Heritability in a SCN5A-mutation founder population with increased female susceptibility to non-nocturnal ventricular tachyarrhythmia and sudden cardiac death

Heart Rhythm. 2017 Dec;14(12):1873-1881. doi: 10.1016/j.hrthm.2017.07.036. Epub 2017 Aug 3.

Abstract

Background: Heritable cardiac-sodium channel dysfunction is associated with various arrhythmia syndromes, some predisposing to ventricular fibrillation. Phenotypic diversity among carriers of identical-by-descent mutations is often remarkable, suggesting influences of genetic modifiers.

Objective: The purpose of this study was to identify a unique SCN5A-mutation founder population with mixed clinical phenotypes and sudden cardiac death, and to investigate the heritability of electromechanical traits besides the SCN5A-mutation effect.

Methods: The 16-generation founder population segregating SCN5A c.4850_4852delTCT, p.(Phe1617del), was comprehensively phenotyped. Variance component analysis was used to evaluate the mutation's effects and assess heritability.

Results: In 45 p.(Phe1617del) positives, the mutation associated strongly with QTc prolongation (472 ± 60 ms vs 423 ± 35 ms in 26 mutation negatives; P <.001; odds ratio for long-QT syndrome 22.4; 95% confidence interval 4.5-224.2; P <.001) and electromechanical window (EMW) negativity (-29 ± 47 ms vs 34 ± 26 ms; P <.001). Overlapping phenotypes including conduction delay and Brugada syndrome were noted in 19. Polymorphic ventricular tachyarrhythmias occurred mostly in the daytime, after arousal-evoked heart-rate acceleration and repolarization prolongation. Cox proportional hazards regression analysis revealed female gender as an independent risk factor for cardiac events (hazard ratio 5.1; 95% confidence interval 1.6-16.3; P = .006). p.(Phe1617del) was an important determinant of QTcbaseline, QTcmax, and EMW, explaining 18%, 28%, and 37%, respectively, of the trait's variance. Significant heritability was observed for PQ interval (P = .003) after accounting for the p.(Phe1617del) effect.

Conclusion: This SCN5A-p.(Phe1617del) founder population with phenotypic divergence and overlap reveals long-QT syndrome-related and arousal-evoked ventricular tachyarrhythmias with a female preponderance. Variance component analysis indicates additional genetic variance for PQ interval hidden in the genome, besides a dominant p.(Phe1617del) effect on QTc and EMW.

Keywords: Gender differences; Genetics; SCN5A; Sudden cardiac death; Ventricular fibrillation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / genetics
  • DNA Mutational Analysis
  • Death, Sudden, Cardiac / etiology*
  • Electrocardiography*
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease*
  • Heart Conduction System / physiopathology*
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism
  • Pedigree
  • Phenotype
  • Retrospective Studies
  • Tachycardia, Ventricular / genetics*
  • Tachycardia, Ventricular / metabolism
  • Tachycardia, Ventricular / physiopathology

Substances

  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • DNA