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.

Aashish N Adhikari,Renata Gallagher,Rajgopal Srinivasan,Robert J Currier,Jennifer M Puck,Dimitar Gavrilov,Hao Tang,Coleman T Turgeon,Steven E Brenner,Pui-Yan Kwok,Uma Sunderam,Robert L Nussbaum

doi:10.3390/ijns6020041

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%.

Highlights

Short-chain acyl-CoA dehydrogenase deficiency (SCADD, OMIM:201470) is a rare autosomal recessive disorder of β-oxidation caused by pathogenic variants in the ACADS gene
The goal of this study was to assess the correlation of the initial dried blood spots (DBSs) C4-acylcarnitine value, the second-tier DBS ethylmalonic acid value, and exome sequencing results in a large cohort of individuals identified as potential cases of SCADD through the California newborn screening program
At the start of the period during which the study cases had newborn screening (2005), the clinical diagnosis of SCADD was primarily based on biochemical testing, with the possibility of additional confirmation through fibroblast studies or genetic sequencing

Summary

Introduction

Short-chain acyl-CoA dehydrogenase deficiency (SCADD, OMIM:201470) is a rare autosomal recessive disorder of β-oxidation caused by pathogenic variants in the ACADS gene. The biochemical signatures of short-chain acyl-CoA dehydrogenase (SCAD) include elevated plasma butyrylcarnitine (C4) and urine ethylmalonic acid (EMA) [1]. Individuals who are homozygotes for either of these variants or who are compound heterozygotes do not have clinical disease, but have reduced SCAD enzyme activity, resulting in elevated blood and urine metabolites. These variants have allele frequencies of 0.2577 (ranging from 0.1252 in East Asians to 0.3660 in Latino populations) and 0.03110 (0.000 in East Asians to 0.06326 in the Finnish population), respectively, [2] (population frequencies from gnomAD, variants 12-121176083-G-A and 12-121175678-C-T, respectively)

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