Genetic spectrum analysis of high-carrier-frequency monogenic disorders based on whole-exome sequencing in the Chinese general population

Carrier screening serves as an effective measure for reproductive planning. Given ancestry/regional variations in genetic spectra, this study aimed to comprehensively identify high carrier frequency genes/variants in the Chinese population, thereby providing evidence for developing tailored expanded carrier screening (ECS) strategies. In this retrospective study, 5,018 healthy participants from Eastern China who visited Peking Union Medical College Hospital between January 2013 and December 2023 underwent ECS. Whole exome sequencing (WES) was employed to detect over 3,000 monogenic disorders with autosomal recessive (AR), X-linked (XL), or X-linked recessive (XLR) inheritance patterns, followed by comprehensive analysis of the WES data. The cumulative carrier rate in the study population was 84% (4,213/5,018), with an average of 1.84 pathogenic/likely pathogenic variants per participant. The study identified 204 at-risk couples, representing an overall risk rate of 8.54%. Additionally, 62 high-frequency genes (carrier frequency ≥ 1/200) were detected, including some ACMG-recommended genes previously excluded from Chinese ECS panels due to unclear carrier frequencies. Further analysis proposed an optimized Chinese ECS strategy incorporating 200–300 key high-frequency pathogenic genes for panel size design and utilizing hybridization capture sequencing to maximize panel efficiency. This study revealed distinctive genetic characteristics of the Chinese population and provides foundation for developing population-specific ECS strategies.