Genotype and severity of long QT syndrome.

OBJECTIVES To describe the state of the art of our understanding of the long QT syndromes and to provide the genetic correlation of clinical severity of patients with this disorder. DATE SOURCES In this review, we outline data that were obtained from work in our laboratory, as well as information reported in the literature. STUDY SELECTION The information in this review spans the last decade; data were obtained from the studies that had the most impact, as well as from recent work at our laboratory. DATA EXTRACTION The data reported herein were extracted from the world literature on sudden death and the clinical aspects of long QT syndrome. The genes identified to date, mutations in these genes, and the biophysical perturbations in the mutated ion channels, as well as the severity of disease, are detailed. DATA SYNTHESIS The extracted data are described as a state-of-the-art review. CONCLUSIONS The long QT syndromes, genetically heterogeneous disorders due to mutations in genes encoding ion channels, are relatively common causes of syncope and sudden death. The affected genes, along with the genetic background of individuals, determine the clinical severity of disease. An understanding of the mechanisms responsible for long QT syndrome is expected to enable development of specific therapies.

[1]  R. Russell,et al.  QT-interval prolongation, paroxysmal ventricular arrhythmias, and convulsive syncope. , 1971, Annals of internal medicine.

[2]  M. Leppert,et al.  Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. , 1991, Science.

[3]  J. Brugada,et al.  Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. , 1992, Journal of the American College of Cardiology.

[4]  A. Moss,et al.  Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity , 1994, Nature Genetics.

[5]  P. Schwartz,et al.  Evidence of Genetic Heterogeneity in Romano‐Ward Long QT syndrome: Analysis of 23 Families , 1994, Circulation.

[6]  Arthur J Moss,et al.  SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome , 1995, Cell.

[7]  M. Keating,et al.  Long QT syndrome associated with syndactyly identified in females. , 1995, The American journal of cardiology.

[8]  F. Charpentier,et al.  Mapping of a gene for long QT syndrome to chromosome 4q25-27. , 1995, American journal of human genetics.

[9]  M. Sanguinetti,et al.  A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel , 1995, Cell.

[10]  A. George,et al.  Molecular mechanism for an inherited cardiac arrhythmia , 1995, Nature.

[11]  A. Moss,et al.  ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. , 1995, Circulation.

[12]  E. Green,et al.  A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome , 1995, Cell.

[13]  M. Sanguinetti,et al.  Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKS potassium channel , 1996, Nature.

[14]  G. Landes,et al.  Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias , 1996, Nature Genetics.

[15]  Jacques Barhanin,et al.  KvLQT1 and IsK (minK) proteins associate to form the IKS cardiac potassium current , 1996, Nature.

[16]  P. Coumel,et al.  A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome , 1997, Nature Genetics.

[17]  Glenn I. Fishman,et al.  A minK–HERG complex regulates the cardiac potassium current IKr , 1997, Nature.

[18]  B. Wollnik,et al.  Pathophysiological Mechanisms of Dominant and Recessive Kvlqt1 K + Channel Mutations Found in Inherited Cardiac Arrhythmias , 1997 .

[19]  M. Keating,et al.  Molecular basis of the long-QT syndrome associated with deafness. , 1997, The New England journal of medicine.

[20]  E. Rosenthal,et al.  Prolongation of the QT interval and the sudden infant death syndrome. , 1998, The New England journal of medicine.

[21]  J. Balser,et al.  Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel. , 1998, Circulation.

[22]  S. Priori,et al.  New mutations in the KVLQT1 potassium channel that cause long-QT syndrome. , 1998, Circulation.

[23]  B. Kerem,et al.  Novel LQT-3 mutation affects Na+ channel activity through interactions between alpha- and beta1-subunits. , 1998, Circulation research.

[24]  S. Priori,et al.  Influence of the genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. , 1998, The New England journal of medicine.

[25]  S. Priori,et al.  A recessive variant of the Romano-Ward long-QT syndrome? , 1998, Circulation.

[26]  B. Kerem,et al.  Novel LQT-3 Mutation Affects Na+ Channel Activity Through Interactions Between α- and β1-Subunits , 1998 .

[27]  G. Breithardt,et al.  Genetic basis and molecular mechanism for idiopathic ventricular fibrillation , 1998, Nature.

[28]  Toshihisa Nagatomo,et al.  Temperature dependence of early and late currents in human cardiac wild-type and long Q-T ΔKPQ Na+ channels. , 1998, American journal of physiology. Heart and circulatory physiology.

[29]  S. Priori,et al.  New Mutations in the KVLQT 1 Potassium Channel That Cause Long-QT Syndrome , 1998 .

[30]  R. Hauer,et al.  Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management , 2022 .

[31]  D M Roden,et al.  Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel. , 1999, Circulation.

[32]  S. Priori,et al.  Cellular dysfunction of LQT5-minK mutants: abnormalities of IKs, IKr and trafficking in long QT syndrome. , 1999, Human molecular genetics.

[33]  M. Keating,et al.  MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia , 1999, Cell.

[34]  C. January,et al.  Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. , 1999, Circulation.

[35]  S. Priori,et al.  Low penetrance in the long-QT syndrome: clinical impact. , 1999, Circulation.

[36]  J. Towbin,et al.  Molecular biology of arrhythmic syndromes , 2000, Current opinion in cardiology.

[37]  W. Allan,et al.  Long QT Syndrome , 1998, Pediatrics.

[38]  S. Priori,et al.  Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. , 2000, Circulation.