients knew that the largest benefit of ECS comes from knowing a partner's results as well as their own. Conclusions: Not all carriers of recessively inherited disorders choose to undergo partner screening. Patients found to be carrier of more debilitating genetic disorders may be more likely to screen their reproductive partners. For many, ECS testing is not covered by insurance, and this test may impose a significant economic burden. For some patients, the results of ECS would not change what they would do when seeking conception. Providers should evaluate whether a patient's ECS result would change their treatment course prior to testing. [ABSTRACT FROM AUTHOR]

Background: Our genetic code is now readable, writable and hackable. The recent escalation of genome-wide sequencing (GS) applications in population diagnostics will not only enable the assessment of risks of transmitting well-defined monogenic disorders at preconceptional stages (i.e. carrier screening), but also facilitate identification of multifactorial genetic predispositions to sub-lethal pathologies, including those affecting reproductive fitness. Through GS, the acquisition and curation of reproductive-related findings will warrant the expansion of genetic assessment to new areas of genomic prediction of reproductive phenotypes, pharmacogenomics and molecular embryology, further boosting our knowledge and therapeutic tools for treating infertility and improving women's health.Objective and Rationale: In this article, we review current knowledge and potential development of preconception genome analysis aimed at detecting reproductive and individual health risks (recessive genetic disease and medically actionable secondary findings) as well as anticipating specific reproductive outcomes, particularly in the context of IVF. The extension of reproductive genetic risk assessment to the general population and IVF couples will lead to the identification of couples who carry recessive mutations, as well as sub-lethal conditions prior to conception. This approach will provide increased reproductive autonomy to couples, particularly in those cases where preimplantation genetic testing is an available option to avoid the transmission of undesirable conditions. In addition, GS on prospective infertility patients will enable genome-wide association studies specific for infertility phenotypes such as predisposition to premature ovarian failure, increased risk of aneuploidies, complete oocyte immaturity or blastocyst development failure, thus empowering the development of true reproductive precision medicine.Search Methods: Searches of the literature on PubMed Central included combinations of the following MeSH terms: human, genetics, genomics, variants, male, female, fertility, next generation sequencing, genome exome sequencing, expanded carrier screening, secondary findings, pharmacogenomics, controlled ovarian stimulation, preconception, genetics, genome-wide association studies, GWAS.Outcomes: Through PubMed Central queries, we identified a total of 1409 articles. The full list of articles was assessed for date of publication, limiting the search to studies published within the last 15 years (2004 onwards due to escalating research output of next-generation sequencing studies from that date). The remaining articles' titles were assessed for pertinence to the topic, leaving a total of 644 articles. The use of preconception GS has the potential to identify inheritable genetic conditions concealed in the genome of around 4% of couples looking to conceive. Genomic information during reproductive age will also be useful to anticipate late-onset medically actionable conditions with strong genetic background in around 2-4% of all individuals. Genetic variants correlated with differential response to pharmaceutical treatment in IVF, and clear genotype-phenotype associations are found for aberrant sperm types, oocyte maturation, fertilization or pre- and post-implantation embryonic development. All currently known capabilities of GS at the preconception stage are reviewed along with persisting and forthcoming barriers for the implementation of precise reproductive medicine.Wider Implications: The expansion of sequencing analysis to additional monogenic and polygenic traits may enable the development of cost-effective preconception tests capable of identifying underlying genetic causes of infertility, which have been defined as 'unexplained' until now, thus leading to the development of a true personalized genomic medicine framework in reproductive health. [ABSTRACT FROM AUTHOR]

Purpose: To explore facilitators and barriers for male partner follow through carrier screening (CS) after their female partners were identified as carriers, from both male and female perspectives. Methods: Participants were either females identified as a carrier through CS (512 participants) or males who had CS (125 participants). Participants were recruited via e-mails with survey links. The survey explored factors surrounding decisions to pursue CS or not. Results: Males who attended the females' CS appointment were more likely to have CS (OR: 2.07). More male partners of females identified as carriers of severe or profound conditions pursued CS (82.0%) than male partners of females who were carriers for moderate conditions (50.0%). Logistic factors were more impactful for males who pursued CS. Females whose male partners did not test endorsed personal belief factors as most impactful, reporting the perceived low risk (75.0%) and his low concern for the specific condition (65.5%) were the top reasons their partners did not test. Conclusion: Many factors impact how male partners appraise reproductive risk from CS and make decisions regarding their own screening. Advising that male partners attend CS appointments may increase the likelihood of follow through CS. Thorough and repeated risk counseling is indicated. [ABSTRACT FROM AUTHOR]

