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

2019; Wiley; Volume: 40; Issue: 11 Linguagem: Inglês

10.1002/humu.23855

1098-1004

Mariana Rodrigues Botton, Xingwu Lu, Geping Zhao, Elena Repnikova, Yoshinori Seki, Andrea Gaedigk, Eric E. Schadt, Lisa Edelmann, Stuart A. Scott,

Cancer Genomics and Diagnostics

Human MutationVolume 40, Issue 11 p. e37-e51 DATA ARTICLE Structural variation at the CYP2C locus: Characterization of deletion and duplication alleles Mariana R. Botton, Mariana R. Botton Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York Sema4, A Mount Sinai venture, Stamford, Connecticut Present address: Mariana R. Botton, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil and Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.Search for more papers by this authorXingwu Lu, Xingwu Lu Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York Sema4, A Mount Sinai venture, Stamford, ConnecticutSearch for more papers by this authorGeping Zhao, Geping Zhao Sema4, A Mount Sinai venture, Stamford, ConnecticutSearch for more papers by this authorElena Repnikova, Elena Repnikova Clinical Genetics and Genomics Laboratories, Children's Mercy Hospital Kansas City, Kansas City, Missouri School of Medicine, University of Missouri-Kansas City, Kansas City, MissouriSearch for more papers by this authorYoshinori Seki, Yoshinori Seki Sema4, A Mount Sinai venture, Stamford, ConnecticutSearch for more papers by this authorAndrea Gaedigk, Andrea Gaedigk Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, MissouriSearch for more papers by this authorEric E. Schadt, Eric E. Schadt Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York Sema4, A Mount Sinai venture, Stamford, ConnecticutSearch for more papers by this authorLisa Edelmann, Lisa Edelmann Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York Sema4, A Mount Sinai venture, Stamford, ConnecticutSearch for more papers by this authorStuart A. Scott, Corresponding Author Stuart A. Scott stuart.scott@mssm.edu orcid.org/0000-0001-5720-1864 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York Sema4, A Mount Sinai venture, Stamford, Connecticut Correspondence Stuart A. Scott, PhD, Associate Professor, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1497, New York, NY 10029. Email: stuart.scott@mssm.eduSearch for more papers by this author Mariana R. Botton, Mariana R. Botton Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York Sema4, A Mount Sinai venture, Stamford, Connecticut Present address: Mariana R. Botton, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil and Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.Search for more papers by this authorXingwu Lu, Xingwu Lu Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York Sema4, A Mount Sinai venture, Stamford, ConnecticutSearch for more papers by this authorGeping Zhao, Geping Zhao Sema4, A Mount Sinai venture, Stamford, ConnecticutSearch for more papers by this authorElena Repnikova, Elena Repnikova Clinical Genetics and Genomics Laboratories, Children's Mercy Hospital Kansas City, Kansas City, Missouri School of Medicine, University of Missouri-Kansas City, Kansas City, MissouriSearch for more papers by this authorYoshinori Seki, Yoshinori Seki Sema4, A Mount Sinai venture, Stamford, ConnecticutSearch for more papers by this authorAndrea Gaedigk, Andrea Gaedigk Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, MissouriSearch for more papers by this authorEric E. Schadt, Eric E. Schadt Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York Sema4, A Mount Sinai venture, Stamford, ConnecticutSearch for more papers by this authorLisa Edelmann, Lisa Edelmann Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York Sema4, A Mount Sinai venture, Stamford, ConnecticutSearch for more papers by this authorStuart A. Scott, Corresponding Author Stuart A. Scott stuart.scott@mssm.edu orcid.org/0000-0001-5720-1864 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York Sema4, A Mount Sinai venture, Stamford, Connecticut Correspondence Stuart A. Scott, PhD, Associate Professor, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1497, New York, NY 10029. Email: stuart.scott@mssm.eduSearch for more papers by this author First published: 01 July 2019 https://doi.org/10.1002/humu.23855Citations: 9 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat 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. CONFLICT OF INTERESTS X. L., G. Z., Y. S., E. E. S., L. E., and S. A. S. are paid employees of Sema4, a Mount Sinai venture, Stamford, CT. Citing Literature Volume40, Issue11November 2019Pages e37-e51 This article also appears in:New Article Type: Data Articles RelatedInformation