The long QT syndromes: genetic basis and clinical implications

J Am Coll Cardiol. 2000 Jul;36(1):1-12. doi: 10.1016/s0735-1097(00)00716-6.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Cardiac Pacing, Artificial
  • Cation Transport Proteins*
  • DNA-Binding Proteins*
  • ERG1 Potassium Channel
  • Electric Countershock
  • Electrocardiography
  • Ether-A-Go-Go Potassium Channels
  • Humans
  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / physiopathology
  • Long QT Syndrome / therapy
  • Mutation
  • NAV1.5 Voltage-Gated Sodium Channel
  • Potassium Channels / genetics
  • Potassium Channels / metabolism
  • Potassium Channels, Voltage-Gated*
  • Purkinje Fibers / metabolism
  • Purkinje Fibers / physiopathology
  • Sodium Channels / genetics
  • Sodium Channels / metabolism
  • Trans-Activators*
  • Transcriptional Regulator ERG


  • Cation Transport Proteins
  • DNA-Binding Proteins
  • ERG protein, human
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • KCNH6 protein, human
  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • NAV1.5 Voltage-Gated Sodium Channel
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • SCN5A protein, human
  • Sodium Channels
  • Trans-Activators
  • Transcriptional Regulator ERG
  • potassium channel protein I(sk)