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

A. H. Ramirez, C. M. Shaffer, J. T. Delaney, D. P. Sexton, S. E. Levy, M. J. Rieder, D. A. Nickerson, A. L. George, D. M. Roden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)325-329
Number of pages5
JournalPharmacogenomics Journal
Volume13
Issue number4
DOIs
StatePublished - Aug 2013

Keywords

  • Adverse drug reaction
  • Next-generation sequencing
  • Sudden cardiac death

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

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