The NBGENS project protocol: Pilot study for genetic newborn screening in Galicia

Abstract

Background Conventional newborn screening (NBS) relies on mainly biochemical assays and remains limited by its dependence on detectable biomarkers within a narrow postnatal window, leaving many treatable genetic disorders unidentified. Advances in next-generation sequencing have enabled projects of genomic newborn screening, which may expand the spectrum of detectable conditions. However, challenges persist regarding variant interpretation, reporting criteria, and integration into public healthcare systems. Methods NBGenS is a prospective, single-center pilot study in Spain that will evaluate the feasibility of integrating whole exome sequencing (WES) into routine NBS. The study will recruit 550 newborns at the University Clinical Hospital of Santiago de Compostela. DNA will be extracted from residual dried blood spots (DBS) obtained through NBS. WES and clinical interpretation will be restricted to a virtual panel of genes associated with severe, highly-penetrant, pediatric-onset diseases for which early intervention is available. Variant interpretation will follow ACMG/AMP and ClinGen recommendations, and only pathogenic or likely pathogenic variants will be considered reportable. Untargeted metabolomics using DBS will be applied in selected cases, particularly for prioritised variants of uncertain significance (VUS), to provide complementary biochemical evidence that may contribute to variant classification. Clinical follow-up, psychosocial assessment, pharmacogenetic analysis, and health economic evaluation will also be incorporated into the study design. Outcomes The project will establish and evaluate a comprehensive clinical workflow encompassing recruitment, sequencing, interpretation, reporting, and follow-up. Key outcomes will include diagnostic yield, parental acceptance, psychological impact, cost-effectiveness, clinical utility, and the added value of metabolomic integration for resolving VUS. Conclusion NBGenS represents one of the first prospective public healthcare pilot studies integrating genomic sequencing and untargeted metabolomics within an established NBS program. The study will generate empirical evidence on the clinical, ethical, psychosocial, and economic implications of neonatal genomic screening and may inform future policy decisions regarding its implementation within national health systems.