Integrating Newborn Genetic Screening with Traditional Screening to Improve Newborn Screening

Abstract Background: Traditional newborn screening (NBS) for inborn errors of metabolism (IEM) and deafness has limitations due to the detection of fewer genetic disorders and variants, higher false-positive rates, and longer detection periods. This study aimed to explore the clinical validity of newborn genetic screening (NBGS) in newborns with IEM and deafness. Methods: We retrospectively enrolled 223 cases screened for IEM by tandem mass spectrometry (MS/MS)-next-generation sequencing (NGS), including 55 positive, 68 suspected positive, and 100 negative cases. Additionally, 196 cases screened for deafness were enrolled, including 96 variant-positive and 100 negative cases. Dry blood spot samples from the newborns were used for NBGS. Results: For IEM, NBGS detected 34 positives in 55 positive cases with a sensitivity of 61.8% (34/55), whereas variants were not detected in 21 cases. Four additional positive cases were found, including one at risk of glucose-6-phosphate dehydrogenase deficiency and three at risk of deafness. The diagnostic time observed between the two methods exhibited a significant difference: 13 days for NBGS and 35 days for MS/MS-NGS. For deafness, the consistency in the positive results between the two methods was 96.9% (93/96). Unexpectedly, three mitochondrial gene (MT-RNR1) heterogeneous variants (m.1555A>G and m.7445A>G) were not detected by NBGS. We also detected nine variants out of 100 negative cases, including seven GJB2 (c.109G>A), one GJB3 (c.547G>A), and one MYO15A (c.10250_10252delCCT), with a 9% (9/100) detection rate by NBGS. Conclusion: As a novel screening method for newborns, NBGS can detect more gene variants, reduce the false-positive rate, and shorten the diagnostic cycle. Our research provides a foundation for the clinical application of NBGS.