Long QT syndrome with compound mutations is associated with a more severe phenotype: a Japanese multicenter study

Heart Rhythm. 2010 Oct;7(10):1411-8. doi: 10.1016/j.hrthm.2010.06.013. Epub 2010 Jun 9.


Background: Long QT syndrome (LQTS) can be caused by mutations in the cardiac ion channels. Compound mutations occur at a frequency of 4% to 11% among genotyped LQTS cases.

Objective: The purpose of this study was to determine the clinical characteristics and manner of onset of cardiac events in Japanese patients with LQTS and compound mutations.

Methods: Six hundred three genotyped LQTS patients (310 probands and 293 family members) were divided into two groups: those with a single mutation (n = 568) and those with two mutations (n = 35). Clinical phenotypes were compared between the two groups.

Results: Of 310 genotyped probands, 26 (8.4%) had two mutations in the same or different LQTS-related genes (compound mutations). Among the 603 LQTS patients, compound mutation carriers had significantly longer QTc interval (510 ± 56 ms vs 478± 53 ms, P = .001) and younger age at onset of cardiac events (10 ± 8 years vs 18 ± 16 years, P = .043) than did single mutation carriers. The incidence rate of cardiac events before age 40 years and use of beta-blocker therapy among compound mutation carriers also were different than in single mutation carriers. Subgroup analysis showed more cardiac events in LQTS type 1 (LQT1) and type 2 (LQT2) compound mutations compared to single LQT1 and LQT2 mutations.

Conclusion: Compound mutation carriers are associated with a more severe phenotype than single mutation carriers.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Arrhythmias, Cardiac / etiology
  • Asian Continental Ancestry Group
  • Child
  • Disease-Free Survival
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / genetics
  • Female
  • Genotype
  • Heart Arrest / etiology
  • Humans
  • KCNQ1 Potassium Channel / genetics
  • Long QT Syndrome / complications
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / mortality
  • Male
  • Muscle Proteins / genetics
  • Mutation*
  • NAV1.5 Voltage-Gated Sodium Channel
  • Phenotype*
  • Sodium Channels / genetics
  • Syncope / etiology
  • Young Adult


  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Muscle Proteins
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Sodium Channels