Arrhythmia Risk in Long QT Syndrome

Abstract

Congenital long QT syndrome (LQTS) is a genetically heterogeneous disorder of myocardial repolarization that affects an estimated 1:2000 individuals and often manifests clinically as a prolonged heart rate–corrected QT interval (QTc) on ECG and as an increased proclivity for torsadogenic-mediated syncope, seizures, and sudden death.1 From a genetic perspective, LQTS has been considered classically an autosomal dominant genetic disorder, with heterozygous mutations in the 3 major LQTS-susceptibility genes accounting for ≈75% of clinically robust, nonsyndromic LQTS cases ( KCNQ1 /LQT1, 30%–35%; KCNH2 /LQT2, 25%–30%, and SCN5A /LQT3, 5%–10%).2,3 However, since the identification of the 3 major LQTS-susceptibility genes in 1995 and 1996, it has become clear that LQTS, like many other monogenic/Mendelian disorders, is at best described as an autosomal dominant disorder with marked incomplete penetrance and variable expressivity whereby related individuals who harbor the same LQTS-causative mutation often assume vastly different clinical courses in terms of QTc duration and frequency of cardiac events.4 Article see p 354 In retrospect, strong evidence for this extensive phenotypic variability in LQTS was encountered long before the specific ion channel genes were implicated in the pathogenesis of the disorder. In 1992, 4 years before KCNQ1 was identified as the culprit, LQT1-causative gene residing within the chromosome 11p15.5 genetic locus, Vincent et al5 described both a significant overlap in the range of QTc values between 11p15.5 locus carriers (410–590 ms; mean, 490 ms) and noncarriers (380–470 ms; mean, 420 ms) and marked variability in the frequency and severity of cardiac events between carriers of the same 11p genetic marker (63% with syncope; 5% with sudden cardiac arrest).4 Subsequent studies, including those involving large founder populations such as the South African KCNQ1-A341V LQT1 kindred, went on to demonstrate that few LQTS-causative mutations completely escape the genetic phenomena of incomplete …