Brugada syndrome (BrS) is an inherited cardiac electrical disorder, presented in patients by irregular heart rhythm. It is often asymptomatic, therefore it can be unnoticed. However it can also cause sudden cardiac death, typically in patients between age 25-55. First degree relatives have a 50% chance to develop BrS, putting a high burden on a family. Although some genes have been causally involved, for roughly 75% of the patients the genetic background is unknown. This project aims to fill this knowledge gap, by searching for novel genetic alterations implicated in BrS. We have gathered DNA samples from individuals from 10 genetically unresolved BrS families. We will sequence the whole genome of 3 selected patients per family. For the 3 largest families, we will combine sequencing with a dedicated linkage approach to identify genomic regions shared by patients. After genetic identification of new disease-causing mutations, their effects will be investigated in an advanced cell model, consisting of heart cells created from the patient's own skin cells. This allows us to mimic the environment of the heart in vitro and study what is happening at the molecular level. This will lead to better insight into mechanisms causing BrS, driving the development of novel therapies and ultimately resulting in more accurate risk prediction and personalized management of the BrS patients.