Clinical presentation
The Long QT syndrome (LQTS) is an inherited arrhythmogenic disease occurring in the structurally normal heart that may cause sudden death and that usually manifests in children and teen-agers. The estimated prevalence of this disorder is between 1:10000 and 1:5000. Two major phenotypic variants have been originally described in the early sixties: one autosomal dominant (Romano Ward syndrome) and one rare autosomal recessive (Jervell and Lange-Nielsen syndrome) also presenting with sensorineural deafness.
Sporadic LQTS patients have also been clinically described. Molecular genetic has allowed to clarify that these patients may represent real "de novo" mutations but they may also be the only clinically affected subject in a family with low penetrance (Priori et al. ) or, probably in rare instances, they may derive from parental mosaicism (Miller et al).
The LQTS is caused by an abnormal cardiac excitability. As a results, the affected patients have prolonged repolarization (QT interval at the surface electrocardiogram), abnormal T wave morphology, and by life threatening cardiac arrhythmias (see here and here). The mean age of onset of symptoms (syncope or sudden death) is 12 years and earlier onset is usually associated with more severe form of the disease. Cardiac events are often precipitated by physical or emotional stress even if in a smaller subset of individuals cardiac events occur at rest (Schwartz et al). For this reason antiadrenergic intervention with beta blockers is the cornerstone of therapy in the LQTS. For patients unresponsive to this approach, ICD and/or cardiac sympathetic denervation were proposed. Very recently Priori et al. have a demonstrated that the response to beta blocker therapy is significantly modulated by the genotype and, specifically, the protection afforded by this approach is only partial for LQT2 and LQT3 patients.

Genetic bases and pathophysiology
As of today seven LQTS genes have been identified. The typical LQTS phenotype with or without deafness may be due to mutations in 5 different genes while two variants present QT interval prolongation in the context of a multiorgan disease (Andersen syndrome) or with peculiar electrocardiographic features (LQT4 - see below). The discovery of the genetic basis of LQTS started in the early nineties with the mapping of four LQTS loci on chromosomes 11, 3, 7 and 4. The genes for these loci have been subsequently identified as KCNQ1 (LQT1) KCNH2 (LQT2) and SCN5A (LQT3) . More recently mutations in two additional genes on chromosome 21, KCNE1 (LQT5) and KCNE2 (LQT6) were reported. All the LQT1-3 and LQT5-6 genes encode for cardiac ion channels subunits. The exception is represented by LQT4 caused by mutations in the ANK2 genes: an intracellular protein called Ankyrin B that is involved in ion channels anchoring to the cellular membrane (6).

LQT1, LQT5, JLN1 and JLN2
KCNQ1 (causing LQT1 and JLN1) and KCNE1 (causing LQT5 and JLN2) encode respectively for the alpha (KvLQT1) and the beta (MinK) subunits of the potassium channel conducting the IKs current, the slow component of the delayed rectifier current (IK) the major repolarising current during phase 3 of the cardiac action potential. In order to form a functional channel, KvLQT1 proteins form homotetramers and it must also co-assemble with mink subunits.
LQT1 is the most prevalent genetic form of LQTS accounting for approximately 50% of genotyped patients. Several different mutations have been reported and in vitro expression studies of mutated proteins suggested multiple biophysical consequences all of them ultimately inducing a loss of function (7). Homozygous or compound heterozygous mutations of KCNQ1 also cause Jervell and Lange-Nielsen form of LQTS (JLN1).
KCNE1 (LQT5) mutations are rather infrequent accounting approximately of 2-3% of genotyped LQTS patients and they may cause both Romano-Ward (LQT5) and, if homozygous, Jervell and Lange-Nielsen (JLN2).
From a clinical standpoint LQT1 patients are those presenting a more straightforward adrenergic trigger for cardiac events (Schwartz et al). LQT1 is also characterised by the lower penetrance and a more benign prognosis compared with LQT2 and LQT3 (Priori et al.) .

LQT2 and LQT6.
KCNH2 (LQT2) and KCNE2 (causing LQT6) gene encode respectively for the alpha (HERG) and the beta (MiRP) subunits of the potassium channel conducting the IKr current the rapid component of the cardiac delayed rectifier. The KCNH2 encoded protein, HERG, forms homotetramers in the plasmalemma in order to make up functional channels. The role or MiRP protein to recapitulate a fully operational current has been postulated but questioned by other authors. LQT2 is the second most common variant of LQTS accounting for 35%-40% of mutations. Functional expression studies have demonstrated that KCNH2 mutations cause a reduction of IKr current, but, similarly to LQT1 mutations, this effect is realized through different biophysical mechanisms and also though trafficking abnormalities of the mutant proteins. LQT2 is characterized by higher penetrance and severity than LQT1, especially for females (Priori et al.). Mutations in the KCNE2 gene cause the LQT6 variant of LQTS, which a very uncommon variant of the disease (<1%) and the associated phenotypes are characterised by incomplete penetrance and very mild manifestations.

