PloS one
The NBGENS project protocol: Pilot study for genetic newborn screening in Galicia
By Lis-López L, López-López C, López-Valverde L and 9 others.
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.