Genetic and environmental factors in cardiac sodium channel disease

Cardiac sodium channelopathies, such as long QT syndrome type3 (LQT3), Brugada syndrome (BrS) and cardiac conduction disease (CCD), are heritable diseases associated with mutations in the SCN5A gene and sudden cardiac death. They were classically thought to be a monogenic disease. However, while LQT3 has a strong monogenic component, the genetic architecture of others has recently been questioned. Familial studies in BrS have shown that not all family members carrying the familial mutation develop symptoms. Among mutation carriers, a few develop fatal arrhythmia whereas many develop only ECG abnormalities typical of BrS without major arrhythmic events. Interestingly, certain SCN5A mutations even develop phenotypic overlap of LQT3, BrS and CCD that are attributed to two different mechanisms (i.e. increased sodium current in LQT3 and decreased sodium current in BrS and CCD). Such varied genotype-phenotype relationships in sodium channelopathies indicate their complex mechanism. While environmental factors such as gender have been shown to modify phenotypes in sodium channelopathies, genetic factors may also contribute to phenotypic variability. Recently, genome-wide association studies have uncovered multiple genetic loci that modulate electrocardiographic parameters, which represent intermediate phenotypes in search of genetic factors that impact on rhythm abnormalities. This indicates that common genetic variants may play a role in diseases with complex genetic architecture such as BrS. Therefore, in this thesis, we aimed at dissecting genetic and environmental modifiers of sodium channelopathies. Part I focuses on sodium channelopathies, in particular, genetic modifiers of overlap sodium channelopathy. Part II focuses on genetic and environmental factors in BrS.