Contribution of Cardiac Sodium Channel β-Subunit Variants to Brugada Syndrome

Abstract

Background:Brugada syndrome (BrS) is an inheritable cardiac disease associated with syncope, malignant ventricular arrhythmias and sudden cardiac death. The largest proportion of mutations in BrS is found in theSCN5Agene encoding the α-subunit of cardiac sodium channels (Nav1.5). CausalSCN5Amutations are present in 18–30% of BrS patients. The additional genetic diagnostic yield of variants in cardiac sodium channel β-subunits in BrS patients was explored and functional studies on 3 novel candidate variants were performed.Methods and Results:TheSCN1B-SCN4Bgenes were screened, which encode the 5 sodium channel β-subunits, in aSCN5Anegative BrS population (n=74). Five novel variants were detected; in silico pathogenicity prediction classified 4 variants as possibly disease causing. Three variants were selected for functional study. These variants caused only limited alterations of Nav1.5 function. Next generation sequencing of a panel of 88 arrhythmia genes could not identify other major causal mutations.Conclusions:It was hypothesized that the studied variants are not the primary cause of BrS in these patients. However, because small functional effects of these β-subunit variants can be discriminated, they might contribute to the BrS phenotype and be considered a risk factor. The existence of these risk factors can give an explanation to the reduced penetrance and variable expressivity seen in this syndrome. We therefore recommend including theSCN1-4Bgenes in a next generation sequencing-based gene panel.