Population-scale genomic screening reveals high frequency of actionable secondary findings in Chinese newborns.

Abstract

Secondary findings (SFs) from genome sequencing have significant implications for disease prevention and early intervention, yet their population-specific spectrum remains poorly characterized in non-European cohorts. We performed whole-genome sequencing of 6685 Chinese newborns and evaluated pathogenic variants in 84 genes from the American College of Medical Genetics and Genomics (ACMG) SF v3.3 list according to ACMG/Association for Molecular Pathology (AMP) classification guidelines, and cross-referenced against ClinVar. We identified 306 unique actionable variants, comprising 172 known pathogenic variants (KP) and 134 expected pathogenic variants (EP). When heterozygous carriers of autosomal recessive (AR) variants were included, 9.12% (610/6685) of newborns carried at least one pathogenic variant. Under ACMG SF criteria, clinically actionable variants were identified in 5.06% (338/6685) of newborns, predominantly affecting cardiovascular disease genes (3.49%) and cancer predisposition genes (1.26%), most commonly involving LDLR, TTN, and BRCA2. Importantly, 28 variants across 12 genes showed significant allele frequency divergence between Chinese and European ancestries, highlighting ancestry-specific genetic architecture. Our findings support the inclusion of high-penetrance genes prevalent in East Asian populations in population-tailored genomic screening panels, providing essential reference data for the equitable implementation of precision newborn genomics in underrepresented populations.