Clinical utility of carrier screening using whole genome sequencing (WGS) for reproductive risk assessment

Genetic carrier screening has considerable potential to prevent the transmission of hereditary diseases. Assessing reproductive risk enables the identification of asymptomatic individuals carrying pathogenic variants that can be transmitted to their offspring. In this study, whole-genome sequencing (WGS) was performed on 1567 individuals (398 couples) enrolled in the NAGEN program. Participants underwent opportunistic screening using a ‘Tier 1’ reproductive risk panel comprising cystic fibrosis, fragile X syndrome, and spinal muscular atrophy. A subcohort of 149 individuals (74 couples) undergoing assisted reproduction was then analysed using a ‘Tier 3’ expanded panel including 113 genes associated with autosomal recessive and X-linked disorders, as recommended by the American College of Medical Genetics and Genomics (ACMG). The ‘Tier 1’ analysis identified pathogenic variants in 6% of individuals, including two couples in which both partners carried variants in the CFTR gene, placing them at risk of having affected offspring. Expanding the panel from 3 to 113 genes introduced analytical challenges but increased the carrier detection rate from 6% to 40%. This broader analysis identified a couple carrying pathogenic variants in the ARSA gene, associated with metachromatic leukodystrophy, and a woman carrying a pathogenic variant in the X-linked RS1 gene, associated with retinoschisis 1. All carriers were offered reproductive options, including preimplantation testing for monogenic diseases (PGT-M). The increase in carrier detection highlights the value of integrating preconception genetic screening into healthcare systems. This approach could reduce the medical, social, and economic burden of Mendelian disorders by raising awareness of carrier status and enabling reproductive options.