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Novel rare variants in congenital cardiac arrhythmia genes are frequent in drug-induced torsades de pointes

The Pharmacogenomics Journal volume 13, pages 325–329 (2013)Cite this article

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Abstract

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 is 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 with 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 the 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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Acknowledgements

We thank the NHLBI GO Exome Sequencing Project and its ongoing studies that produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). We also thank Kris Norris for patient enrollment, Christie Ingram for project management, Eric Torstenson for C++ programming and Laura Short in the Sanger sequencing core facility. Funding for this study was provided by U01 HL65962 and GM007569 from the National Institutes of Health and by a trans-Atlantic network alliance grant from the Fondation Leducq (‘Preventing Sudden Cardiac Death’).

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Authors and Affiliations

  1. Department of Medicine, Vanderbilt University, Nashville, TN, USA

    A H Ramirez, J T Delaney, A L George Jr & D M Roden

  2. Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA

    C M Shaffer & D P Sexton

  3. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA

    S E Levy

  4. HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA

    S E Levy

  5. Department of Genome Sciences, University of Washington, Seattle, WA, USA

    M J Rieder & D A Nickerson

  6. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    A L George Jr & D M Roden

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  1. A H Ramirez
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Correspondence to D M Roden.

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Competing interests

Drs George and Roden have received royalties for a US Letters Patent No. 6 458 542, issued 1 October 2002 for ‘Method of Screening for Susceptibility to Drug-Induced Cardiac Arrhythmia’.

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Ramirez, A., Shaffer, C., Delaney, J. et al. Novel rare variants in congenital cardiac arrhythmia genes are frequent in drug-induced torsades de pointes. Pharmacogenomics J 13, 325–329 (2013). https://doi.org/10.1038/tpj.2012.14

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