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Novel Rare Variants in Congenital Cardiac Arrhythmia Genes are Frequent in Drug-induced Torsades de Pointes

Marked prolongation of the QT interval and polymorphic ventricular tachycardia following medication (drug-induced long QT syndrome, diLQTS) is a severe adverse drug reaction (ADR) that phenocopies congenital long QT syndrome (cLQTS) and one of the leading causes for drug withdrawal and relabeling. W...

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Autores principales: Ramirez, Andrea H., Shaffer, Christian M., Delaney, Jessica T., Sexton, David P., Levy, Shawn E., Rieder, Mark J., Nickerson, Deborah A., George, Alfred L., Roden, Dan M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422407/
https://www.ncbi.nlm.nih.gov/pubmed/22584458
http://dx.doi.org/10.1038/tpj.2012.14
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author Ramirez, Andrea H.
Shaffer, Christian M.
Delaney, Jessica T.
Sexton, David P.
Levy, Shawn E.
Rieder, Mark J.
Nickerson, Deborah A.
George, Alfred L.
Roden, Dan M.
author_facet Ramirez, Andrea H.
Shaffer, Christian M.
Delaney, Jessica T.
Sexton, David P.
Levy, Shawn E.
Rieder, Mark J.
Nickerson, Deborah A.
George, Alfred L.
Roden, Dan M.
author_sort Ramirez, Andrea H.
collection PubMed
description Marked prolongation of the QT interval and polymorphic ventricular tachycardia following medication (drug-induced long QT syndrome, diLQTS) is a severe adverse drug reaction (ADR) that phenocopies congenital long QT syndrome (cLQTS) and one of the leading causes for drug withdrawal and relabeling. We evaluated the frequency of rare non-synonymous variants in genes contributing to the maintenance of heart rhythm in cases of diLQTS using targeted capture coupled to next generation sequencing. Eleven of 31 diLQTS subjects (36%) carried a novel missense mutation in genes with known congenital arrhythmia associations or a known cLQTS mutation. In the 26 Caucasian subjects, 23% carried a highly conserved rare variant predicted to be deleterious to protein function in these genes compared with only 2-4% in public databases (p < 0.003). We conclude that rare variation in genes responsible for congenital arrhythmia syndromes is frequent in diLQTS. Our findings demonstrate that diLQTS is a pharmacogenomic syndrome predisposed by rare genetic variants.
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spelling pubmed-34224072014-02-01 Novel Rare Variants in Congenital Cardiac Arrhythmia Genes are Frequent in Drug-induced Torsades de Pointes Ramirez, Andrea H. Shaffer, Christian M. Delaney, Jessica T. Sexton, David P. Levy, Shawn E. Rieder, Mark J. Nickerson, Deborah A. George, Alfred L. Roden, Dan M. Pharmacogenomics J Article Marked prolongation of the QT interval and polymorphic ventricular tachycardia following medication (drug-induced long QT syndrome, diLQTS) is a severe adverse drug reaction (ADR) that phenocopies congenital long QT syndrome (cLQTS) and one of the leading causes for drug withdrawal and relabeling. We evaluated the frequency of rare non-synonymous variants in genes contributing to the maintenance of heart rhythm in cases of diLQTS using targeted capture coupled to next generation sequencing. Eleven of 31 diLQTS subjects (36%) carried a novel missense mutation in genes with known congenital arrhythmia associations or a known cLQTS mutation. In the 26 Caucasian subjects, 23% carried a highly conserved rare variant predicted to be deleterious to protein function in these genes compared with only 2-4% in public databases (p < 0.003). We conclude that rare variation in genes responsible for congenital arrhythmia syndromes is frequent in diLQTS. Our findings demonstrate that diLQTS is a pharmacogenomic syndrome predisposed by rare genetic variants. 2012-05-15 2013-08 /pmc/articles/PMC3422407/ /pubmed/22584458 http://dx.doi.org/10.1038/tpj.2012.14 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Ramirez, Andrea H.
Shaffer, Christian M.
Delaney, Jessica T.
Sexton, David P.
Levy, Shawn E.
Rieder, Mark J.
Nickerson, Deborah A.
George, Alfred L.
Roden, Dan M.
Novel Rare Variants in Congenital Cardiac Arrhythmia Genes are Frequent in Drug-induced Torsades de Pointes
title Novel Rare Variants in Congenital Cardiac Arrhythmia Genes are Frequent in Drug-induced Torsades de Pointes
title_full Novel Rare Variants in Congenital Cardiac Arrhythmia Genes are Frequent in Drug-induced Torsades de Pointes
title_fullStr Novel Rare Variants in Congenital Cardiac Arrhythmia Genes are Frequent in Drug-induced Torsades de Pointes
title_full_unstemmed Novel Rare Variants in Congenital Cardiac Arrhythmia Genes are Frequent in Drug-induced Torsades de Pointes
title_short Novel Rare Variants in Congenital Cardiac Arrhythmia Genes are Frequent in Drug-induced Torsades de Pointes
title_sort novel rare variants in congenital cardiac arrhythmia genes are frequent in drug-induced torsades de pointes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422407/
https://www.ncbi.nlm.nih.gov/pubmed/22584458
http://dx.doi.org/10.1038/tpj.2012.14
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