Abstract
Background: Newborn screening (NBS) for rare genetic disorders traditionally relies on biochemical assays with limited sensitivity. Long-read sequencing (LRS) offers potential for comprehensive genomic analysis in a single test. Methods: We conducted a prospective study comparing LRS-based NBS with standard biochemical screening in 1,200 newborns. LRS targeted 125 genes associated with treatable rare disorders. Diagnostic yield, turnaround time, and false-positive rates were assessed. Results: LRS detected 14 confirmed cases (1.17%) compared to 9 (0.75%) by standard NBS (p=0.045). Median turnaround time was 7 days (IQR 5-9) for LRS versus 14 days (IQR 10-18) for standard NBS. False-positive rate was lower with LRS (0.25% vs 0.58%, p=0.03). LRS identified three conditions not covered by current panels. Conclusions: Integration of LRS into NBS improves diagnostic yield, reduces turnaround time, and lowers false positives, supporting its feasibility for population-based screening. Genomic sequencing should be considered for expansion of NBS programs.