LAUSR

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.