Abstract
Background: Although newborn screening (NBS) for metabolic defects using the marker butyl carnitine (C4) combined with the C4-to-acetylcarnitine ratio is adequate, the incorporation of novel parameters may improve differential testing for these disorders without compromising sensitivity.Methods: Analytical and clinical performance was evaluated by MS/MS using 237 initially positive neonatal samples between March 2019 and March 2020 at the Newborn Screening Center of Xuzhou Maternity and Child Health Care Hospital. Additionally, second-tier testing by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) combined with the quantification of ethylmalonate (EMA) or isobutyryl-glycine (IBG) in dried blood spots (DBSs) was performed to reduce the false-positive rate.Results: We reviewed initial MS/MS data for DBSs from 469,730 neonates, and a second-tier test was performed using 237 samples that exceeded the C4 concentration cutoff value. Eleven variants of the ACADS gene were identified, with c.1031A>G (p.E344G) being the most common. Fifteen ACAD8 mutations were identified in seven patients, and Swiss modeling and amino acid conservation analyses were conducted for the novel variants. Based on a retrospective analysis of EMA and IBG, the application of second-tier tests before the release of neonatal screening results reduced referrals by over 91.89% and improved the positive predictive value (PPV) for short-chain acyl-CoA dehydrogenase deficiency/isobutyryl-CoA dehydrogenase deficiency (SCADD/IBDD) screening.Conclusion: A screening algorithm including EMA/IBG improves target differential testing for NBS and may eliminate unnecessary referrals while maintaining 100% sensitivity. Second-tier screening using UPLC-MS/MS as a rapid and convenient supplemental DNA sequencing method may be beneficial for differential detection.
Highlights
Acylcarnitine profiling of dried blood spots (DBSs) by tandem mass spectrometry (MS/MS) is a valuable measurement tool for high-throughput newborn screening (NBS), which is important for diagnosing deficiencies, including those in fatty acid β-oxidation (FAO) and branched-chain amino acid metabolism [1]
We investigated whether the combined consideration of multiple test results improves the specificity of NBS for the differentiation of short-chain acyl-CoA dehydrogenase deficiency (SCADD)/isobutyryl-CoA dehydrogenase deficiency (IBDD) from other disorders in an effort to reduce the burden of follow-up testing and unnecessary anxiety for families
Further statistical analysis revealed a significant difference between individuals with SCADD or IBDD and the no-mutation group (p < 0.001)
Summary
Acylcarnitine profiling of dried blood spots (DBSs) by tandem mass spectrometry (MS/MS) is a valuable measurement tool for high-throughput newborn screening (NBS), which is important for diagnosing deficiencies, including those in fatty acid β-oxidation (FAO) and branched-chain amino acid metabolism [1]. This method is utilized without the differentiation of acylcarnitine into isomers, isobaric compounds, and contaminants based on non-derivatization MS/MS. A new ultraperformance liquid chromatography (UPLC–MS/MS) method that assesses special analytes as markers for short-chain acyl-CoA dehydrogenase deficiency (SCADD), isobutyryl-CoA dehydrogenase deficiency (IBDD), and other disorders has been developed [1, 2]. Newborn screening (NBS) for metabolic defects using the marker butyl carnitine (C4) combined with the C4-to-acetylcarnitine ratio is adequate, the incorporation of novel parameters may improve differential testing for these disorders without compromising sensitivity
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