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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Published online: February 08, 2023
Publication stageIn Press Journal Pre-Proof
Funding Sources: This work was supported by the Netherlands CardioVascular Research Initiative (CVON PREDICT2, grant 2018-30), Den Haag, the Netherlands, and by the Health Foundation Limburg, Maastricht, the Netherlands.
Disclosures: The authors have no conflicts of interest to disclose.
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- Unraveling the influence of genomic context on pleiotropy in SCN5A-mediated cardiac channelopathies: Insights from the Worm StudyHeart Rhythm
- PreviewDisease-causative variants in the SCN5A-encoded pore-forming α subunit of the Nav1.5 cardiac sodium channel cause a spectrum of electrical and structural genetic heart disorders including type 1 Brugada syndrome (BrS1; Nav1.5 loss-of-function), type 3 long QT syndrome (LQT3; Nav1.5 gain-of-function), multifocal ectopic Purkinje-related premature contractions (Nav1.5 gain-of-function), progressive cardiac conduction disease (PCCD; Nav1.5 loss-of-function), and dilated cardiomyopathy (Nav1.5 loss-of-function, gain-of-function, and overlapping functional effects).