Neonatal genetic sequencing as a first-tier option: a real-world clinical implementation study in Northern China

Abstract

Abstract Objective: To evaluate real-world implementation of newborn genetic screening (NBGS) in terms of positivity rate, carrier frequency, and diagnostic accuracy for inherited metabolic disorders (IMDs), and to explore feasibility and challenges in regional clinical application. Methods: This study enrolled 1590 newborns (August 2023–November 2024) whose parents opted for NBGS. A targeted sequencing panel covering 465 genes for 596 diseases alongside traditional biochemical screening for 46 disorders were performed. Variants were classified per ACMG guidelines. Positive cases were recalled for confirmatory Sanger sequencing and auxiliary biochemical tests. We calculated uptake, carrier frequency, identified hotspot variants, and compared allele frequencies with gnomAD_EAS. Diagnostic performance was compared with biochemical screening. Results: Uptake was 10.41% (1590/15,272). Overall positivity was 7.74% (123/1590). Among these, 10 were positive for IMDs‑related genes, with 8 confirmed, giving a positive predictive value (PPV) of 80.00% for IMDs – significantly higher than biochemical screening’s 5.71%. We detected 2,354 variants, with carrier frequency 70.94%. Hotspot IMDs variants included MMACHC c.609G>A, c.658_660del, and MUT c.1286A>G, whose minor allele frequencies differed from gnomAD, indicating regional specificity. High carrier rates were also seen for lysosomal storage genes (GALC c.1901T>C, 53.57%; c.2041G>A, 32.14%). Conclusion: NBGS offers high PPV and specificity, reducing false positives and providing early molecular evidence for IMDs. Regional hotspot and MAF differences underscore the need for a local genetic database. Although the acceptance of NBGS is increasing, factors such as cost and varying levels of awareness among healthcare providers remain barriers to its broader implementation. This study provides preliminary data supporting the implementation of regional newborn genetic screening programs and informs secondary and tertiary prevention strategies.