Identification of novel therapeutic targets of Brugada Syndrome through discovery and characterization of genetic modifiers.

Brugada syndrome (BrS) is an inherited electrical disorder of the heart, presenting in patients with an irregular heart rhythm. This can go unnoticed throughout life, but also lead to sudden cardiac death, typically in patients between age 25-55. At present, more than 25 genes have been identified that can explain about 30% of BrS cases. The question remains why in the same family individuals with the identical genetic alteration can live without symptoms, have few or many arrhythmia episodes or even experience sudden death. I will look for an answer to this question in a group of families with a known error in the SCN5A gene causing BrS. I will study the exact effect of this genetic error and I will compare the difference in genetic signals between a selection of patients without symptoms and patients with severe symptoms, using whole genome and RNA sequencing techniques. Since it is important to work with heart cells in this study, I will use an advanced method that allows me to create heart cells from the patient's own skin or blood cells. Analysis of the genetic signals will lead us to the 'modifier genes' responsible for the differences in BrS disease severity. Identification of these modifiers will lead to a better 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.

Keywords:CARDIOGENETICS

Disciplines:Cardiac and vascular medicine