A candidate genetic modifier and autosomal recessive cause of Brugada syndrome that may alter the circadian expression of SCN5A

Abstract

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by a generous grant from the Newnham College Senior Members Research Support fund. Introduction Inherited cardiac arrhythmias (ICAs) are a major cause of sudden cardiac death (SCD) in the young. ICAs are caused by variants in genes encoding ion channels that predispose individuals to life-threatening arrhythmic events. Early diagnosis to facilitate implementation of effective clinical interventions that greatly reduce SCD risk is critical. ICAs have traditionally been considered monogenic diseases. However, the genomic architecture of ICAs is likely a continuum, ranging from monogenic and near-monogenic (strong genetic factor influenced by a few genetic modifiers) to oligogenic (cumulative effects of coinheritance of many genetic modifiers). The circadian clock, which is predicted to control the expression of one third of the protein-coding genome, has been implicated in contributing to ICAs because the incidence of arrhythmic events in ICA patients oscillates with a period of 24 hours. We therefore hypothesised that it may contribute to oligogenic disease. Purpose To identify variants that may contribute to ICAs and that are located in cis-regulatory motifs that are both functionally predicted to be binding sites for clock transcription factors and located in the promoters of ICA-associated genes predicted to exhibit diurnal rhythmic expression. Methods Genes associated with ICAs and predicted to be rhythmically expressed were identified and the region 1kb upstream of their transcription start sites screened for mammalian circadian motifs. Whole genome sequencing data from participants with ICAs in The 100,000 Genomes Project was interrogated for variants within these motifs. Results Two variants in the SCN5A promoter were significantly associated with Brugada syndrome (BrS) (OR = 2.77, p-value <2.2E-16; OR = 2.11, p-value = 6.23E-14). The variants were found in high linkage disequilibrium (D’=0.988, p-value <2.2E-16). This 2-variant haplotype was enriched in BrS patients who did (OR = 2.43, p-value = 7.07E-08; OR = 1.32, p-value = 0.0204) and did not (OR = 3.00, p-value <2.2E-16; OR = 1.78, p-value = 8.30E-09) have a likely genomic cause, implying that it may be a genetic modifier of BrS. This haplotype in the homozygous state was significantly enriched in individuals with BrS in whom a likely genomic cause had not been identified, suggesting it may be an autosomal recessive cause (OR = 0.102, Fisher’s p-value = 0.0120). Conclusion This haplotype has previously been reported to modulate BrS severity in a large family with a pathogenic SCN5A variant and has demonstrated a trend towards reduced SCN5A expression in murine cardiomyocytes – a molecular mechanism that slows cardiac conduction, predisposing individuals to BrS. Therefore, this 2-variant haplotype, or 1 variant therein, in the SCN5A promoter is a putative genetic modifier and autosomal recessive cause of BrS. Future work includes functional assay in human cardiomyocytes to characterise its molecular consequences on SCN5A expression and the circadian clock.