Structural variation at the CYP2C locus: Characterization of deletion and duplication alleles
Structural variation at the CYP2C locus: Characterization of deletion and duplication alleles
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DOI：
10.1002/humu.23855
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发表时间：
2019-11-01
期刊：
影响因子：
3.9
通讯作者：
Scott, Stuart A.
中科院分区：
文献类型：
--
作者：
Botton, Mariana R.;Lu, Xingwu;Scott, Stuart A.
人CYP 2C基因座含有多态性CYP 2C 18、CYP 2C 19、CYP 2C 9和CYP 2C 8基因，其中，CYP 2C 19和CYP 2C 9直接参与约15%的药物代谢。目前由Pharmacogene Variation（PharmVar）Consortium编目的所有变体CYP 2C 19和CYP 2C 9星星（*）等位基因单倍型均由序列变体定义。为了确定结构变异是否也发生在CYP 2C基因座上，在两个学术医学中心测试的20，642名患者的去识别临床染色体微阵列（CMA）数据中询问了10q23.33区域。在临床CMA队列中检测到14种影响CYP 2C基因编码区的拷贝数变异，其大小范围为39.2至1，043.3 kb。通过MLPA或ddPCR确认选定的缺失和重复。分析临床CMA以及来自基因组变异数据库（DGV）和ClinGen的额外78，839例病例（总n = 99，481）表明，CYP 2C结构变异体的携带频率约为1/1，000，其中约1/2，000为CYP 2C 19全基因或部分基因缺失携带者，由PharmVar指定为CYP 2C 19 *36和 *37，分别虽然这些结构变异在一般人群中很少见，但在研究和/或临床试验中进行询问时，它们的检测可能会改善代谢者表型预测。
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.