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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2012
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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. |
format | Online Article Text |
id | pubmed-3422407 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
record_format | MEDLINE/PubMed |
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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