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Article

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

1
Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720, USA
2
Department of Pediatrics, University of California, San Francisco, CA 94158, USA
3
Genetic Disease Screening Program, California Department of Public Health, Richmond, CA 94804, USA
4
Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
5
Invitae, San Francisco, CA 94103, USA
6
Innovation Labs, Tata Consultancy Services, Hyderabad 500081, India
7
Institute for Human Genetics, University of California, San Francisco, CA 94153, USA
8
Cardiovascular Research Institute, University of California, San Francisco, CA 94153, USA
9
Department of Dermatology, University of California, San Francisco, CA 94153, USA
10
Center for Computational Biology, University of California, Berkeley, CA 94720, USA
11
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA
12
Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA
13
UCSF Benioff Children’s Hospital, Division of Allergy, Immunology and Blood and Marrow Transplantation, San Francisco, CA 94153, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Joint last authors.
Int. J. Neonatal Screen. 2020, 6(2), 41; https://doi.org/10.3390/ijns6020041
Received: 18 April 2020 / Revised: 18 May 2020 / Accepted: 22 May 2020 / Published: 26 May 2020
(This article belongs to the Special Issue CLIR Applications for Newborn Screening)
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%. View Full-Text
Keywords: newborn screening; short-chain acyl-CoA dehydrogenase deficiency; SCADD; ACADS; second-tier testing; ethylmalonic acid; exome sequence; butyrylcarnitine newborn screening; short-chain acyl-CoA dehydrogenase deficiency; SCADD; ACADS; second-tier testing; ethylmalonic acid; exome sequence; butyrylcarnitine
MDPI and ACS Style

Adhikari, A.N.; Currier, R.J.; Tang, H.; Turgeon, C.T.; Nussbaum, R.L.; Srinivasan, R.; Sunderam, U.; Kwok, P.-Y.; Brenner, S.E.; Gavrilov, D.; Puck, J.M.; Gallagher, R. 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. Int. J. Neonatal Screen. 2020, 6, 41. https://doi.org/10.3390/ijns6020041

AMA Style

Adhikari AN, Currier RJ, Tang H, Turgeon CT, Nussbaum RL, Srinivasan R, Sunderam U, Kwok P-Y, Brenner SE, Gavrilov D, Puck JM, Gallagher R. 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. International Journal of Neonatal Screening. 2020; 6(2):41. https://doi.org/10.3390/ijns6020041

Chicago/Turabian Style

Adhikari, Aashish N., 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, and Renata Gallagher. 2020. "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" International Journal of Neonatal Screening 6, no. 2: 41. https://doi.org/10.3390/ijns6020041

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