Molecular basis of inherited arrhythmias

The identification of the genetic origin of the congenital arrhythmias will transform our understanding of these hereditary diseases, as it has been the case for the long QT syndromes (LQTS), the Jervell and Lange-Nielsen (JLNS) and the Romano-Ward (RWS) syndromes. These syndromes, characterized by prolongation of the QTc interval on the ECG and syncopes or sudden death triggered by stress, are differentiated by their modes of transmission, recessive or dominant, and by the presence or absence of deafness. Recent advances have shown that they are genetically heterogenous and primary diseases of cardiac ion channels. Abnormalities in either inward (INa) or outward currents (IKs and IKr) can cause RWS. Abnormalities of IKs due to mutations in one the two genes (KVLQT1 and KCNE1) encoding channel subunits cause both RWS at the heterozygous state and JLNS at the homozygous state. These two genes are expressed in the cardiac cells and in the marginal cells of the stria vascularis where they regulate the endolymph homeostasis, thus explaining the deafness in JLNS patients. Ongoing studies are evaluating the function of the mutant channels and the relationship between individual mutations and the clinical manifestations of the syndrome.