Genetics of cardiac arrhythmias

Primary cardiac arrhythmias are inherited cardiac diseases. Genetic defects causal to the primary cardiac arrhythmias e.g. Long QT syndrome (LQTS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) are usually found in a gene that are responsible for cardiac action potential generation and eventual rhythmic contraction of the heart. Three most common genes associated with LQTS are KCNQ1, KCNH2, and SCN5A. In addition, CPVT causal genetic defects are found in Ca2+ handling genes e.g. RYR2, CASQ2, TECRL, CALM1, CALM2 and CALM3; clinical phenotype is usually severe. Mutations in CALM1, CALM2 and CALM3, though initially described in CPVT patients, but later they were found predominantly in LQTS patients with severe forms. Variability in clinical penetrance is observed mostly in carriers with a mutation in KCNQ1, KCNH2, and SCN5A genes. In 3-5% of patients, genetic defects could be found ≥ 2 genes, phenotype is usually severe in these patients. In addition, our study has also revealed that in some communities arrhythmia propensity could be severer due to recessive inheritance of the disease.Detection of a disease causal mutation facilitates in proper clinical diagnosis, which also leads to gene targeted therapeutic and behavioral management. Most importantly, mutation detection leads to cascade screening of the family members, where preventive measures could be implemented to prevent unwarranted sudden occurrence of ventricular fibrillation and/or sudden cardiac deaths.In my presentation, I will present different types of cardiac arrhythmias caused by defects in the aforementioned genes; pathophysiology of primary arrhythmias and their clinical management will be addressed. In particular, I will focus on a new type of hereditary malignant arrhythmia, CPVT3 (OMIM: 614021), which we have first reported in 2007.