Understanding cardiac electrical phenotypes in the genomic era

Sudden cardiac death (SCD) is defined as unexpected death due to a cardiac cause. It most often results from life-threatening ventricular fibrillation (VF) and ranks among the most common causes of death worldwide, with an incidence in the community varying between 0.6 and >1.4 per 1,000 individuals. Because SCD mostly occurs in individuals without previously known cardiac disease, the identification of patients at risk for SCD and implementation of preventive measures could save many lives.
The etiology of SCD is complex and susceptibility to SCD is likely governed by a combination of inherited and environmental factors.
The identification of genetic factors that modulate risk for sudden cardiac arrest (SCA) is important as it allows the pre-symptomatic identification of individuals at risk for SCA. The identification of such genetic factors also provides molecular leads for mechanistic studies that may in turn lead to better-targeted therapies. Similarly, as the electrocardiogram (ECG) reflects the electrical activity of the heart (and is instrumental for the diagnosis of many cardiac disorders), a deep understanding of molecular factors that modulate the different ECG parameters is pertinent. This thesis has accordingly focused on the identification of novel genes and genetic variants that (i) are associated with cardiac disease and SCD in affected families, or (ii) modulate ECG parameters. The thesis primarily focused on the genetics of cardiac electrical phenotypes (a word that stems from the Greek words phainein meaning "to show" and typos meaning "type"). To achieve this aim we used a broad range of state-of-the-art technologies and experimental approaches ranging from human genetic studies to studies in genetically engineered mice.