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

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.

PharmVar GeneFocus: CYP2C19

“…Gene copy number variations (CNVs) may also affect activity in rare cases. Numerous deletion and duplication events, affecting the CYP2C gene locus, have been described 69,70 . Many of the gene deletion and duplication events involve CYP2C19 , as well as other CYP2C gene(s) and, in some instances also other genes within the chromosomal region.…”

“…Many of the gene deletion and duplication events involve CYP2C19 , as well as other CYP2C gene(s) and, in some instances also other genes within the chromosomal region. PGx genotyping tests typically do not interrogate CYP2C19 CNVs; these are more commonly interrogated by copy number arrays and other quantitative molecular assays (e.g., quantitative PCR multiplex ligation‐dependent probe amplification) 70 . PharmVar has recently catalogued the CYP2C19*36 and *37 alleles, which represent full and partial (with including at least exon 1) CYP2C19 gene deletions, respectively.…”

“…In addition, high quality data are needed in order to generate reliable genotype calls with next‐generation sequencing. Finally, CNVs affecting the CYP2C19 gene locus may also lead to misinterpretation in rare cases 70 …”

“…Numerous deletion and duplication events, affecting the CYP2C gene locus, have been described. 69,70 Many of the gene deletion and duplication events involve CYP2C19, as well as other CYP2C gene(s) and, in some instances also other genes within the chromosomal region. PGx genotyping tests typically do not interrogate CYP2C19 CNVs; these are more commonly interrogated by copy number arrays and other quantitative molecular assays (e.g., quantitative PCR multiplex ligation-dependent probe amplification).…”

Cross-validation of technologies for genotypingCYP2D6andCYP2C19

“…[10][11][12] The CYP2C19 gene encoding the CYP2C19 enzyme is likewise located at chromosome 10q23.33 together with other similar genes, namely CYP2C18 (not expressed at the protein level), CYP2C9, and CYP2C8. [13][14][15] While structural variants of CYP2C19 have recently been identified, 16 the more commonly studied "star allele" variants result from single base changes in the DNA sequence (single nucleotide variants or SNVs); more than 30 different variants in CYP2C19 have been catalogued to date. 17 Each CYP2D6 or CYP2C19 haplotype or "star allele" is associated with different levels of enzyme activity, ranging from poor metabolizer (PM) alleles, which give rise to no functional enzyme; to intermediate metabolizer (IM) alleles, which are associated with an enzyme with reduced metabolic activity; to ultrarapid metabolizer alleles (UMs), associated with increased activity.…”