Genomic Analysis of Historical Cases with Positive Newborn Screens for Short-Chain Acyl-CoA Dehydrogenase Deficiency Shows That a Validated Second-Tier Biochemical Test Can Replace Future Sequencing

Abstract

by Aashish N. Adhikari,Robert J. Currier,Hao Tang,Coleman T. Turgeon,Robert L. Nussbaum,Rajgopal Srinivasan,Uma Sunderam,Pui-Yan Kwok,Steven E. Brenner,Dimitar Gavrilov,Jennifer M. Puck andRenata Gallagher
Int. J. Neonatal Screen. 2020, 6(2), 41; https://doi.org/10.3390/ijns6020041 - 26 JAN 2022
Cited by 10 | Viewed by 3716
Abstract
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive disorder of β-oxidation caused by pathogenic variants in the ACADS gene. Analyte testing for SCADD in blood and urine, including newborn screening (NBS) using tandem mass spectrometry (MS/MS) on dried blood spots (DBSs), is complicated by the presence of two relatively common ACADS variants (c.625G>A and c.511C>T). Individuals homozygous for these variants or compound heterozygous do not have clinical disease but do have reduced short-chain acyl-CoA dehydrogenase (SCAD) activity, resulting in elevated blood and urine metabolites. As part of a larger study of the potential role of exome sequencing in NBS in California, we reviewed ACADS sequence and MS/MS data from DBSs from a cohort of 74 patients identified to have SCADD. Of this cohort, approximately 60% had one or more of the common variants and did not have the two rare variants, and thus would need no further testing. Retrospective analysis of ethylmalonic acid, glutaric acid, 2-hydroxyglutaric acid, 3-hydroxyglutaric acid, and methylsuccinic acid demonstrated that second-tier testing applied before the release of the newborn screening result could reduce referrals by over 50% and improve the positive predictive value for SCADD to above 75%. Full article
(This article belongs to the Special Issue CLIR Applications for Newborn Screening)
13 pages, 1352 KiB
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