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

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.

Denaturing high-performance liquid chromatography screening of the long QT syndrome-related cardiac sodium and potassium channel genes and identification of novel mutations and single nucleotide polymorphisms

“…Mutations with minor functional changes are compatible with normal life and torsades des pointes happen only upon use of offending agents. Past research targeted at identifying variations in all LQT genes has demonstrated that 5-15% of patients have minor mutations in these long QT genes (Paulussen et al 2004). In a large-scale screening study of 95 patients, Yang et al (2002) reported that the incidence of SCN5A SNPs was not significantly different between patients and a control group.…”

“…KCNQ1 is also responsible for familial atrial fibrillation, while SCN5A mutations are responsible for Brugada syndrome, congenital cardiac conduction defect and sudden infant death syndrome (Priori 2004). Mutations in these genes might also be responsible for drug-induced LQTS (Paulussen et al 2004).…”

HERG Is Protected from Pharmacological Block by α-1,2-Glucosyltransferase Function

“…It is now recognized that aLQTS has a genetic component, as patients with increased vulnerability for the syndrome and carrying mutations in LQTS-linked genes have been identified (11). However, not all family members who carry specific gene mutations develop aLQTS, suggesting "incomplete penetrance" and implying that hidden factors influence the pathology in individual patients (37).…”

Atrio-Ventricular Block-Induced Torsades de Pointes: An Update

“…Polymorphisms that confer susceptibility to the development of ventricular arrhythmia have also been documented in sodium channel Na1.5. This is the case of the H558R polymorphism (Viswanathan, 2003), which is present in up to 30% of the population, or S1103Y, found mainly in blacks, with an incidence of nearly 13%, and associated with an increased risk of sudden death in childhood (Splawski, 2002, Paulussen, 2004. Most of these DNA polymorphisms do not occur in coding regions and may either have no functional significance, or modulate expression levels of functionally normal proteins.…”