A Genomic Sequencing Approach to Newborn Mass Screening and Its Opportunities

Next-generation sequencing (NGS) has the potential to revolutionize newborn screening (NBS) by enabling the early identification of actionable genetic conditions not detectable by traditional methods. However, its integration into routine screening programs remains limited due to challenges related to feasibility, interpretation, and clinical impact.

To investigate the acceptability and feasibility as well as the clinical implications of an NGS-based NBS program using DNA extracted from dried blood spots (DBSs).

This prospective, nonpharmacological, interventional, single-center cohort study was proposed to parents whose newborns were delivered between October 1, 2023, and July 31, 2024, in a tertiary-level hospital in Turin, Italy, serving as a referral center for high-risk pregnancies. Newborns were consecutively selected at birth and enrolled after obtaining parental consent during the maternity stay.

Whole-exome sequencing (WES) using an in silico panel of 521 genes associated with pediatric-onset, actionable conditions. Only pathogenic or likely pathogenic variants were reported.

Primary outcome was the technical feasibility of WES on DBSs. Secondary outcomes were establishment of a genomic sequencing database for rapid reanalysis if subsequent clinical indications arise and preliminary qualitative evaluation of selected example cases to explore the clinical implications of NGS-based NBS results to inform future implementation in routine care.

Of 4709 eligible newborns, 4067 (86.4%) were enrolled (2078 males [51.1%]; mean [SD] gestational age, 38.7 [1.9] weeks). Sequencing was successful in 4054 of newborns (99.7%). Of 4054 newborns analyzed, 542 (13.4%) screened positive. After orthogonal confirmation and family segregation studies, 568 actionable molecular diagnoses were retained, affecting 529 newborns (13.0%). During follow-up, 45 newborns underwent WES reanalysis due to clinical suspicion of a genetic disease, of whom 9 (20.0%) received a diagnosis not included in the initial screening panel.

Genomic NBS using WES from DBSs was technically feasible and allowed early identification of actionable genetic conditions. Integration of genomic methods into NBS, although ethical, logistical, and clinical challenges remain, is a logical step but requires adequate genetic counseling and long-term follow-up.