Epigenetic regulation of electromechanical continuity might determine phenotypic heterogeneity in SCN5A mutation carriers in Brugada syndrome

Brugada syndrome (BrS) is an inherited cardiac disorder characterized by electrical disturbances. Pathogenic variants in the SCN5A gene are implicated in 25-30% of probands. Although loss-of-function mutations in SCN5A gene drive clinical severity, incomplete penetrance and interindividual susceptibility suggest additional contributing factors. Emerging evidence highlights the role of microRNAs (miRNAs), short non-coding nucleotides involved in post-transcriptional gene regulation, in cardiovascular pathophysiology. We sought to identify differences in circulating miRNAs in SCN5A gene mutation carriers according to their phenotype. 27 patients from 10 families with SCN5A gene mutations were included. Among them, 15 had a confirmed diagnosis of BrS by spontaneous or induced electrocardiographic pattern 1, while the other 12 were asymptomatic mutation carriers. Circulating miRNAs profile differences were identified by using miScript miRNA PCR-Arrays and validated by qPCR-Taqman assay. Gene set enrichment analyses (GSEA) were performed. miScript miRNA screening showed statistical differences in 10 of 84 analyzed miRNAs. Taqman analysis verified a significant downregulation of miR-320a in SCN5A mutation carriers associated with BrS phenotype. GSEA revealed a wide range of signaling pathways, including cellular adhesion and actin cytoskeleton regulatory pathways. Receiver operating characteristic curve analysis indicates that dysregulated miR-320a may help predict phenotypic differences in SCN5A mutation carriers, supporting the potential of circulating miRNAs, particularly reduced miR-320a levels, as possible predictive biomarkers for the manifestation of BrS. Additionally, our results indicate that phenotype might depend on epigenetic regulation of the electromechanical properties of the heart.