Recent advancements in reproductive genetics have resulted in the availability of an extraordinary amount of new and detailed information for patients and providers. Whereas this information can inform many who are facing difficult clinical decisions, it can also introduce complex and uncertain choices. Expanded carrier screening and preimplantation genetic diagnosis for aneuploidy are important examples of new genetic techniques that are now widely used in reproductive medicine. This paper will explore these techniques through a medical-legal prism to better understand the opportunities and obligations incumbent on both patients and providers in this new age of genetic diagnosis. [ABSTRACT FROM AUTHOR]

The Assisted Reproductive Technologies ("ART") have resulted in over eight million births to date, heralding remarkable advances in reproductive medicine with a transformational impact on both medicine and law. The effects have been acutely felt on the modern family, as well as on a myriad of areas of legal practice—including Family Law, Estate Planning, Contract, Health, Constitutional, Criminal, Discrimination, Tort Law and, for international arrangements, Immigration and Citizenship laws. This article examines the historical context, present impact, and future trends of ART and the Law. Its purpose is to help better understand these unique developments in order to help law and policy makers harness and craft the policies and frameworks that will be needed to monitor, shape and guide these remarkable possibilities for participants, professionals, law and society. Practitioner's Key Points: Medical Advances in ART have transformed parentage laws.Third‐party ART introduces unique legal issues and challenges for estate planners and family lawyers.Cryopreserved IVF embryos can trigger Tort, Contract, Family Law, Negligence and Professional Liability Litigation.Dramatic changes in current trends in gamete donation and surrogacy have direct implications for lawyers representing intended parents and ART professionals. [ABSTRACT FROM AUTHOR]

Capitalizing on breakthroughs in reproductive genetics, the utilization of in vitro embryo culture and stem cell technologies heralds a transformative era in addressing global challenges posed by rare genetic diseases. These cutting-edge practices illuminate the intricacies of early human development, elucidate the mechanisms behind rare diseases, and guide the development of potential therapies. Balancing this remarkable innovation with necessary ethical considerations, these technologies have the potential to revolutionize the trajectory of rare genetic disorders, transforming the landscape of diagnosis, treatment, and genetic counseling while offering renewed hope for affected individuals and families worldwide., Competing Interests: This work was supported by four projects of the National Natural Science Foundation of China (grant no. 82374243 to L Wang, grant no. 82304906 to LL Li, grant no. 82060881 to TW Zhang, grant no. 82260950 to YY Zhou).The authors have no conflicts of interest to disclose., (2024, International Research and Cooperation Association for Bio & Socio - Sciences Advancement.)

Keywords: reproductive genetics; aneuploidy screening; expanded carrier screening; chromosomal microarray analysis; whole-exome sequencing; balanced chromosomal abnormalities; early pregnancy loss; preimplantation genetic testing EN reproductive genetics aneuploidy screening expanded carrier screening chromosomal microarray analysis whole-exome sequencing balanced chromosomal abnormalities early pregnancy loss preimplantation genetic testing 1 3 3 12/22/21 20211217 NES 211217 There has been a geometric explosion in genetic capabilities such that currently a wide variety of prenatal screening and diagnostic testing for fetal chromosomal abnormalities are available. Chromosomal microarray analysis, reproductive genetics, aneuploidy screening, expanded carrier screening, whole-exome sequencing, balanced chromosomal abnormalities, early pregnancy loss, preimplantation genetic testing Next-generation sequencing (NGS) allows identification of sequence variants across many genes and hence screening for multiple genetic conditions at the same time. [Extracted from the article]

