Genetic of Long QT, Brugada and Other Channelopathies

In the early nineties the seminal work of Mark Keating and his group introduced the concept that inherited DNA abnormalities of the genes encoding cardiac ion channels create an arrhythmogenic substrate predisposing to sudden cardiac death (1-3). Despite Keating and coworkers mainly focused on the Long QT Syndrome (LQTS), it became shortly evident that genes encoding ion channels represent the genetic substrate for several other arrhythmogenic syndromes occurring in the structurally intact heart that are frequently labeled as “idiopathic ventricular fibrillation”. In the last ten years, thank to the concerted effort of several research teams around the world, major conceptual innovations have occurred in the field of inherited arrhythmogenic syndromes. At least ten genes have been associated with genetically determined electrical instability of the heart confirming the high genetic heterogeneity of arrhythmogenic diseases. It is now recognized that for each clinical entity (long QT Syndrome, catecholaminergic VT …) there are multiple genetic substrates. Remarkably, genotype-phenotype correlation studies have highlighted the presence of major distinguishing features of each genetic variant of inherited arrhythmogenic diseases suggesting that each of them should be regarded as a separate disease. For example, albeit all LQTS patients share the electrocardiographic feature of prolonged QT interval, the phenotypical differences that exist in the different genetic forms outweigh the apparent similarities. Accordingly, the development of gene-specific risk stratification algorithms and gene-specific treatments are being developed suggesting that when genetic testing will becomes available as a routine procedure, diagnosis of inherited diseases and their management will be based on the genetic defect of the individual patient. This will require that the classification and the nomenclature of inherited arrhythmogenic syndromes is redefined incorporating not only the phenotype but also the molecular substrate and its functional consequences. Here we propose a novel classification for inherited arrhythmogenic diseases that is centered on the genetic defect rather than on the clinical manifestations. In this classification we identify three major clusters of diseases based on the control of similar subcellular pathways (transmembrane action potential control, intracellular calcium handling, targeting or anchoring proteins): 1) diseases of voltage-dependent ion channels, 2) diseases of intracellular calcium handling proteins 3) diseases of anchoring proteins. Each cluster includes one or more disease types according to the specific function of the abnormal proteins. We will therefore define as affected by “IKr disease” patients with genetic defect on the genes encoding HERG and MIRP proteins that are the alpha- and the beta- subunit of the IKr conducting channel. To distinguish patients affected by mutations on each specific gene, disease subtypes are identified such as in the previous example the term LQT1 and LQT5 diseases will identify mutations on KCNH2 and on KCNE2, respectively (table I). This classification reflects the complexity of arrhythmogenic diseases but it provides a scheme to formulate a comprehensive diagnosis that incorporates multiple information spanning from the genetic defect to the function of the affected protein and to the clinical phenotype. Applying the proposed classification we will describe the molecular basis of the different diseases, their functional consequences and the distinguishing phenotypical features of each sub-type: clinical aspects related to clinical management of patients with this syndromes are discussed in chapters (Moss LQT, Schwartz LQT, Napolitano CPVT, Brugada BRUGADA).