Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients
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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.
KeywordsLong QT syndrome Drug-induced Arrhythmia Mutation analysis
Congenital long QT syndrome
Acquired long QT syndrome
Torsade de pointes
Polymerase chain reaction
We thank Rosemary Zvonar (Department of Pharmaceutical Services, The Ottawa Hospital, Canada) for providing a patient sample. E. Schulze-Bahr and W. Haverkamp are supported by grants from the Deutsche Forschungsgemeinschaft (grants Schu1082/2–2 and SFB556-A1) and the Fondation Leducq (France). P. Doevendans is supported by the Interuniversitary Cardiology Institute (The Netherlands).
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