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 Adhikari¹, Robert J Currier², Hao Tang³, Coleman T Turgeon⁴, Robert L Nussbaum⁵, Rajgopal Srinivasan⁶, Uma Sunderam⁶, Pui-Yan Kwok^{7

8

9}, Steven E Brenner^{1

7

10

11}, Dimitar Gavrilov^{4

12}, Jennifer M Puck^{2

7

8

13}, Renata Gallagher^{2

7}

Affiliations

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.

PMID: 32802992
PMCID: PMC7423011
DOI: 10.3390/ijns6020041

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 et al. Int J Neonatal Screen. 2020 Jun.

. 2020 Jun;6(2):41.

doi: 10.3390/ijns6020041. Epub 2020 May 26.

Authors

Affiliations

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.

PMID: 32802992
PMCID: PMC7423011
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%.

Keywords: ACADS; SCADD; butyrylcarnitine; ethylmalonic acid; exome sequence; newborn screening; second-tier testing; short-chain acyl-CoA dehydrogenase deficiency.

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Conflict of interest statement

Conflicts of Interest: A.N.A. is currently an employee of Illumina, Inc. U.S. and R.S. are employees of Tata Consultancy Services (TCS). R.L.N. is an employee of Invitae. J.M.P. is the spouse of R.L.N., who is an employee of Invitae. S.E.B. receives support at the University of California Berkeley from a research agreement from TCS. The remaining authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

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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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous