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

• Main Authors: Aashish N. Adhikari (Author), Robert J. Currier (Author), Hao Tang (Author), Coleman T. Turgeon (Author), Robert L. Nussbaum (Author), Rajgopal Srinivasan (Author), Uma Sunderam (Author), Pui-Yan Kwok (Author), Steven E. Brenner (Author), Dimitar Gavrilov (Author), Jennifer M. Puck (Author), Renata Gallagher (Author)
• Format: Book
• Published: MDPI AG, 2020-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive disorder of β-oxidation caused by pathogenic variants in the <i>ACADS</i> 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 <i>ACADS</i> 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 <i>ACADS</i> 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%.

Item Description

10.3390/ijns6020041
2409-515X