The optimal disease spectrum for carrier screening (CS) remains debated. We aimed to characterise the carrier landscape and quantify the at-risk couple rate (ACR) components in a Chinese population to guide panel design.
Using a 334-gene expanded CS panel, we screened 3748 individuals from Sichuan, China. Pathogenic/likely pathogenic (P/LP) variants were classified by allele frequency and geographic specificity.
Overall, 65.55% of participants carried at least one P/LP variant. We identified 83 at-risk couples (ACR 5.19%), including 55 couples at risk for autosomal recessive (AR) disorders. We catalogued 1372 P/LP variants for AR conditions. Notably, 46 variants were classified as low frequency (minor allele frequency ≥0.1%). Among these 46 low-frequency variants, 54% (25/46) were identified as East Asian-specific. Strikingly, these 25 East Asian-specific variants contributed 41.8% (23/55) to the AR at-risk couples, whereas 11 globally shared alleles contributed only 9.1%. Three regionally enriched variants in HBB, GJB2 and SLC25A13 alone contributed 20% to the AR ACR.
East Asian-specific low-frequency variants significantly contribute to the carrier burden in this population, accounting for nearly half of the AR risk. These findings provide empirical evidence that CS panels should prioritise population-specific carrier frequencies over global data to maximise clinical utility in regions with specific ethnic compositions.