Oocyte maturation defect is a challenging situation in the management of infertility, the etiology may be related to endocrine causes, protocols used in ovarian stimulation, oocyte intrinsic defects or procedures in embryology laboratory. We report three Mexican females in treatment for primary infertility with non-mature oocytes after ovary stimulation and oocyte capture in whom a genetic diagnosis of TUBB8-oocyte maturation defect was revealed by exome sequencing. Two couples achieved pregnancies though oocyte donation after establishing the genetic etiology. Our results expand the role of TUBB8-disorders in patients of non-Asian ethnicity. Oocyte maturation defects of monogenic origin are a growing group of disorders that endocrinologists and reproductive medicine specialists should be aware in order to provide referral to genetics for establish a correct and opportune diagnosis. [ABSTRACT FROM AUTHOR]

Background: Through carrier screening, prospective parents can acquire information about whether they have an increased risk of conceiving a child affected with an autosomal recessive or X-linked condition. Within the last decade, advances in genomic technologies have facilitated a shift from condition-directed carrier screening to expanded carrier screening (ECS). Following the introduction of ECS, several studies have been performed to gauge the interest in this new technology among individuals and couples in the general population.Objective and Rationale: The aim of this systematic review was to synthesize evidence from empirical studies that assess the interest in ECS among individuals and couples in the general population. As the availability and accessibility of ECS grow, more couples who are a priori not at risk based on their personal or family history will be presented with the choice to accept or decline such an offer. Their attitudes and beliefs, as well as the perceived usefulness of this screening modality, will likely determine whether ECS is to become a widespread reproductive genetic test.Search Methods: Four databases (Pubmed, Web of Science, CINAHL, Cochrane Library) were systematically searched to identify English language studies performed between January 2009 and January 2019 using the following search terms: carrier screening, carrier testing, attitudes, intention, interest, views, opinions, perspectives and uptake. Studies were eligible for inclusion if they reported on intentions to undergo a (hypothetical) ECS test, uptake of an actual ECS offer or both. Two researchers performed a multistep selection process independently for validation purposes.Outcomes: Twelve empirical studies performed between 2015 and 2019 were included for analysis. The studies originated from the USA (n = 6), the Netherlands (n = 3), Belgium (n = 1), Sweden (n = 1) and Australia (n = 1). The sample size of the studies varied from 80 to 1669. In the included studies, 32%-76% of respondents were interested in a (hypothetical) ECS test, while uptake rates for actual ECS offers ranged from 8% to 50%. The highest overall uptake was observed when ECS was offered to pregnant women (50%). By contrast, studies focusing on the preconception population reported lower overall uptake rates (8-34%) with the exception of one study where women were counseled preconception in preparation for IVF (68.7%).Wider Implications: Our findings suggest that there may be discrepancies between prospective parents' reported intentions to undergo ECS and their actual uptake, particularly during the preconception period. As ECS is a new and relatively unknown test for most future parents, the awareness and comprehension within the general population could be rather limited. Adequate pre- and post-test counseling services should be made available to couples offered ECS to ensure informed reproductive decision-making, together with guidelines for primary health care professionals. Due to restricted nature of the samples and methods of the underlying primary studies, some of the reported results might not be transferable to a broader population. More research is needed to see if the observed trends also apply to a broader and more diverse population. [ABSTRACT FROM AUTHOR]

