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

doi:10.1016/j.hrthm.2017.07.036

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 journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	1873-1881
Number of pages	9
Journal	Heart Rhythm
Volume	14
Issue number	12
DOIs	https://doi.org/10.1016/j.hrthm.2017.07.036
Publication status	Published - 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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10.1016/j.hrthm.2017.07.036

Cite this

ter Bekke, R. M. A., Isaacs, A., Barysenka, A., Hoos, M. B., Jongbloed, J. D. H., Hoorntje, J. C. A., Patelski, A. S. M., Helderman-van den Enden, A. T. J. M., van den Wijngaard, A., Stoll, M., & Volders, P. G. A. (2017). Heritability in a SCN5A-mutation founder population with increased female susceptibility to non-nocturnal ventricular tachyarrhythmia and sudden cardiac death. Heart Rhythm, 14(12), 1873-1881. https://doi.org/10.1016/j.hrthm.2017.07.036

@article{68a83358d4c9476bba80387f3eb56f79,

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

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; PCONCLUSION 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, LONG-QT SYNDROME, BRUGADA-SYNDROME, RISK STRATIFICATION, SODIUM-CHANNEL, MUTATIONS, MANIFESTATIONS, HETEROGENEITY, POLYMORPHISM, ARRHYTHMIAS, EXPRESSION",

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

year = "2017",

month = dec,

doi = "10.1016/j.hrthm.2017.07.036",

language = "English",

volume = "14",

pages = "1873--1881",

journal = "Heart Rhythm",

issn = "1547-5271",

publisher = "Elsevier Science",

number = "12",

}

ter Bekke, RMA , Isaacs, A, Barysenka, A, Hoos, MB, Jongbloed, JDH, Hoorntje, JCA, Patelski, ASM, Helderman-van den Enden, ATJM, van den Wijngaard, A, Stoll, M & Volders, PGA 2017, 'Heritability in a SCN5A-mutation founder population with increased female susceptibility to non-nocturnal ventricular tachyarrhythmia and sudden cardiac death', Heart Rhythm, vol. 14, no. 12, pp. 1873-1881. https://doi.org/10.1016/j.hrthm.2017.07.036

TY - JOUR

T1 - Heritability in a SCN5A-mutation founder population with increased female susceptibility to non-nocturnal ventricular tachyarrhythmia and sudden cardiac death

AU - ter Bekke, Rachel M. A.

AU - Isaacs, Aaron

AU - Barysenka, Andrei

AU - Hoos, Marije B.

AU - Jongbloed, Jan D. H.

AU - Hoorntje, Jan C. A.

AU - Patelski, Alfons S. M.

AU - Helderman-van den Enden, Apollonia T. J. M.

AU - van den Wijngaard, Arthur

AU - Stoll, Monika

AU - Volders, Paul G. A.

PY - 2017/12

Y1 - 2017/12

N2 - 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; PCONCLUSION 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.

AB - 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; PCONCLUSION 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.

KW - Gender differences

KW - Genetics

KW - SCN5A

KW - Sudden cardiac death

KW - Ventricular fibrillation

KW - LONG-QT SYNDROME

KW - BRUGADA-SYNDROME

KW - RISK STRATIFICATION

KW - SODIUM-CHANNEL

KW - MUTATIONS

KW - MANIFESTATIONS

KW - HETEROGENEITY

KW - POLYMORPHISM

KW - ARRHYTHMIAS

KW - EXPRESSION

U2 - 10.1016/j.hrthm.2017.07.036

DO - 10.1016/j.hrthm.2017.07.036

M3 - Article

C2 - 28782696

SN - 1547-5271

VL - 14

SP - 1873

EP - 1881

JO - Heart Rhythm

JF - Heart Rhythm

IS - 12

ER -