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

Rachel M. A. ter Bekke, Aaron Isaacs, Andrei Barysenka, Marije B. Hoos, Jan D. H. Jongbloed, Jan C. A. Hoorntje, Alfons S. M. Patelski, Apollonia T. J. M. Helderman-van den Enden, Arthur van den Wijngaard, Monika Stoll, Paul G. A. Volders*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

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 +/- 6 60 ms vs 423 +/- 6 35 ms in 26 mutation negatives; P

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.

Original languageEnglish
Pages (from-to)1873-1881
Number of pages9
JournalHeart Rhythm
Volume14
Issue number12
DOIs
Publication statusPublished - Dec 2017

Keywords

  • Gender differences
  • Genetics
  • SCN5A
  • Sudden cardiac death
  • Ventricular fibrillation
  • LONG-QT SYNDROME
  • BRUGADA-SYNDROME
  • RISK STRATIFICATION
  • SODIUM-CHANNEL
  • MUTATIONS
  • MANIFESTATIONS
  • HETEROGENEITY
  • POLYMORPHISM
  • ARRHYTHMIAS
  • EXPRESSION

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