It is becoming clear that mutations in the KVLQT1, human "ether-a-go-go" related 
gene, cardiac voltage-dependent sodium channel gene, minK and MiRP1 genes, 
respectively, are responsible for the LQT1, LQT2, LQT3, LQT5 and LQT6 variants 
of the Romano-Ward syndrome, characterized by autosomal dominant transmission 
and no deafness. The much rarer Jervell-Lange-Nielsen syndrome (with marked QT 
prolongation and sensorineural deafness) arises when a child inherits mutant 
KVLQT1 or minK alleles from both parents. In addition, some families are not 
linked to the known genetic loci. Cardiac voltage-dependent sodium channel gene 
encodes the cardiac sodium channel, and long QT syndrome (LQTS) mutations 
prolong action potentials by increasing inward plateau sodium current. The other 
mutations cause a decrease in net repolarizing current by reducing potassium 
currents through "dominant negative" or "loss of function" mechanisms. 
Polymorphic ventricular tachycardia (torsade de pointes) is thought to be 
initiated by early after-depolarizations in the Purkinje system and maintained 
by reentry in the myocardium. Clinical presentations vary with the specific gene 
affected and the specific mutation. Nevertheless, patients with identical 
mutations can also present differently, and some patients with LQTS mutations 
may have no manifest baseline phenotype. The question of whether the latter 
situation is one of high risk for administration of QT prolonging drugs or 
during myocardial ischemia is under active investigation. More generally, the 
identification of LQTS genes has provided tremendous new insights for our 
understanding of normal cardiac electrophysiology and its perturbation in a wide 
range of conditions associated with sudden death. It seems likely that the 
approach of applying information from the genetics of uncommon congenital 
syndromes to the study of common acquired diseases will be an increasingly 
important one in the next millennium.