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ClinPharmSeq: A targeted sequencing panel for clinical pharmacogenetics implementation

The accurate identification of genetic variants contributing to therapeutic drug response or adverse effects is the first step in implementation of precision drug therapy. Targeted sequencing has recently become a common methodology for large-scale studies of genetic variation thanks to its favorabl...

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Autores principales: Lee, Seung-been, Shin, Jong-Yeon, Kwon, Nak-Jung, Kim, Changhoon, Seo, Jeong-Sun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9333201/
https://www.ncbi.nlm.nih.gov/pubmed/35901010
http://dx.doi.org/10.1371/journal.pone.0272129
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author Lee, Seung-been
Shin, Jong-Yeon
Kwon, Nak-Jung
Kim, Changhoon
Seo, Jeong-Sun
author_facet Lee, Seung-been
Shin, Jong-Yeon
Kwon, Nak-Jung
Kim, Changhoon
Seo, Jeong-Sun
author_sort Lee, Seung-been
collection PubMed
description The accurate identification of genetic variants contributing to therapeutic drug response or adverse effects is the first step in implementation of precision drug therapy. Targeted sequencing has recently become a common methodology for large-scale studies of genetic variation thanks to its favorable balance between low cost, high throughput, and deep coverage. Here, we present ClinPharmSeq, a targeted sequencing panel of 59 genes with associations to pharmacogenetic (PGx) phenotypes, as a platform to explore the relationship between drug response and genetic variation, both common and rare. For validation, we sequenced DNA from 64 ethnically diverse Coriell samples with ClinPharmSeq to call star alleles (haplotype patterns) in 27 genes using the bioinformatics tool PyPGx. These reference samples were extensively characterized by multiple laboratories using PGx testing assays and, more recently, whole genome sequencing. We found that ClinPharmSeq can consistently generate deep-coverage data (mean = 274x) with high uniformity (30x or above = 94.8%). Our genotype analysis identified a total of 185 unique star alleles from sequencing data, and showed that diplotype calls from ClinPharmSeq are highly concordant with that from previous publications (97.6%) and whole genome sequencing (97.9%). Notably, all 19 star alleles with complex structural variation including gene deletions, duplications, and hybrids were recalled with 100% accuracy. Altogether, these results demonstrate that the ClinPharmSeq platform offers a feasible path for broad implementation of PGx testing and optimization of individual drug treatments.
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spelling pubmed-93332012022-07-29 ClinPharmSeq: A targeted sequencing panel for clinical pharmacogenetics implementation Lee, Seung-been Shin, Jong-Yeon Kwon, Nak-Jung Kim, Changhoon Seo, Jeong-Sun PLoS One Research Article The accurate identification of genetic variants contributing to therapeutic drug response or adverse effects is the first step in implementation of precision drug therapy. Targeted sequencing has recently become a common methodology for large-scale studies of genetic variation thanks to its favorable balance between low cost, high throughput, and deep coverage. Here, we present ClinPharmSeq, a targeted sequencing panel of 59 genes with associations to pharmacogenetic (PGx) phenotypes, as a platform to explore the relationship between drug response and genetic variation, both common and rare. For validation, we sequenced DNA from 64 ethnically diverse Coriell samples with ClinPharmSeq to call star alleles (haplotype patterns) in 27 genes using the bioinformatics tool PyPGx. These reference samples were extensively characterized by multiple laboratories using PGx testing assays and, more recently, whole genome sequencing. We found that ClinPharmSeq can consistently generate deep-coverage data (mean = 274x) with high uniformity (30x or above = 94.8%). Our genotype analysis identified a total of 185 unique star alleles from sequencing data, and showed that diplotype calls from ClinPharmSeq are highly concordant with that from previous publications (97.6%) and whole genome sequencing (97.9%). Notably, all 19 star alleles with complex structural variation including gene deletions, duplications, and hybrids were recalled with 100% accuracy. Altogether, these results demonstrate that the ClinPharmSeq platform offers a feasible path for broad implementation of PGx testing and optimization of individual drug treatments. Public Library of Science 2022-07-28 /pmc/articles/PMC9333201/ /pubmed/35901010 http://dx.doi.org/10.1371/journal.pone.0272129 Text en © 2022 Lee et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Lee, Seung-been
Shin, Jong-Yeon
Kwon, Nak-Jung
Kim, Changhoon
Seo, Jeong-Sun
ClinPharmSeq: A targeted sequencing panel for clinical pharmacogenetics implementation
title ClinPharmSeq: A targeted sequencing panel for clinical pharmacogenetics implementation
title_full ClinPharmSeq: A targeted sequencing panel for clinical pharmacogenetics implementation
title_fullStr ClinPharmSeq: A targeted sequencing panel for clinical pharmacogenetics implementation
title_full_unstemmed ClinPharmSeq: A targeted sequencing panel for clinical pharmacogenetics implementation
title_short ClinPharmSeq: A targeted sequencing panel for clinical pharmacogenetics implementation
title_sort clinpharmseq: a targeted sequencing panel for clinical pharmacogenetics implementation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9333201/
https://www.ncbi.nlm.nih.gov/pubmed/35901010
http://dx.doi.org/10.1371/journal.pone.0272129
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