Since the initial description of congenital deafness, prolongation of the QT interval, and sudden death by Jervell and Lange-Nielsen in 1957 (3), our understanding of the genetic basis of the congenital LQTS has progressed significantly. Shortly after the autosomal recessive Jervell-Lange-Nielsen syndrome was described, Romano and Ward each independently described an “autosomal dominant” form without congenital deafness (4,5). The findings that the QT interval could be prolonged by right stellectomy and the successful treatment of a medically refractory young patient with the LQTS by left stellectomy led to the hypothesis that the disease was primarily a disorder of cardiac sympathetic innervation (6). Although we now know that this is not the primary cause of the LQTS, the importance of these early observations is evident in that autonomic modulation remains an important therapeutic approach in patients with this syndrome.

The subsequent theory that the underlying cause of the LQTS was an alteration of one of the repolarizing K currents was proposed nearly 10 years before the identification of the first LQTS genes in 1995 (1,2,7,8). Indeed, four forms of the LQTS, and the two most common forms (LQT1 and LQT2), are caused by mutations in genes that encode proteins that form repolarizing K channels. In the late 1990s, the first five LQTS genes were identified (see Table 58.1), all of which encoded proteins that form ion channels underlying the cardiac action potential (Fig. 58.1). The most commonly identified genes, KCNQ1 and KCNH2, encode proteins that form the α-subunits of two major repolarizing K currents, I_Ks and I_Kr. Two other LQTS genes encode for the corresponding β-subunits (KCNE1 and KCNE2). The other major LQTS gene, SCN5A, encodes the α-subunit of the cardiac Na channel. Either loss-of-function mutations in K channel genes or gain-of-function mutations in the cardiac Na or Ca channels lead to prolongation of ventricular repolarization and therefore a prolonged QT interval. Furthermore, we now know that the Jervell-Lange-Nielsen syndrome is simply a more severe form of the LQTS, because patients with Romano-Ward syndrome carry a single mutation, whereas it is now accepted that homozygous mutations of KCNQ1 or KCNE1 cause Jervell-Lange-Nielsen syndrome (Fig. 58.2) (9,10). The extracardiac finding of congenital deafness requires the presence of two mutant alleles and results from lack of functioning I_Ks in the inner ear (11). Patients with Jervell-Lange-Nielsen syndrome are also thought to be highly susceptible to arrhythmias; thus, arrhythmia risk seems partly dependent on “gene dosage.” These first five forms of the LQTS represent classic LQTS, in that single mutations in ion channel genes resulted in action potential prolongation and prolonged QT intervals, with an increased risk for torsades de pointes and sudden death, without significant extracardiac manifestations.

With the finding of ANK2 mutations underlying LQT4 (12), we find that the spectrum of LQTS genes is not limited to genes that encode ion channel proteins. ANK2 encodes ankyrin-B, one isoform of a ubiquitously expressed family of proteins originally identified in the erythrocyte as a link between membrane proteins. Cardiomyocytes heterozygous for a null mutation in ankyrin-B display reduced expression and abnormal localization of the Na/Ca exchanger, Na/K adenosine triphosphatase, and InsP₃ receptor, but normal expression and localization of other cardiac proteins, including the L-type Ca²⁺ channel and the cardiac Na⁺ channel (13). Action potential duration is normal, but myocytes display abnormalities in Ca homeostasis leading to early and delayed afterdepolarizations (12). Further clinical characterization of patients with ANK2 mutations reveals that although these patients are at risk for sudden death, they do not uniformly display prolonged QT intervals (13), a finding suggesting that ankyrin-B diseases are distinct from the LQTS (14). Andersen-Tawil syndrome (ATS), termed by some as LQT7 (15), is the result of mutations in KCNJ2 and is associated with significant extracardiac findings, including periodic paralysis, hypertelorism, and clinodactyly (16). Because many patients with ATS have mild or no prolongation of the QT interval, and the clinical manifestations, electrocardiographic (ECG) characteristics, and outcomes are quite different from those of the LQTS, it seems that ATS is not a subtype of the LQTS, and it has been recommended that the annotation of KCNJ2-positive ATS individuals should be ATS1 rather than LQT7 (17). Recently, mutations in the gene encoding the L-type Ca channel have been found to underlie Timothy syndrome, a rare multisystem disorder characterized by QT prolongation as well as syndactyly, autism, and immune deficiencies (18). This has been termed LQT8 (19), and it does cause a gain of function of I_Ca due to slowed inactivation, which directly prolongs the QT interval (see Fig. 58.1), similar to the other forms of the LQTS. However, the first described case of Timothy syndrome differs from classic forms of the LQTS in that it is associated with significant extracardiac manifestations. More recently, other Ca²⁺ channel gene (CACNA1C) mutations have been identified that increase the QT interval but result in less severe extracardiac manifestations (20).