Clinical exome sequencing for carrier screening in assisted reproductive technology and sperm donation.

Objective: To assess the efficacy of clinical exome sequencing (CES) in individuals involved in assisted reproductive technology (ART) or sperm donor programs, with a specific focus on its impact on clinical decision-making.

Methods: A total of 3991 individuals without a family history of genetic disorders underwent CES targeting 5595 genes at a reproductive center between December 2022 and April 2024. The cohort comprised 217 sperm donors, 232 female recipients, and 1771 couples (3542 patients) undergoing ART with their own gametes. At-risk couples (ARCs) were identified when both partners had a pathogenic or likely pathogenic variant (P/LP) in the same autosomal recessive gene or X-linked variants in females. The analysis primarily examined carrier frequencies, reproductive choices, and outcomes of ARCs.

Results: Among the 3991 individuals screened, 3895 (97.6%) were found to carry at least one P/LP variant, with an average carrier burden of 3.8 variants per individual, showing no significant disparity in carrier status between individuals with infertility and sperm donors/recipients. Within the screened couples, 9.3% were identified as ARCs and 2.3% opted for preimplantation genetic testing for monogenic diseases (PGT-M). As of now, 31 ARCs proceeded with the transfer of euploid and unaffected blastocysts, resulting in 8 healthy live births and 13 ongoing pregnancies.

Conclusions: The findings reveal a significant prevalence of carrier status for autosomal recessive and X-linked diseases, irrespective of fertility status. This highlights the critical importance of integrating genetic risk counseling and informed reproductive decision-making into fertility clinics and sperm banks.