Development and Analytical Validation of a 29 Gene Clinical Pharmacogenetic Genotyping Panel: Multi-Ethnic Allele and Copy Number Variant Detection.
Development and Analytical Validation of a 29 Gene Clinical Pharmacogenetic Genotyping Panel: Multi-Ethnic Allele and Copy Number Variant Detection.
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DOI：
10.1111/cts.12844
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Edelmann L
中科院分区：
文献类型：
--
作者：
Scott SA;Scott ER;Seki Y;Chen AJ;Wallsten R;Owusu Obeng A;Botton MR;Cody N;Shi H;Zhao G;Brake P;Nicoletti P;Yang Y;Delio M;Shi L;Kornreich R;Schadt EE;Edelmann L
为了开发一种新的药物遗传学基因分型小组，一个多学科小组评估了现有的证据，并选择了29个涉及个体间药物反应变异性的基因，包括130个序列变异和额外的拷贝数变异（CNV）。在29个基因中，有11个基因有临床药物遗传学实施联盟发布的指南。靶向基因分型和CNV询问分别通过使用MassARRAY平台（Mrsana Biosciences）的多重单碱基延伸和多重连接依赖性探针扩增（MRC Holland）完成。通过对170个独特的参考材料DNA样本进行的> 500个独立测试的策略组合来完成面板的分析验证，其中包括序列变体和CNV准确性，再现性和标本（血液，唾液和口腔拭子）对照。在准确度对照品中，有32份来自1000个基因组项目的样本，这些样本是根据药物遗传学样本组（VarCover.org）中包含的序列变体富集情况选择的。结合来自遗传测试参考材料协调计划（GeT-RM）的公开可用样品，准确性验证材料可用于大多数（77%）询问的序列变体（100%，平均等位基因频率> 0.1%），以及具有独特拷贝数签名的额外结构等位基因（例如，CYP 2D 6 *5、*13、*36、*68; CYP 2B 6 *29;和CYP 2C 19 *36）。基因分型和拷贝数的准确性和再现性均> 99.9%，表明优化的组平台是精确和稳健的。重要的是，询问的变异体的多种族等位基因频率表明，绝大多数一般人群携带至少一种这些临床相关的药物遗传学变异体，支持在药物遗传学研究和/或临床实施项目中实施该样本组。
To develop a novel pharmacogenetic genotyping panel, a multidisciplinary team evaluated available evidence and selected 29 genes implicated in interindividual drug response variability, including 130 sequence variants and additional copy number variants (CNVs). Of the 29 genes, 11 had guidelines published by the Clinical Pharmacogenetics Implementation Consortium. Targeted genotyping and CNV interrogation were accomplished by multiplex single‐base extension using the MassARRAY platform (Agena Biosciences) and multiplex ligation‐dependent probe amplification (MRC Holland), respectively. Analytical validation of the panel was accomplished by a strategic combination of > 500 independent tests performed on 170 unique reference material DNA samples, which included sequence variant and CNV accuracy, reproducibility, and specimen (blood, saliva, and buccal swab) controls. Among the accuracy controls were 32 samples from the 1000 Genomes Project that were selected based on their enrichment of sequence variants included in the pharmacogenetic panel (VarCover.org). Coupled with publicly available samples from the Genetic Testing Reference Materials Coordination Program (GeT‐RM), accuracy validation material was available for the majority (77%) of interrogated sequence variants (100% with average allele frequencies > 0.1%), as well as additional structural alleles with unique copy number signatures (e.g., CYP2D6*5, *13, *36, *68; CYP2B6*29; and CYP2C19*36). Accuracy and reproducibility for both genotyping and copy number were > 99.9%, indicating that the optimized panel platforms were precise and robust. Importantly, multi‐ethnic allele frequencies of the interrogated variants indicate that the vast majority of the general population carries at least one of these clinically relevant pharmacogenetic variants, supporting the implementation of this panel for pharmacogenetic research and/or clinical implementation programs.
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DOI：
10.1146/annurev-pharmtox-010814-124835
发表时间：
2015
影响因子：
12.5
作者：
Dunnenberger HM;Crews KR;Hoffman JM;Caudle KE;Broeckel U;Howard SC;Hunkler RJ;Klein TE;Evans WE;Relling MV
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影响因子：
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DOI：
10.1038/tpj.2014.27
发表时间：
2014-12
期刊：
The pharmacogenomics journal
影响因子：
--
作者：
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影响因子：
4.1
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影响因子：
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