Genomic Newborn Screening in the Era of Next Generation Sequencing: Evidence, Opportunities, and Challenges

Advances in next-generation sequencing have prompted growing interest in integrating genomic technologies into newborn screening (NBS) programs.While conventional biochemical NBS effectively identifies a limited set of inherited metabolic disorders, its analyte-based design restricts expansion to numerous clinically significant genetic conditions.Genomic NBS (gNBS), utilizing whole-exome or whole-genome sequencing, has emerged as a potential complementary approach to broaden disease detection and enable earlier diagnosis and precision-based care.International pilot studies, such as the BabySeq Project and the Genomic Uniform-screening Against Rare Diseases In All Newborns (GUARDIAN) Study in the United States and the Generation Study in the United Kingdom, have evaluated the feasibility and clinical utility of gNBS.These initiatives demonstrate that gNBS can identify pathogenic variants associated with childhood-onset, medically actionable conditions often missed by traditional methods.However, significant challenges persist, including variant interpretation uncertainty, ethical concerns regarding future autonomy, data governance, and cost-effectiveness.This review emphasizes that gNBS should complement rather than replace conventional NBS through an evidence-based, stepwise implementation tailored to specific healthcare systems.For successful integration, establishing a multidisciplinary framework involving neonatologists, subspecialists in each field, and clinical geneticists is essential.Ultimately, gNBS must be implemented cautiously, ensuring that clinical benefits outweigh potential psychosocial harms while maintaining public health integrity.