Nominating Genetically Driven Immune Disease Genes for BEACONS: The First U.S. Multistate Genomic Newborn Screening Initiative

Background T cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiency (SCID) has improved early diagnosis, treatment, and survival of SCID infants and identified additional cases of T lymphopenia requiring intervention. Early detection by whole-genome sequencing (WGS)-based NBS could benefit infants with many additional genetically driven immune diseases (GDIs) that lack traditional NBS screening biomarkers. Building Evidence and Collaboration for GenOmics in Nationwide Newborn Screening (BEACONS), the first research study to integrate WGS into multiple U.S. public health laboratories, will sequence up to 30,000 newborns with parental consent. An NBS-WGS task force established at the 2025 Clinical Immunology Society (CIS) Meeting is collaborating with BEACONS to select early-onset, actionable GDIs to be identified by sequence analysis and reported. Methods Task force experts reviewed GDI disease mechanisms, penetrance, and expressivity to prioritize those requiring targeted surveillance or treatment in the first year of life to prevent morbidity and mortality. Candidate GDI gene sources included the U.S. Recommended Uniform Screening Panel (RUSP), 2024 International Union of Immunological Societies (IUIS) inborn errors of immunity tables, GenIA database, ClinGen Gene Curation Expert Panel (GCEP) curations, OMIM, prior NBS-WGS studies, and GDI clinicians and researchers. Inclusion in the GDI-associated gene list required published evidence for clinical manifestations by age 1 year and alignment with consensus criteria of the International Consortium of Newborn Sequencing (ICoNS). Results The initial BEACONS draft list of 100 immune genes (20 of them RUSP SCID genes) was circulated to NBS-WGS task force members from immunology, genetics, rheumatology, transplant, and related specialties. Thirty-five experts from 20 academic institutions augmented and curated the list, submitting 407 genes associated with early-onset GDI to the BEACONS Gene List Working Group and Steering Committee. The overall final BEACONS list (∼800 genes) will be completed by January 2026, after additional review by participating public health laboratories and the public. Conclusion BEACONS is establishing a consensus-driven, evidence-based gene list as an initial research tool for multiple state public health laboratories, enabling prospective evaluation of the feasibility of population-wide NBS-WGS. The CIS NBS-WGS task force is now providing input regarding variant reporting, educational information sheets to accompany reports, and follow-up diagnostic evaluations and management measures required for each gene-disease relationship.