Study Question: Has the number of preimplantation genetic testing (PGT) cycles in the UK and USA changed between 2014 and 2016?Summary Answer: From 2014 to 2016, the number of PGT cycles in the UK has remained the same at just under 2% but in the USA has increased from 13% to 27%.What Is Known Already: PGT was introduced as a treatment option for couples at risk of transmitting a known genetic or chromosomal abnormality to their child. This technology has also been applied as an embryo selection tool in the hope of increasing live birth rates per transfer. ART cycles are monitored in the UK by the Human Fertilisation and Embryology Authority (HFEA) and in the USA by the Society for Assisted Reproductive Technology (SART). Globally, data are monitored via the ESHRE PGT Consortium.Study Design, Size, Duration: This cross-sectional study used the HFEA and SART databases to analyse PGT cycle data and make comparisons with IVF data to examine the success of and changes in patient treatment pathways. Both data sets were analysed from 2014 to 2016. The UK data included 3385 PGT cycles and the USA data included 94 935 PGT cycles.Participants/materials, Setting, Methods: Following an extensive review of both databases, filters were applied to analyse the data. An assessment of limitations of each database was also undertaken, taking into account data collection by the ESHRE PGT Consortium. In the UK and USA, the publicly available information from these datasets cannot be separated into different indications.Main Results and the Role Of Chance: The proportion of PGT cycles as a total of ART procedures has remained the same in the UK but increased annually in the USA from 13% to 27%. Between 2014 and 2016 inclusive, 3385 PGT cycles have been performed in the UK, resulting in 1074 PGT babies being born. In the USA 94 935 PGT cycles have been performed, resulting in 26 822 babies being born. This gave a success rate per egg collection for PGT of 32% for the UK and 28% for the USA. Analysis of the data by maternal age shows very different patient populations between the UK and USA. These differences may be related to the way PGT is funded in the UK and USA and the lack of HFEA support for PGT for aneuploidy.Limitations, Reasons For Caution: Data reported by the HFEA and SART have different limitations. As undertaken by the ESHRE PGT Consortium, both data sets should separate PGT data by indication. Although the HFEA collects data from all IVF clinics in the UK, SART data only represent 83% of clinics in the USA.Wider Implications Of the Findings: Worldwide, a consistent reporting scheme is required in which success rates can convey the effectiveness of PGT approaches for all indications.Study Funding/competing Interest(s): No specific funding was obtained and there are no competing interests to declare that are directly related to this project. Joyce Harper is the director of the Embryology and PGD Academy, which offers education in these fields. [ABSTRACT FROM AUTHOR]

Unexplained infertility affects 2%–3% of reproductive-aged couples. One approach to identifying genes involved in infertility is to study subjects with this clinical phenotype and a de novo balanced chromosomal aberration (BCA). While BCAs may reduce fertility by production of unbalanced gametes, a chromosomal rearrangement may also disrupt or dysregulate genes important in fertility. One such subject, DGAP230, has severe oligozoospermia and 46,XY,t(20;22)(q13.3;q11.2). We identified exclusive overexpression of SYCP2 from the der(20) allele that is hypothesized to result from enhancer adoption. Modeling the dysregulation in budding yeast resulted in disrupted structural integrity of the synaptonemal complex, a common cause of defective spermatogenesis in mammals. Exome sequencing of infertile males revealed three heterozygous SYCP2 frameshift variants in additional subjects with cryptozoospermia and azoospermia. In sum, this investigation illustrates the power of precision cytogenetics for annotation of the infertile genome, suggests that these mechanisms should be considered as an alternative etiology to that of segregation of unbalanced gametes in infertile men harboring a BCA, and provides evidence of SYCP2- mediated male infertility in humans. [ABSTRACT FROM AUTHOR]

The recent introduction of polygenic risk scores within preimplantation genetic testing (PGT-P) has been met with many concerns. To get more insights into the perspectives of relevant stakeholders on the socio-ethical aspects of PGT-P, an interview study with 31 healthcare professionals involved in reproductive medicine and genetics in Europe and North-America was performed. Healthcare professionals in our study were concerned that PGT-P was going too far in terms of selection, with regards to both medical conditions and non-medical traits. Healthcare professionals were worried about the ethical 'slippery slope' of PGT-P, the increasing medicalization of reproductive health, the commercial context of PGT-P, and potential stigmatization and discrimination. There were also concerns that the availability and the 'technological imperative' of PGT-P could lead to pressure and a sense of responsibility for parents to use PGT-P. Additionally, it could cause new anxieties about the child's health before the child has even been born. Since PGT-P provides polygenic risk scores before birth, the autonomy of the child has to be considered. These socio-ethical concerns heighten existing debates regarding reproductive genetic technologies and show that the specifics of PGT-P make this screening option especially ethically controversial. • Introduction of polygenic risk scores in preimplantation genetic testing. • Healthcare professionals concerned about socio-ethical implications. • Associated with 'slippery slope', going too far, discrimination and stigmatization. • Increased sense of medicalization and commercialization of reproduction and health. • Worries about effects on prospective parents and on the future child's autonomy. [ABSTRACT FROM AUTHOR]

