Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome With Life-Threatening Arrhythmias in Japanese Patients

JAMA Cardiol. 2019 Mar 1;4(3):246-254. doi: 10.1001/jamacardio.2018.4925.


Importance: Long QT syndrome (LQTS) is caused by several ion channel genes, yet risk of arrhythmic events is not determined solely by the responsible gene pathogenic variants. Female sex after adolescence is associated with a higher risk of arrhythmic events in individuals with congenital LQTS, but the association between sex and genotype-based risk of LQTS is still unclear.

Objective: To examine the association between sex and location of the LQTS-related pathogenic variant as it pertains to the risk of life-threatening arrhythmias.

Design, setting, and participants: This retrospective observational study enrolled 1124 genotype-positive patients from 11 Japanese institutions from March 1, 2006, to February 28, 2013. Patients had LQTS type 1 (LQT1), type 2 (LQT2), and type 3 (LQT3) (616 probands and 508 family members), with KCNQ1 (n = 521), KCNH2 (n = 487) and SCN5A (n = 116) genes. Clinical characteristics such as age at the time of diagnosis, sex, family history, cardiac events, and several electrocardiographic measures were collected. Statistical analysis was conducted from January 18 to October 10, 2018.

Main outcomes and measures: Sex difference in the genotype-specific risk of congenital LQTS.

Results: Among the 1124 patients (663 females and 461 males; mean [SD] age, 20 [15] years) no sex difference was observed in risk for arrhythmic events among those younger than 15 years; in contrast, female sex was associated with a higher risk for LQT1 and LQT2 among those older than 15 years. In patients with LQT1, the pathogenic variant of the membrane-spanning site was associated with higher risk of arrhythmic events than was the pathogenic variant of the C-terminus of KCNQ1 (HR, 1.60; 95% CI, 1.19-2.17; P = .002), although this site-specific difference in the incidence of arrhythmic events was observed in female patients only. In patients with LQT2, those with S5-pore-S6 pathogenic variants in KCNH2 had a higher risk of arrhythmic events than did those with others (HR, 1.88; 95% CI, 1.44-2.44; P < .001). This site-specific difference in incidence, however, was observed in both sexes. Regardless of the QTc interval, however, female sex itself was associated with a significantly higher risk of arrhythmic events in patients with LQT2 after puberty (106 of 192 [55.2%] vs 19 of 94 [20.2%]; P < .001). In patients with LQT3, pathogenic variants in the S5-pore-S6 segment of the Nav1.5 channel were associated with lethal arrhythmic events compared with others (HR, 4.2; 95% CI, 2.09-8.36; P < .001), but no sex difference was seen.

Conclusions and relevance: In this retrospective analysis, pathogenic variants in the pore areas of the channels were associated with higher risk of arrhythmic events than were other variants in each genotype, while sex-associated differences were observed in patients with LQT1 and LQT2 but not in those with LQT3. The findings of this study suggest that risk for cardiac events in LQTS varies according to genotype, variant site, age, and sex.

Publication types

  • Comparative Study
  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Adolescent
  • Adult
  • Arrhythmias, Cardiac / diagnosis
  • Arrhythmias, Cardiac / epidemiology
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / physiopathology
  • Child
  • Child, Preschool
  • ERG1 Potassium Channel / genetics
  • Female
  • Genotype
  • Humans
  • Incidence
  • Japan / epidemiology
  • KCNQ1 Potassium Channel / genetics
  • Long QT Syndrome / congenital*
  • Long QT Syndrome / epidemiology
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / physiopathology*
  • Male
  • Retrospective Studies
  • Risk Factors
  • Sex Characteristics
  • Young Adult


  • ERG1 Potassium Channel
  • KCNH2 protein, human
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human