Targeted next generation sequencing as a tool for precision medicine

被引：66

作者：

Gulilat, Markus ^{[1
,2
]}

Lamb, Tyler ^{[2
]}

Teft, Wendy A. ^{[1
]}

Wang, Jian ^{[3
]}

Dron, Jacqueline S. ^{[3
]}

Robinson, John F. ^{[3
]}

Tirona, Rommel G. ^{[1
,2
]}

Hegele, Robert A. ^{[3
]}

Kim, Richard B. ^{[1
,2
]}

Schwarz, Ute I. ^{[1
]}

机构：

[1] Western Univ, London Hlth Sci Ctr, Univ Hosp, Div Clin Pharmacol,Dept Med, 339 Windermere Rd, London, ON N6A 5A5, Canada

[2] Western Univ, Dept Physiol & Pharmacol, Med Sci Bldg,Room 216, London, ON N6A 5C1, Canada

[3] Western Univ, Robarts Res Inst, 1151 Richmond St N, London, ON N6A 5B7, Canada

来源：

BMC MEDICAL GENOMICS | 2019年 / 12卷 / 1期

基金：

加拿大健康研究院;

关键词：

Targeted exome sequencing; Next generation sequencing; Pharmacogenes; Copy number variation; In silico prediction; IMPLEMENTATION CONSORTIUM GUIDELINES; THIOPURINE METHYLTRANSFERASE GENOTYPE; GENETIC-VARIATION; CPIC GUIDELINE; CYP2C19; GENOTYPE; RARE; VARIANTS; PANEL; PHARMACOGENOMICS; POLYMORPHISMS;

D O I：

10.1186/s12920-019-0527-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

BackgroundTargeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)(7) TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1*28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response.MethodsA panel of capture probes was generated to assess 422kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms.ResultsAdequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC)20x for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1*28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy.ConclusionsPGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine.

引用

页数：17

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