Purpose: Expanded genetic carrier screening (ECS) is an important part of gynecological practice and preconception planning. We evaluated the awareness and attitudes among women regarding ECS and factors that may influence decision-making in a family planning context. Methods: A 32-question survey in an academic university practice was given to 521 women who were either currently pregnant (n = 108), undergoing gynecologic care who were considering future fertility (n = 308), and considering or receiving fertility treatment (n = 105). Data are reported descriptively. Results: Forty-seven percent (n = 246) of patients were aware of ECS. Though most reported feeling positive or neutral towards ECS, 51% (n = 263) reported no desire for testing. Fifty-eight percent (n = 303) felt it beneficial to know their carrier status, and 55% (n = 257) said it was their responsibility to undergo testing. Those considering future fertility were found to have a more positive attitude towards ECS (51.4%) than those considering or receiving fertility treatment (34%). For positive carriers of a genetic disorder, 228 (49%) of patients would proceed with having their partner screened, 58 (13%) would undergo prenatal screening only and 12 (2.6%) would continue with vitro fertilization (IVF). Related to cost for ECS, 53.5% (n = 191) would be willing to pay at least $50–100 for testing, while 29% (n = 146) would not pay anything out of pocket. Conclusions: Despite patients' beliefs that it would be beneficial and their responsibility to undergo carrier status testing, the majority reported no desire for ECS and many were unwilling to pay out of pocket. Further education is necessary to reconcile the gap between technology and patient decision-making. [ABSTRACT FROM AUTHOR]

Currently, we are witnessing revolutionary advances in the analytical power of genetic tools. An enormous quantity of data can now be obtained from samples; however, the translation of genetic findings to the general status of individuals, or their offspring, should be done with caution. This is especially relevant in the reproductive context, where the concepts of "transmission" and "inheritability" of a trait are crucial. Against this background, we offer new insight based on a systemic view of genetic constitution in the compartmentalized organism, that is, the human body. This model considers the coexistence of "different" genomes in the same individual and the repercussion of this on reproductive efficacy and offspring. Herein, we review the major differences between somatic, germinal, embryonic, and fetal/placental genomes and their contribution to the next generation and its reproductive efficacy. The major novelty of our approach is the holistic interaction between microsystems within a macrosystem (i.e., the reproductive system). This panoramic model allows us to sketch the future implications of genetic results in function of the origin (compartment) of the sample: peripheral blood or other somatic tissues, gametes, zygotes, preimplantation embryos, fetus, or placenta. We believe this perspective can be of great use in the context of reproductive genetic counseling. [ABSTRACT FROM AUTHOR]

Purpose: Expanded carrier screening (ECS) is an available component of preconception and prenatal care. There is complexity around offering, administering, and following-up test results. The goal of this study is to evaluate current physicians’ utilization and attitudes towards ECS in current practice.Methods: This was a prospective qualitative survey study. A 32-question electronic survey was distributed during a 1-year period to obstetricians-gynecologists who were identified using a Qualtrics listserv database.Results: While more than 90% of physicians offered ethnic-based carrier screening (CS), ECS was offered significantly less (2010, 20.6%, and 2016, 27.1%). Physicians who were not fellowship-trained in reproductive endocrinology and infertility (REI) preferred ethnic-based carrier screening (95.9 vs 16.8%; P < 0.001). REI subspecialists were more likely to offer ECS (80%) compared to 70% of maternal fetal medicine physicians (MFM). Physicians were comfortable discussing negative results (53.6%) compared to positive results (48.4%). Most physicians (56%) believed that ECS should not be offered until the significance of each disease is understood; 52% believed that testing should be restricted to those conditions important to couples; while 26% felt that testing should be done regardless of the clinical significance.Conclusions: Discussion and application of ECS has increased in clinical practice. However, lack of comfort with counseling and varying beliefs surrounding ECS continue to hinder its utilization. Further education and training programs, and subsequent evaluation are warranted. [ABSTRACT FROM AUTHOR]

