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Structural variation at the CYP2C locus: Characterization of deletion and duplication alleles.

Authors
  • Botton, Mariana R1, 2
  • Lu, Xingwu1, 2
  • Zhao, Geping2
  • Repnikova, Elena3, 4
  • Seki, Yoshinori2
  • Gaedigk, Andrea5
  • Schadt, Eric E1, 2
  • Edelmann, Lisa1, 2
  • Scott, Stuart A1, 2
  • 1 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 2 Sema4, A Mount Sinai venture, Stamford, Connecticut.
  • 3 Clinical Genetics and Genomics Laboratories, Children's Mercy Hospital Kansas City, Kansas City, Missouri.
  • 4 School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri.
  • 5 Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri.
Type
Published Article
Journal
Human Mutation
Publisher
Wiley (John Wiley & Sons)
Publication Date
Nov 01, 2019
Volume
40
Issue
11
Identifiers
DOI: 10.1002/humu.23855
PMID: 31260137
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The human CYP2C locus harbors the polymorphic CYP2C18, CYP2C19, CYP2C9, and CYP2C8 genes, and of these, CYP2C19 and CYP2C9 are directly involved in the metabolism of ~15% of all medications. All variant CYP2C19 and CYP2C9 star (*) allele haplotypes currently cataloged by the Pharmacogene Variation (PharmVar) Consortium are defined by sequence variants. To determine if structural variation also occurs at the CYP2C locus, the 10q23.33 region was interrogated across deidentified clinical chromosomal microarray (CMA) data from 20,642 patients tested at two academic medical centers. Fourteen copy number variants that affected the coding region of CYP2C genes were detected in the clinical CMA cohorts, which ranged in size from 39.2 to 1,043.3 kb. Selected deletions and duplications were confirmed by MLPA or ddPCR. Analysis of the clinical CMA and an additional 78,839 cases from the Database of Genomic Variants (DGV) and ClinGen (total n = 99,481) indicated that the carrier frequency of a CYP2C structural variant is ~1 in 1,000, with ~1 in 2,000 being a CYP2C19 full gene or partial-gene deletion carrier, designated by PharmVar as CYP2C19*36 and *37, respectively. Although these structural variants are rare in the general population, their detection will likely improve metabolizer phenotype prediction when interrogated for research and/or clinical testing. © 2019 Wiley Periodicals, Inc.

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