Targeted genetic screening for identifying carrier status and early-onset disease risks in Chinese newborns

Expanded newborn genetic screening can identify a wide range of inherited conditions early in life. However, the prevalence and distribution of pathogenic and likely pathogenic variants in large-scale cohorts remain underexplored in the Chinese population.

We screened 33,894 newborns using targeted sequencing of 465 genes associated with monogenic disorders. Variants were classified with locally optimized American College of Medical Genetics and Genomics guidelines, focusing on pathogenic and likely pathogenic variants. We analyzed cumulative carrier rates, disease-specific prevalence, and regional differences.

Here we show that among 33,894 newborns, 16,687 (49.2%) carry at least one pathogenic/likely pathogenic variant. In total, 22,457 such alleles are detected across 427 (91.8%) genes. Detection rates are higher in the south (52.1%) than in the north (48.5%). On average, each newborn carries 0.7 variants. The most frequent genes (allele frequency >1%) include GJB2 (5.56%), PAH (1.41%), and SLC26A4 (1.30%). The cumulative predicted incidence of 57 inborn errors of metabolism included in newborn tandem mass spectrometry screening is 1/2,177, with PAH, MMACHC, SLC22A5, MMUT and SLC25A13 as the main contributors. Regional analysis reveales significant geographic variation, with three inborn errors of metabolism (e.g., methylmalonic aciduria, phenylketonuria) more common in the north, five disorders (e.g. G6PD deficiency, thalassemia) more common in the south.

This large-scale study highlights the utility of targeted genetic screening for identifying carrier status and early-onset disease risks in newborns. The findings provide a critical foundation for integrating genetic screening into routine newborn care and for optimizing public health strategies.