Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac electrical disorder, characterized by ventricular arrhythmias and a significant risk for sudden cardiac death (SCD). It accounts for up to 20% of SCD cases in young individuals (<45 years) with structurally normal hearts. At present over 25 genes, including SCN5A, have been associated with BrS, but mutations in these genes explain only 30% of the cases. One other major unresolved aspect of BrS concerns the significant variability in disease expression, from completely asymptomatic over mild arrhythmia to SCD, observed even within families with an established disease-causative mutation. Genetic modifiers must play an important role in this phenomenon, and the identification of such modifiers is the aim of this project. Hereto, I will use a unique collection of BrS families recruited through our cardiogenetics clinic, sharing a Belgian SCN5A founder mutation and displaying remarkable variable expressivity. I will perform whole genome sequencing and RNA-sequencing on the advanced model of induced pluripotent stem cell (iPSC)-derived cardiomyocytes from eight carefully selected mutation carriers, four at each end of the disease severity spectrum. An in-depth combined analysis of the resulting genome and transcriptome data will certainly reveal the modifier gene(s) underlying intra-familial phenotypic variability in BrS. This will lead to a significantly improved insight into the mechanisms causing BrS, drive the development of novel therapies and result in more accurate risk prediction and personalized management of BrS patients.