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Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes

Although several pharmacogenetic (PGx) predispositions affecting drug efficacy and safety are well established, drug selection and dosing as well as clinical trials are often performed in a non-pharmacogenetically-stratified manner, ultimately burdening healthcare systems. Pre-emptive PGx testing of...

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Autores principales: Caspar, Sylvan M., Schneider, Timo, Meienberg, Janine, Matyas, Gabor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178228/
https://www.ncbi.nlm.nih.gov/pubmed/32225115
http://dx.doi.org/10.3390/ijms21072308
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author Caspar, Sylvan M.
Schneider, Timo
Meienberg, Janine
Matyas, Gabor
author_facet Caspar, Sylvan M.
Schneider, Timo
Meienberg, Janine
Matyas, Gabor
author_sort Caspar, Sylvan M.
collection PubMed
description Although several pharmacogenetic (PGx) predispositions affecting drug efficacy and safety are well established, drug selection and dosing as well as clinical trials are often performed in a non-pharmacogenetically-stratified manner, ultimately burdening healthcare systems. Pre-emptive PGx testing offers a solution which is often performed using microarrays or targeted gene panels, testing for common/known PGx variants. However, as an added value, whole-genome sequencing (WGS) could detect not only disease-causing but also pharmacogenetically-relevant variants in a single assay. Here, we present our WGS-based pipeline that extends the genetic testing of Mendelian diseases with PGx profiling, enabling the detection of rare/novel PGx variants as well. From our in-house WGS (PCR-free 60× PE150) data of 547 individuals we extracted PGx variants with drug-dosing recommendations of the Dutch Pharmacogenetics Working Group (DPWG). Furthermore, we explored the landscape of DPWG pharmacogenes in gnomAD and our in-house cohort as well as compared bioinformatic tools for WGS-based structural variant detection in CYP2D6. We show that although common/known PGx variants comprise the vast majority of detected DPWG pharmacogene alleles, for better precision medicine, PGx testing should move towards WGS-based approaches. Indeed, WGS-based PGx profiling is not only feasible and future-oriented but also the most comprehensive all-in-one approach without generating significant additional costs.
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spelling pubmed-71782282020-04-28 Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes Caspar, Sylvan M. Schneider, Timo Meienberg, Janine Matyas, Gabor Int J Mol Sci Article Although several pharmacogenetic (PGx) predispositions affecting drug efficacy and safety are well established, drug selection and dosing as well as clinical trials are often performed in a non-pharmacogenetically-stratified manner, ultimately burdening healthcare systems. Pre-emptive PGx testing offers a solution which is often performed using microarrays or targeted gene panels, testing for common/known PGx variants. However, as an added value, whole-genome sequencing (WGS) could detect not only disease-causing but also pharmacogenetically-relevant variants in a single assay. Here, we present our WGS-based pipeline that extends the genetic testing of Mendelian diseases with PGx profiling, enabling the detection of rare/novel PGx variants as well. From our in-house WGS (PCR-free 60× PE150) data of 547 individuals we extracted PGx variants with drug-dosing recommendations of the Dutch Pharmacogenetics Working Group (DPWG). Furthermore, we explored the landscape of DPWG pharmacogenes in gnomAD and our in-house cohort as well as compared bioinformatic tools for WGS-based structural variant detection in CYP2D6. We show that although common/known PGx variants comprise the vast majority of detected DPWG pharmacogene alleles, for better precision medicine, PGx testing should move towards WGS-based approaches. Indeed, WGS-based PGx profiling is not only feasible and future-oriented but also the most comprehensive all-in-one approach without generating significant additional costs. MDPI 2020-03-26 /pmc/articles/PMC7178228/ /pubmed/32225115 http://dx.doi.org/10.3390/ijms21072308 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Caspar, Sylvan M.
Schneider, Timo
Meienberg, Janine
Matyas, Gabor
Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes
title Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes
title_full Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes
title_fullStr Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes
title_full_unstemmed Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes
title_short Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes
title_sort added value of clinical sequencing: wgs-based profiling of pharmacogenes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178228/
https://www.ncbi.nlm.nih.gov/pubmed/32225115
http://dx.doi.org/10.3390/ijms21072308
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