Arrhythmia Risk in Long QT Syndrome

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.4Article see p 354In 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 …