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Standing genetic variation affects phenotypic heterogeneity in an SCN5A-mutation founder population with excess sudden cardiac death

创始人效应 遗传学 单倍型 人口 生物 遗传异质性 心源性猝死 猝死 突变 遗传变异 基因型 表型 心脏病学 医学 基因 环境卫生
作者
Aaron Isaacs,Andrei Barysenka,Rachel M.A. ter Bekke,Apollonia T.J.M. Helderman-van den Enden,Arthur van den Wijngaard,Paul G.A. Volders,Monika Stoll
出处
期刊:Heart Rhythm [Elsevier BV]
卷期号:20 (5): 720-727 被引量:4
标识
DOI:10.1016/j.hrthm.2023.02.004
摘要

The Worm Study, ascertained from a multigeneration pedigree segregating a single amino acid deletion in SCN5A (c.4850_4852delTCT, p.(Phe1617del), rs749697698), is characterized by substantial phenotypic heterogeneity and overlap of sudden cardiac death, long-QT syndrome, cardiac conduction disease, Brugada syndrome, and isorhythmic atrioventricular dissociation. Linkage analysis for a synthetic trait derived from these phenotypes identified a single peak (logarithm of the odds [LOD] = 4.52) at the SCN5A/SCN10A/SCN11A locus on chromosome 3.This study explored the role of additional genetic variation in the chromosome 3 locus as a source of phenotypic heterogeneity in the Worm Study population.Genotypes underlying the linkage peak (n = 70) were characterized using microarrays. Haplotypes were determined using family-aware phasing and a population-specific reference panel. Variants with minor allele frequencies >0.10 were tested for association with cardiac conduction disease and isorhythmic dissociation using LAMP and logistic regression.Only 1 haplotype carried the p.Phe1617del/rs749697698 deletion, suggesting relatively recent development (∼18 generations); this haplotype contained 5 other missense variants spanning SCN5A/SCN10A/SCN11A. Noncarrier haplotypes (n = 74) ranged in frequency from 0.5% to 5%. Although no variants were associated with cardiac conduction disease, a homozygous missense variant in SCN10A was associated with isorhythmic dissociation after correction for multiple comparisons (odds ratio 11.23; 95% confidence interval 2.76-23.39; P = 1.2 × 10-4). This variant (rs12632942) was previously associated with PR interval.Our data suggest that other variants, alongside a pathogenic mutation, are associated with phenotypic heterogeneity. Single-mutation screening may be insufficient to predict electrical heart disease in patients and family members. In the Worm Study population, segregating a pathogenic SCN5A mutation, compound variation in the SCN5A/SCN10A/SCN11A locus determines arrhythmic outcome.
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