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Abstract Study question What is the prevalence of at-risk couples for recessive genetic diseases, and can preconception carrier testing effectively identify these potential couples at risk? Summary answer High-risk couples, comprising mostly carriers of the ABCA4 and HBB genes, accounted for 3.7% of the analyzed cases, while another 3.2% categorized as moderate risk. What is known already It is widely recognized that approximately 2-3% of couples may be at risk of having an affected child with a genetic recessive disease. Expanded carrier screening tests (ECS) are currently employed to identify carrier status in healthy individuals for various severe recessive and X-linked diseases that manifest early in life, and often lack treatment options. ECS facilitates the detection of couples sharing mutated genes, allowing for risk calculation and further interventions to avoid affected pregnancies. Study design, size, duration In this retrospective descriptive study, we evaluated couples in which both partners elected to complete ECS before undergoing medically assisted reproduction across our Spanish and Italian clinics between August 2018 and January 2024. A total of 873 non-consanguineous couples were identified during the study period. Participants/materials, setting, methods All couples received pre-test genetic counseling alongside the informed consent for ECS. Saliva or blood samples were sent to an external genetics lab for the analysis of 309 genes (recessive and X linked), using NGS and complementary molecular techniques to detect pathogenic and likely pathogenic variants. Each couple’s risk was subsequently calculated. Post-test genetic counselling was offered to all of couples. Main results and the role of chance A total of 55 couples were identified as having reproductive risk, carrying pathogenic or likely pathogenic variants in genes exhibiting recessive or recessive digenic inheritance. These couples were categorized into high and moderate-risk groups based on the severity, actionability, and probability of causing classical gene-linked diseases. Ultimately, 3.5% (n = 31/873) of couples were deemed high-risk, with ABCA4 and HBB being the most frequently mutated genes, observed in 6 and 5 couples respectively (0.7% and 0.6%). Additionally, 24 couples (2.74%) were classified as moderate risk, primarily carrying a classical pathogenic variant and a non-classical pathogenic variant in the CFTR gene. This allele combination could result in a child presenting a mild cystic fibrosis phenotype, predominantly observed in males, and characterized by the absence of a vas deferens. Limitations, reasons for caution The main limitation of the study rests in interpreting the variants in healthy patients. The study does not delve into exploring the genetic heterogeneity within the identified risk groups, which may influence the severity and manifestation of diseases. Wider implications of the findings The cumulative risk observed in close to 6% of the cohort underscores the critical importance of carrier testing in guiding preconception interventions and the role and importance of having a well-trained, multidisciplinary genetics team to support these couples in reproductive decision-making with minimal anxiety and maximum knowledge. Trial registration number Not Applicable
Bellés et al. (Mon,) studied this question.