Integrating newborn genetic screening with traditional screening to improve newborn screening

Traditional newborn screening (tNBS) for inborn errors of metabolism (IEMs) and deafness has limitations, including the detection of few genetic disorders and variants, high false-positive rates, and long turnaround times. This study aimed to explore the clinical validity of newborn genetic screening (NBGS) in newborns screened for IEMs and deafness. We retrospectively enrolled 223 cases screened for IEMs using tandem mass spectrometry-next-generation sequencing (MS/MS-NGS), including 55 study-defined positive, 68 study-defined suspected positive, and 100 negative cases. Additionally, 196 cases screened for deafness were enrolled, including 96 variant-positive and 100 negative cases. Dried blood spot samples (DBSs) from newborns were used for NBGS. For IEM, NBGS detected 34 positives in 55 study-defined positive cases with a sensitivity of 61.8% (34/55), no variants were detected in 21 cases. Four additional positive cases were identified, including one at risk of glucose-6-phosphate dehydrogenase deficiency and three at risk of deafness. The turnaround time was significantly different between the two methods: 13 days for NBGS versus 35 days for MS/MS-NGS. For deafness, the consistency of the positive results between the two methods was 96.9% (93/96). Unexpectedly, three mitochondrial gene (MT-RNR1) heteroplasmy variants (m.1555A > G and m.7445A > G) were not detected by NBGS. We also detected nine variants in the 100 negative cases, including seven variants in GJB2 (c.109G > A), one in GJB3 (c.547G > A), and one in MYO15A (c.10250_10252delCCT), for a 9% (9/100) detection rate by NBGS. As an emerging screening method for newborns, NBGS offers the potential to detect a broader spectrum of pathogenic gene variants, reduce false-positive rates, and shorten the diagnostic cycle. However, current NBGS technology has limitations and cannot fully supplant traditional detection methods. Therefore, integrating both approaches can become a critical strategy for enhancing the accuracy and efficiency of newborn screening.