The concept of precision medicine relies on a thorough understanding of the consequences of unique features of individual patients, such as environmental exposures and genetic profiles. A key component of implementing individualized care in this paradigm will be improved assessment of genetic risk. Compared with single gene tests, multigene panel testing-which has recently become commercially available for female infertility-offers the possibility of a more comprehensive and efficient risk evaluation. However, as the use of multigene panel testing for breast cancer risk has shown, this approach must be used judiciously to ensure its usefulness in a clinical setting. Key challenges which have been encountered in oncology include the interpretation of gene variants of questionable clinical effect and a lack of evidence to guide management after variants are identified. In this review, the core concepts of multigene panel testing for risk assessment are discussed, with careful attention to both its shortcomings as well as its potential for benefit in reproductive medicine. [ABSTRACT FROM AUTHOR]

We report herein results of a study performed in the Balearic Islands which had the following goals: 1) Determine the proportion of pregnant or non-pregnant women planning pregnancy, who would choose to undergo a screening test for Fragile X Syndrome (FXS), if it is accompanied by the appropriate information; 2) Assess satisfaction and any increase in stress among women who participate in screening; 3) Collect epidemiological information about the incidence of the disease in our population; and 4) Collect demographic and health history data and assess participants' awareness of the disease. Screening was performed on 3,731 pregnant and non-pregnant women of childbearing age and the results indicate: a very high voluntary rate of participation; a high level of self-reported satisfaction and low levels of stress because of the test; a very high incidence of premutation (1/106) in our population; and a low level of awareness about the existence of FXS (25 %). Additional findings indicate no significant correlation between self-reported health history and premutation detection, and the high premutation incidence does not seem to be specific to the indigenous Balearic population. Based on these results, we discuss the pros and cons of an implementation of preconception and pregnant women screening for FXS within a public health screening program. [ABSTRACT FROM AUTHOR]

Objective: To describe in vitro development of human embryos derived from an individual with a homozygous pathogenic variant in NLRP7 (19q13.42) and recurrent hydatidiform mole (HM), an autosomal recessive condition thought to occur secondary to an oocyte defect. Methods: A patient with five consecutive HM pregnancies was genomically evaluated via next generation sequencing followed by controlled ovarian hyperstimulation, in vitro fertilization (IVF) with intracytoplasmic sperm injection, embryo culture, and preimplantation genetic screening. Findings in NLRP7 were recorded and embryo culture and biopsy data were tabulated as a function of parental origin for any identified ploidy error. Results: The patient was found to have a pathogenic variant in NLRP7 (c.2810+2T>G) in a homozygous state. Fifteen oocytes were retrieved and 10 embryos were available after fertilization via intracytoplasmic sperm injection. Developmental arrest was noted for all 10 embryos after 144 hours in culture, thus no transfer was possible. These non-viable embryos were evaluated by karyomapping and all were diploid biparental; two were euploid and eight had various aneuploidies all of maternal origin. Conclusion: This is the first report of early human embryo development from a patient with any NLRP7 mutation. The pathogenic variant identified here resulted in global developmental arrest at or before blastocyst stage. Standard IVF should therefore be discouraged for such patients, who instead need to consider oocyte (or embryo) donation with IVF as preferred clinical methods to treat infertility. [ABSTRACT FROM AUTHOR]

Purpose: The American College of Medical Genetics and Genomics emphasizes a "consistent and equitable approach for offering carrier screening." At our academic center, publicly insured prenatal patients underwent universal expanded carrier screening (ECS) to promote equitable care. The aim of the study was to evaluate rates, time, and barriers to complete ECS. This was defined as post-test counseling and partner testing after a patient was found heterozygous for a pathogenic variant., Methods: In this descriptive retrospective cohort study from 2018 to 2021, patients were offered ECS, consisting of 283 recessive and X-linked genes. Heterozygotes were contacted by genetic counselors (≤5 attempts) for education and partner testing. Rates of counseling, partner testing, diagnostic procedures, follow-up times, and barriers to completion were assessed., Results: During this time, 643 women underwent ECS. Of these 643 women, 462 were heterozygotes and 326 of 462 had undergone counseling. Two hundred twenty-two of 462 partners obtained testing, with a median of 32 days from patient to partner result. Approximately 21 couples were heterozygous for the same pathogenic variant. One patient pursued diagnostic testing., Conclusion: ECS offers useful information; however, this study highlights significant barriers to completion. There was suboptimal patient follow-up and low partner screening, perhaps from insufficient time to educate and counsel. Future directions include implementing quality measures to ensure optimal completion., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)