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Original Investigation
February 13, 2019

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

Author Affiliations
  • 1Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
  • 2Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan
  • 3Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Suita, Japan
  • 4Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan
  • 5Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan
  • 6Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Japan
  • 7Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • 8Department of Cardiovascular and Internal Medicine, Kanazawa University, Kanazawa, Japan
  • 9Department of Cardiovascular Therapeutics, Okayama University Graduate School of Medicine, Okayama, Japan
  • 10Department of Pediatrics, Kagoshima Medical Center, Kagoshima, Japan
  • 11Department of Cardiology, Keio University, Tokyo, Japan
  • 12Division of Preventive Cardiology, National Cerebral and Cardiovascular Center, Suita, Japan
  • 13Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  • 14Department of Pediatric Cardiology, Saitama Medical University International Medical Center, Saitama, Japan
  • 15Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan
  • 16Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  • 17Department of Advanced Arrhythmia and Translational Medical Science, National Cerebral and Cardiovascular Center, Suita, Japan
JAMA Cardiol. 2019;4(3):246-254. doi:10.1001/jamacardio.2018.4925
Key Points

Question  Is there a sex-specific difference in the genotype-based risk stratification of long QT syndrome?

Findings  In this cohort study of 1124 genotype-positive patients with long QT syndrome, pathogenic variants in the pore areas of the channels in each genotype were associated with higher risk of arrhythmic events than other variants, while sex-associated differences were observed in patients with long QT syndrome type 1 and long QT syndrome type 2 but not in those with long QT syndrome type 3. Regardless of the QTc interval, female sex was associated with a significantly higher risk of arrhythmic events in long QT syndrome type 2.

Meaning  Risk for arrhythmic events in patients with long QT syndrome appears to vary according to genotype, variant site, age, and sex.

Abstract

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.

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