Complexity of Molecular Genetics in the Inherited Cardiac Arrhythmias

The cardiac channelopathies are a group of heritable disorders that are associated with arrhythmia and sudden cardiac death in the presence of a structurally normal heart. These disorders have been associated to mutations in genes that encode cardiac ion channel subunits or proteins that interact with, and regulate, ion channels. Despite the identification of the underlying genetic defect in affected families, challenges remain. The observations of large phenotypic variability and reduced penetrance among carriers of the same familial mutation point out that in addition to the primary genetic defect, other genetic and nongenetic factors modify the manifestation of the disease. The role of common genetic variants identified through genome-wide association studies of electrocardiographic parameters in the general population, which could act as genetic modifiers for the cardiac channelopathies, is now being explored. In this chapter we will discuss the genetic substrate and the increasing understanding of the genetic complexity of these disorders.