SCN5A (LQT3)
SCN5A encodes for cardiac sodium channel conducting the sodium inward current (INa). At variance with KvLQT1 and HERG proteins mutation a single SCN5A transcript forms a fully functional channel protein (called Nav1.5) . The first reported SCN5A mutations were clustered in regions functionally associated with channel inactivation. Subsequently several allelic variants have been reported and functional expression studies showed that, at variance with LQT1 and LQT2-asociated mutations, LQT3 defects cause a gain of function with an increased INa (Napolitano et al). The prevalence of LQT3 among LQTS patient is estimated to be 10-15%, it is probably the more malignant form of LQTS and the one in which beta-blockers are less effective.

ANK2 (LQT4)

As of today, only one family linked to this locus (4q25-q27) has been reported. Of note, the phenotype of the LQT4 patients differs from the typical LQTS. Most of the affected individuals, besides, QT interval prolongation, also present with severe sinus bradycardia, paroxysmal atrial fibrillation (detected in >50% of the patients) and with polyphasic T waves. Recently, a missense mutation in the ANK2 gene was identified one family (Mohler et al). ANK2 encodes for an intracellular protein (Ankyrin B) that regulates the proper intracellular localization of plasmalemmal ion channels (calcium channel, sodium channel, sodium/calcium exchanger), sarcoplasmic reticulum channels (ryanodine receptor, inositol triphosphate receptor), and other adhesion molecules. The low number of LQT4 patients genotyped so far prevents the definition of prevalence (which appears low) and phenotypic features of this variant of LQTS. Additional ANKB mutations have been reported in patients with different forms of cardiac rhythm disturbances, thus further supporting the important role of this protein in the pathogenesis of cardiac arrhythmias.

Genotype-Phenotype correlation
In the last few years several studies have outlined the distinguishing features of the three most common genetic variants of LQTS (LQT1, LQT2, LQT3), which account for approximately 97% of all genotyped patients.
Gene-specific repolarization morphology and gene-specific triggers for cardiac events have been described. LQT1 patients usually develop symptoms during physical activity, conversely LQT3 have events at rest. Auditory stimuli and arousal are a relatively specific trigger for LQT2 patients while swimming is a predisposing setting for cardiac events in LQT1 patients.
Gene-specific differences of the natural history of LQTS have also been demonstrated and allow genotype-based risk stratification. Indeed, QT interval duration, genotype and gender are significantly associated with the outcome with a QTc interval >500ms, and a LQT2 or LQT3 genotype determining the worst prognosis. Gender modulated the differentially modulates the outcome according to the underlying genetic defect: the LQT3 males and LQT2 females are the highest risk subgroups (Priori et al.).

CACNA1c (LQT8 - Timothy syndrome)

Long QT syndrome type 8 (LQT8) is a rare variant of LQTS characterized by marked QT interval prolongation (often presenting with 2:1 functional atrioventricular block and macroscopic T wave alternans), and cutaneus syndactyly at both hands and feet. Severe prognosis has been observed in all cases described so far. All but one patients reported are sporadic. Ten of the 17 children with TS reported by Splawski et al in 2004, died, and the average age of death was 2.5 years. All affected individuals had severe prolongation of the QT interval on electrocardiogram, syndactyly, and abnormal teeth and were bald at birth. Arrhythmias were the most serious aspect of TS, and 12 of 17 children had life-threatening episodes. Individuals with TS also had congenital heart disease, including patent ductus arteriosus, patent foramen ovale, ventricular septal defects, and tetralogy of Fallot. Some children had dysmorphic facial features, including flat nasal bridge, small upper jaw, low-set ears, or small or misplaced teeth. Episodic serum hypocalcemia was described in 4 individuals. Many of the surviving children showed developmental delays consistent with language, motor, and generalized cognitive impairment.

Molecular screening of several cardiac ion channel encoding genes allowed the identification of a missense mutation (G406R) in the voltage-gated calcium channel gene (CACNA1c). Interestingly the same mutation was present in all probands analyzed and in one case parental mosaicism was demonstrated. Functional expression revealed that the G406R mutation produced maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent inactivation. In the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia. In other tissues and during fetal development this mutation is likely to cause intracellular calcium overload, a well known mechanism of tissue damage.