Rachel M A Ter Bekke1, Aaron Isaacs2, Andrei Barysenka3, Marije B Hoos4, Jan D H Jongbloed5, Jan C A Hoorntje6, Alfons S M Patelski7, Apollonia T J M Helderman-van den Enden8, Arthur van den Wijngaard8, Monika Stoll9, Paul G A Volders10. 1. Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands. 2. Maastricht Centre for Systems Biology (MaCSBio) and Department of Biochemistry, CARIM, Maastricht University, Maastricht, The Netherlands. 3. Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany. 4. Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands; Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands. 5. Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands. 6. Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands; Department of Cardiology, Zuyderland Medical Centre, Heerlen, The Netherlands. 7. History and Archaeology Association Limburg, Maastricht, The Netherlands. 8. Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands. 9. Maastricht Centre for Systems Biology (MaCSBio) and Department of Biochemistry, CARIM, Maastricht University, Maastricht, The Netherlands; Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany. 10. Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands. Electronic address: p.volders@maastrichtuniversity.nl.
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.
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 SCN5Ac.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.
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