From a monogenic model to polygenic risk: genetic modifiers of Brugada Syndrome

BrS is an inherited cardiac channelopathy classically regarded as a monogenic, autosomal-dominant disorder caused by loss-of-function variants in SCN5A, encoding the cardiac sodium channel Nav1.5. This model has been substantially revised over the past two decades. This narrative, nonsys-tematic review was structured with reference to the SANRA quality criteria and was based on a PubMed/MEDLINE search (finalized in January 2026) combining the term “Brugada syndrome” with “genome-wide association”, “polygenic risk score”, “genetic testing”, “cascade screening” and “oli-gogenic”. A pathogenic SCN5A variant is identified in only about 20% of clinically diagnosed patients, and penetrance is highly variable even within families carrying the same variant, reflecting modu-lation by sex, additional rare variants, and the common polygenic background. Genome-wide asso-ciation studies have identified more than a dozen common-variant loci, with a largely shared archi-tecture across European and Japanese cohorts. In a large Italian cohort, a three-SNP PRS was inde-pendently associated with a first life-threatening arrhythmic event (hazard ratio 1.3; 95% confidence interval 1.0–1.6) after adjustment for SCN5A status, although a confidence interval approaching unity indicates an uncertain effect. BrS is better conceptualised as an oligogenic-to-polygenic disease, in which the phenotype results from interaction between a rare, high-penetrance variant and a background polygenic profile. PRS show a modest but independent association with arrhythmic outcomes; prospective validation, standardization and cross-ancestry confirmation are required before routine clinical use.