Original Article

Journal of Molecular Medicine

, Volume 82, Issue 3, pp 182-188

First online:

Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients

  • Aimée D. C. PaulussenAffiliated withDepartment of Pharmacogenomics, Johnson & Johnson Pharmaceutical Research and Development
  • , Ronaldus A. H. J. GilissenAffiliated withDepartment of Pharmacogenomics, Johnson & Johnson Pharmaceutical Research and Development
  • , Martin ArmstrongAffiliated withDepartment of Pharmacogenomics, Johnson & Johnson Pharmaceutical Research and Development
  • , Pieter A. DoevendansAffiliated withDepartment of Cardiology, Academic Hospital
  • , Peter VerhasseltAffiliated withDepartment of Functional Genomics, Johnson & Johnson Pharmaceutical Research and Development
  • , Hubert J. M. SmeetsAffiliated withDepartment of Genetics and Cell Biology, Cardiovascular Research Institute Maastricht (CARIM)
  • , Eric Schulze-BahrAffiliated withDepartment of Cardiology and Angiology, Hospital of the Westfalian Wilhelms-University, Institute for Arteriosclerosis Research, University of Münster
  • , Wilhelm HaverkampAffiliated withDepartment of Cardiology and Angiology, Hospital of the Westfalian Wilhelms-University, Institute for Arteriosclerosis Research, University of Münster
  • , Günter BreithardtAffiliated withDepartment of Cardiology and Angiology, Hospital of the Westfalian Wilhelms-University, Institute for Arteriosclerosis Research, University of Münster
    • , Nadine CohenAffiliated withDepartment of Pharmacogenomics, Johnson & Johnson Pharmaceutical Research and Development
    • , Jeroen AerssensAffiliated withDepartment of Pharmacogenomics, Johnson & Johnson Pharmaceutical Research and Development Email author 

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Abstract

Administration of specific drugs may occasionally induce acquired long QT syndrome (aLQTS), a disorder that predisposes to ventricular arrhythmias, typically of the torsade de pointes (TdP) type, and sudden cardiac death. “Forme fruste” mutations in congenital LQTS (cLQTS) genes have been reported repeatedly as the underlying cause of aLQTS, and are therefore considered as an important risk factor. We evaluated the impact of genetic susceptibility for aLQTS through mutations in cLQTS genes. Five cLQTS genes (KCNH2, KCNQ1, SCN5A, KCNE1, KCNE2) were thoroughly screened for genetic variations in 32 drug-induced aLQTS patients with confirmed TdP and 32 healthy individuals. Missense forme frust mutations were identified in four aLQTS patients: D85N in KCNE1 (two cases), T8A in KCNE2, and P347S in KCNH2. Three other missense variations were found both in patients and controls, and are thus unlikely to significantly influence aLQTS susceptibility. In addition, 13 silent and six intronic variations were detected, four of which were found in a single aLQTS patient but not in the controls. We conclude that missense mutations in the examined cLQTS genes explain only a minority of aLQTS cases.

Keywords

Long QT syndrome Drug-induced Arrhythmia Mutation analysis