Targeted next generation sequencing as a tool for precision medicine

Background Targeted 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...

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Veröffentlicht in:BMC medical genomics Jg. 12; H. 1; S. 81 - 17
Hauptverfasser: Gulilat, Markus, Lamb, Tyler, Teft, Wendy A., Wang, Jian, Dron, Jacqueline S., Robinson, John F., Tirona, Rommel G., Hegele, Robert A., Kim, Richard B., Schwarz, Ute I.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London BioMed Central 03.06.2019
BioMed Central Ltd
Springer Nature B.V
BMC
Schlagworte:
Adult
Algorithms
Alleles
Anticoagulants
Bioinformatics
Biomarkers
Biomedical and Life Sciences
Biomedicine
Child
Computational biology
Computer Simulation
Consortia
Copy number
Copy number variation
CYP2D6 protein
Cytochrome
Cytochrome P-450
Cytochrome P-450 CYP2D6 - genetics
Cytochrome P450
Data processing
Deoxyribonucleic acid
DNA
DNA Copy Number Variations
DNA probes
DNA sequencing
Drug dosages
Drug therapy
Enzymes
Gene Expression
Gene frequency
Gene polymorphism
Genes
Genetic diversity
Genetic variation
Genomes
Genomics
Genotype & phenotype
Genotyping
Glucuronosyltransferase
Glucuronosyltransferase - genetics
High-Throughput Nucleotide Sequencing
Homology
Human Genetics
Humans
In silico prediction
Metabolism
Microarrays
Molecular Sequence Annotation
Next generation sequencing
Novels
Pediatrics
Pharmacogenes
Polymorphism
Population genetics
Precision medicine
Precision Medicine - methods
Prognostics and diagnostics/biomarkers
Pseudogenes
Targeted exome sequencing
Technical Advance
Pharmacogenes
Copy number variation
Next generation sequencing
Targeted exome sequencing
In silico prediction
ISSN:1755-8794, 1755-8794
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Zusammenfassung:Background Targeted 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. Methods A panel of capture probes was generated to assess 422 kb 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. Results Adequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× 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. Conclusions PGxSeq 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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:1755-8794
1755-8794
DOI:10.1186/s12920-019-0527-2