Research Article|Articles in Press

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

Published:February 08, 2023DOI:


      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.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Heart Rhythm
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Deo R.
        • Albert C.M.
        Epidemiology and genetics of sudden cardiac death.
        Circulation. 2012; 125: 620-637
        • Chugh S.S.
        • Kelly K.L.
        • Titus J.L.
        Sudden cardiac death with apparently normal heart.
        Circulation. 2000; 102: 649-654
        • Borecki I.B.
        • Province M.A.
        Genetic and genomic discovery using family studies.
        Circulation. 2008; 118: 1057-1063
        • Preston M.D.
        • Dudbridge F.
        Utilising family-based designs for detecting rare variant disease associations.
        Ann Hum Genet. 2014; 78: 129-140
        • Ter Bekke R.M.A.
        • Isaacs A.
        • Barysenka A.
        • et al.
        Heritability in a SCN5A-mutation founder population with increased female susceptibility to non-nocturnal ventricular tachyarrhythmia and sudden cardiac death.
        Heart Rhythm. 2017; 14: 1873-1881
        • Bezzina C.R.
        • Barc J.
        • Mizusawa Y.
        • et al.
        Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death.
        Nat Genet. 2013; 45: 1044-1049
        • Arking D.E.
        • Pulit S.L.
        • Crotti L.
        • et al.
        Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
        Nat Genet. 2014; 46: 826-836
        • Sotoodehnia N.
        • Isaacs A.
        • de Bakker P.I.
        • et al.
        Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.
        Nat Genet. 2010; 42: 1068-1076
        • van der Harst P.
        • van Setten J.
        • Verweij N.
        • et al.
        52 Genetic loci influencing myocardial mass.
        J Am Coll Cardiol. 2016; 68: 1435-1448
        • Genome of the Netherlands Consortium
        Whole-genome sequence variation, population structure and demographic history of the Dutch population.
        Nat Genet. 2014; 46: 818-825
        • Purcell S.
        • Neale B.
        • Todd-Brown K.
        • et al.
        PLINK: a tool set for whole-genome association and population-based linkage analyses.
        Am J Hum Genet. 2007; 81: 559-575
        • Abecasis G.R.
        • Cherny S.S.
        • Cookson W.O.
        • Cardon L.R.
        Merlin—rapid analysis of dense genetic maps using sparse gene flow trees.
        Nat Genet. 2002; 30: 97-101
        • Liu F.
        • Kirichenko A.
        • Axenovich T.I.
        • van Duijn C.M.
        • Aulchenko Y.S.
        An approach for cutting large and complex pedigrees for linkage analysis.
        Eur J Hum Genet. 2008; 16: 854-860
        • O’Connell J.
        • Gurdasani D.
        • Delaneau O.
        • et al.
        A general approach for haplotype phasing across the full spectrum of relatedness.
        PLoS Genet. 2014; 10e1004234
        • Li M.
        • Boehnke M.
        • Abecasis G.R.
        Joint modeling of linkage and association: identifying SNPs responsible for a linkage signal.
        Am J Hum Genet. 2005; 76: 934-949
        • Almasy L.
        • Blangero J.
        Multipoint quantitative-trait linkage analysis in general pedigrees.
        Am J Hum Genet. 1998; 62: 1198-1211
        • Nyholt D.R.
        A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other.
        Am J Hum Genet. 2004; 74: 765-769
        • Lange K.
        • Papp J.C.
        • Sinsheimer J.S.
        • Sripracha R.
        • Zhou H.
        • Sobel E.M.
        Mendel: the Swiss army knife of genetic analysis programs.
        Bioinformatics. 2013; 29: 1568-1570
        • Jombart T.
        adegenet: a R package for the multivariate analysis of genetic markers.
        Bioinformatics. 2008; 24: 1403-1405
        • Barrett J.C.
        • Fry B.
        • Maller J.
        • Daly M.J.
        Haploview: analysis and visualization of LD and haplotype maps.
        Bioinformatics. 2005; 21: 263-265
        • Auton A.
        • McVean G.
        Recombination rate estimation in the presence of hotspots.
        Genome Res. 2007; 17: 1219-1227
        • Reeve J.P.
        • Rannala B.
        DMLE+: Bayesian linkage disequilibrium gene mapping.
        Bioinformatics. 2002; 18: 894-895
        • Auton A.
        • Brooks L.D.
        • Durbin R.M.
        • et al.
        • 1000 Genomes Project Consortium
        A global reference for human genetic variation.
        Nature. 2015; 526: 68-74
        • Gandolfo L.C.
        • Bahlo M.
        • Speed T.P.
        Dating rare mutations from small samples with dense marker data.
        Genetics. 2014; 197: 1315-1327
        • Gautier M.
        • Vitalis R.
        rehh: an R package to detect footprints of selection in genome-wide SNP data from haplotype structure.
        Bioinformatics. 2012; 28: 1176-1177
        • Voight B.F.
        • Kudaravalli S.
        • Wen X.
        • Pritchard J.K.
        A map of recent positive selection in the human genome.
        PLoS Biol. 2006; 4: e72
        • ter Bekke R.M.
        • Haugaa K.H.
        • van den Wijngaard A.
        • et al.
        Electromechanical window negativity in genotyped long-QT syndrome patients: relation to arrhythmia risk.
        Eur Heart J. 2015; 36: 179-186
        • Delaney J.T.
        • Muhammad R.
        • Shi Y.
        • et al.
        Common SCN10A variants modulate PR interval and heart rate response during atrial fibrillation.
        Europace. 2014; 16: 485-490
        • Huang Y.
        • Chen X.M.
        • Barajas-Martinez H.
        • Jiang H.
        • Antzelevitch C.
        • Hu D.
        Common variants in SCN10A gene associated with Brugada syndrome.
        Hum Mol Genet. 2021; 31: 157-165
        • Cattaneo M.
        • Tsai M.Y.
        • Bucciarelli P.
        • et al.
        A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V:Q506).
        Arterioscler Thromb Vasc Biol. 1997; 17: 1662-1666
        • Gray B.
        • Behr E.R.
        New insights into the genetic basis of inherited arrhythmia syndromes.
        Circ Cardiovasc Genet. 2016; 9: 569-577
        • Kousi M.
        • Katsanis N.
        Genetic modifiers and oligogenic inheritance.
        Cold Spring Harb Perspect Med. 2015; 5: a017145
        • Li L.
        • Bainbridge M.N.
        • Tan Y.
        • Willerson J.T.
        • Marian A.J.
        A potential oligogenic etiology of hypertrophic cardiomyopathy: a classic single-gene disorder.
        Circ Res. 2017; 120: 1084-1090
        • Niemi M.E.K.
        • Martin H.C.
        • Rice D.L.
        • et al.
        Common genetic variants contribute to risk of rare severe neurodevelopmental disorders.
        Nature. 2018; 562: 268-271

      Linked Article