Incorporating Next-Generation Sequencing in Newborn Screening for Organic Acidemias

TL;DR

This study shows that combining next-generation sequencing with traditional screening improves accuracy and reduces false positives in detecting metabolic disorders in newborns.

Contribution

The study introduces a combined NGS and MS/MS approach to improve newborn screening for organic acidemias.

Findings

NGS identified 17 confirmed cases of OADs with a prevalence of 1 in 9096.

NGS detected a case of methylmalonic acidemia missed by MS/MS screening.

Combined screening reduced false positives and identified two cases of Wilson’s disease.

Abstract

Organic acidemias (OADs) are a group of inherited metabolic disorders with a high false-positive rate in newborn screening. In this study, we aimed to evaluate the clinical performance of next-generation sequencing (NGS) as a combined genetic test for OADs. From September 2022 to August 2025, 154,634 newborns underwent primary screening using tandem mass spectrometry (MS/MS). Among them, 151 neonates with suspected OADs underwent combined genetic screening using a pre-designed NGS panel. Of these, 55 cases tested positive on genetic screening, and 17 were ultimately diagnosed with OADs, yielding a prevalence of 1 in 9096. The positive predictive value of NGS was 30.91% (17/55). The genotypes of nine patients (9/17, 52.9%) were identified through NGS screening. Notably, one case of methylmalonic acidemia that would have been missed by MS/MS screening was successfully identified using the combined genetic screening. Additionally, 37 neonates with positive biochemical screening results were confirmed to be either carriers or unaffected individuals. Two cases of Wilson’s disease were also identified through combined genetic screening. Therefore, integrating NGS into conventional MS/MS-based screening can significantly reduce the false-positive rate and shorten the time from screening to definitive diagnosis. This approach provides a valuable model for improving the efficiency and accuracy of newborn genetic screening.

Figures