Development and Analytical Validation of a 29 Gene Clinical Pharmacogenetic Genotyping Panel: Multi-Ethnic Allele and Copy Number Variant Detection.

Autor: Scott SA; Sema4, Stamford, Connecticut, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Scott ER; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Seki Y; Sema4, Stamford, Connecticut, USA., Chen AJ; Sema4, Stamford, Connecticut, USA., Wallsten R; Sema4, Stamford, Connecticut, USA., Owusu Obeng A; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Botton MR; Sema4, Stamford, Connecticut, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Cody N; Sema4, Stamford, Connecticut, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Shi H; Sema4, Stamford, Connecticut, USA., Zhao G; Sema4, Stamford, Connecticut, USA., Brake P; Sema4, Stamford, Connecticut, USA., Nicoletti P; Sema4, Stamford, Connecticut, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Yang Y; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Delio M; Sema4, Stamford, Connecticut, USA., Shi L; Sema4, Stamford, Connecticut, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Kornreich R; Sema4, Stamford, Connecticut, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Schadt EE; Sema4, Stamford, Connecticut, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Edelmann L; Sema4, Stamford, Connecticut, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Jazyk: angličtina
Zdroj: Clinical and translational science [Clin Transl Sci] 2021 Jan; Vol. 14 (1), pp. 204-213. Date of Electronic Publication: 2020 Aug 05.
DOI: 10.1111/cts.12844
Abstrakt: 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.
(© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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