The heritable arrhythmogenic disorder Brugada syndrome (BrS), a cardiac ion channelopathy first described in 1992, is inherited as an autosomal dominant trait characterized by incomplete penetrance, variable expression, and phenotypic overlap. These characteristics all complicate the elucidation of the underlying molecular genetic pathway. Clearly, SCN5A, the gene encoding the pore-forming alpha subunit of the cardiac sodium channel, is the major susceptibility gene associated with BrS: 20–30% of BrS patients harbour pathogenic variants in this gene and BrS patients have a more than eight times higher burden of rare variants in this gene compared to controls. Rare pathogenic variants have also been reported in several sodium, potassium, and calcium channel genes, pacemaker genes, and sodium channel interacting genes. Given the minor collective contribution of these additional BrS-associated genes to the total genetic diagnostic yield, the hypothesis has been raised that other (genetic) determinants are involved. Indeed, the monogenic nature of BrS has been questioned and more support has recently been gained for the hypothesis of a complex inheritance based on genome-wide and gene panel studies. Probably, the BrS inheritance pattern is a continuum ranging from a monogenic, over an oligogenic towards even a polygenic spectrum. This, however, further impedes the interpretation of the contribution of (likely) pathogenic variants to the phenotype and urges for a cautious policy in a prenatal and preimplantation genetic diagnostic context: in many cases disease prevention will imply a risk reduction instead of an elimination of disease (development).
Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk
