Exome sequencing allows detection of relevant pharmacogenetic variants in epileptic patients

ABSTRACT Beyond the identification of causal genetic variants in the diagnosis of Mendelian disorders, exome sequencing can detect numerous variants with potential relevance for clinical

care. Clinical interventions can thus be conducted to improve future health outcomes for patients and their at-risk relatives, such as predicting late-onset genetic disorders accessible to

prevention, treatment or identifying differential drug efficacy and safety. To evaluate the interest of such pharmacogenetic information, we designed an “in house” pipeline to determine the

status of 122 PharmGKB (Pharmacogenomics Knowledgebase) variant-drug combinations in 31 genes. This pipeline was applied to a cohort of 90 epileptic patients who had previously an exome

sequencing (ES) analysis, to determine the frequency of pharmacogenetic variants. We performed a retrospective analysis of drug plasma concentrations and treatment efficacy in patients

bearing at least one relevant PharmGKB variant. For PharmGKB level 1A variants, _CYP2C9_ status for phenytoin prescription was the only relevant information. Nineteen patients were treated

with phenytoin, among phenytoin-treated patients, none were poor metabolizers and four were intermediate metabolizers. While being treated with a standard protocol (10–23 mg/kg/30 min

loading dose followed by 5 mg/kg/8 h maintenance dose), all identified intermediate metabolizers had toxic plasma concentrations (20 mg/L). In epileptic patients, pangenomic sequencing can

provide information about common pharmacogenetic variants likely to be useful to guide therapeutic drug monitoring, and in the case of phenytoin, to prevent clinical toxicity caused by high

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Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS CLINICAL PHARMACOGENETIC ANALYSIS IN 5,001 INDIVIDUALS WITH DIAGNOSTIC EXOME SEQUENCING DATA Article Open access 18 February

2022 DEVELOPMENT OF AN EXTENSIVE WORKFLOW FOR COMPREHENSIVE CLINICAL PHARMACOGENOMIC PROFILING: LESSONS FROM A PILOT STUDY ON 100 WHOLE EXOME SEQUENCING DATA Article Open access 13 August

2022 A CALL FOR INCREASED INCLUSIVITY AND GLOBAL REPRESENTATION IN PHARMACOGENETIC TESTING Article Open access 22 February 2024 DATA AVAILABILITY For data sharing requests, please contact SV

or YD at [email protected] or [email protected] respectively. CODE AVAILABILITY Code is available at the following link:

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Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank the University of Burgundy Centre de Calcul (CCuB) for providing technical support and management of the

informatics platform. This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR) and the European Union through the FEDER programs. The funders had no role in

study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Suzanne Rankin from the Dijon University Hospital, Nicole Dorssers from

simon fraser university and Cynthia Reichling for proofreading the manuscript. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon,

France Simon Verdez, Quentin Thomas, Philippine Garret, Emilie Tisserant, Antonio Vitobello, Frédéric Tran Mau-Them, Christophe Philippe, Patrick Callier, Christel Thauvin-Robinet, Laurence

Faivre & Yannis Duffourd * Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France Simon Verdez, Quentin Thomas, 

Philippine Garret, Emilie Tisserant, Antonio Vitobello, Frédéric Tran Mau-Them, Christophe Philippe, Patrick Callier, Christel Thauvin-Robinet & Yannis Duffourd * Laboratoire CERBA,

Saint-Ouen l’Aumone, France Philippine Garret * Université Paris-Saclay, Inserm, CESP, Team MOODS, Faculté de médecine, 94270, Le Kremlin-Bicêtre, Paris, France Céline Verstuyft * CHU de

Dijon, Centre d’Investigation Clinique, module plurithématique, 21000, Dijon, France Marc Bardou & Maxime Luu * CHU de Dijon, Centre d’Investigation Clinique, module Epidémiologie

Clinique/Essais cliniques, 21000, Dijon, France Marc Bardou, Maxime Luu & Abderrahmane Bourredjem * Inserm CIC1432, 21000, Dijon, France Abderrahmane Bourredjem * Centre de référence

maladies rares « déficiences intellectuelles de causes rares », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France Christel Thauvin-Robinet * Centre de Référence maladies

rares « Anomalies du Développement et syndromes malformatifs », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France Christel Thauvin-Robinet & Laurence Faivre * Inserm

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inPubMed Google Scholar * Yannis Duffourd View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS SV, PG, LF, NP and YD designed the study. SV, QT

performed the clinical analysis. AV, FTMT, CP, interpreted exome data. FTMT, AV and CP performed the molecular laboratory work. SV, YD and ET performed the bioinformatics analysis. All the

authors contributed to the writing and review of the paper. CORRESPONDING AUTHORS Correspondence to Simon Verdez or Yannis Duffourd. ETHICS DECLARATIONS COMPETING INTERESTS The authors

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SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURE 1 TABLE S1 TABLE S2 TABLE S3 TABLE S4 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Verdez, S., Thomas,

Q., Garret, P. _et al._ Exome sequencing allows detection of relevant pharmacogenetic variants in epileptic patients. _Pharmacogenomics J_ 22, 258–263 (2022).

https://doi.org/10.1038/s41397-022-00280-w Download citation * Received: 03 June 2021 * Revised: 28 April 2022 * Accepted: 09 May 2022 * Published: 19 May 2022 * Issue Date: December 2022 *

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