Clinical utility of next‑generation sequencing-based newborn screening in a prospective cohort of 1125 newborns in China

Conventional newborn screening (NBS) primarily targets inborn errors of metabolism (IEMs) and hearing loss, and has significantly advanced early diagnosis and intervention but remains constrained by limited disease coverage and technical limitations. With the advent of next-generation sequencing (NGS), genomic NBS enables molecular-level detection of a broader spectrum of genetic diseases, and may offer complementary and integrative benefits. This study aimed to assess the clinical utility of genomic NBS and providing evidence to optimize future NBS strategies. A total of 1125 newborns were prospectively enrolled and simultaneously screened by conventional and genomic NBS. The genomic NBS was performed with the NBSure NGS panel covering 358 genes related to 411 diseases. Screening outcomes from the two approaches were systematically compared to evaluate performance. Positive cases were subjected to clinical follow-up. Conventional NBS reported 4 positive cases, while NBSure identified 29 screen-positive newborns, resulting in an additional 2.2% (25/1125; 95% CI, 1.4%-3.1%) increase in the overall detection rate. Fifteen newborns were identified with single-nucleotide variants (SNVs) or insertions/deletions (InDels), and 14 carried copy number variants (CNVs). Follow-up information was available for 72.4% (21/29) of positive cases. Four infants developed disease-related clinical manifestations, of whom two were molecularly diagnosed after further clinical evaluation. Genomic NBS also provided reproductive guidance for 8 families and revealed the molecular diagnosis of family members in 2 families, offering additional counseling and diagnostic value. Genomic NBS with NBSure expanded the identification beyond conventional screening approaches and provided valuable information for familial risk assessment and genetic counseling. Longitudinal follow-up is required to further evaluate the genomic NBS findings, as most screen-positive infants remained asymptomatic during the current follow-up. These findings support further integration of genomic NBS into existing programs to establish a more comprehensive and precise NBS system.