Heritability in a SCN5A-mutation founder population with increased female susceptibility to non-nocturnal ventricular tachyarrhythmia and sudden cardiac death
| Autor: | Aaron Isaacs, Arthur van den Wijngaard, Alfons S.M. Patelski, Jan D. H. Jongbloed, Monika Stoll, Marije B. Hoos, Jan C.A. Hoorntje, Paul G.A. Volders, Apollonia T. J. M. Helderman-van den Enden, Andrei Barysenka, Rachel M.A. ter Bekke |
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| Přispěvatelé: | Promovendi CD, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.01 - Blood proteins & engineering, MUMC+: MA Alg Ond Onderz Cardiologie (9), MUMC+: DA KG Polikliniek (9), MUMC+: DA KG Lab Centraal Lab (9), RS: CARIM - R2.04 - Arrhythmogenisis and cardiogenetics, Cardiovascular Centre (CVC) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male DNA Mutational Analysis 030204 cardiovascular system & hematology Sudden cardiac death NAV1.5 Voltage-Gated Sodium Channel RISK STRATIFICATION Electrocardiography 0302 clinical medicine Gender differences HETEROGENEITY SCN5A Brugada syndrome Genetics Middle Aged Pedigree Phenotype MANIFESTATIONS Mutation (genetic algorithm) cardiovascular system Cardiology Female Cardiology and Cardiovascular Medicine EXPRESSION medicine.medical_specialty Heterozygote Long QT syndrome LONG-QT SYNDROME Biology QT interval BRUGADA-SYNDROME 03 medical and health sciences Heart Conduction System Physiology (medical) Internal medicine medicine Humans Genetic Predisposition to Disease cardiovascular diseases Ventricular fibrillation PR interval Retrospective Studies ARRHYTHMIAS MUTATIONS DNA Heritability medicine.disease SODIUM-CHANNEL POLYMORPHISM 030104 developmental biology Death Sudden Cardiac Mutation Tachycardia Ventricular Founder effect Follow-Up Studies |
| Zdroj: | Heart Rhythm, 14(12), 1873-1881. Elsevier Science Heart Rhythm, 14(12), 1873-1881. ELSEVIER SCIENCE INC |
| ISSN: | 1547-5271 |
| Popis: | 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 P P 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. |
| Databáze: | OpenAIRE |
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