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 La nge-Nielsen (JLNS) and the Romano-Ward (RWS) syndromes. These syndrome s, characterized by prolongation of the QTc interval on the ECG and sy ncopes or sudden death triggered by stress, are differentiated by thei r modes of transmission, recessive or dominant, and by the presence or absence of deafness. Recent advances have shown that they are genetic ally heterogenous and primary diseases of cardiac ion channels. Abnorm alities in either inward (INa) or outward currents (IKs and IKr) can c ause RWS. Abnormalities of IKs due to mutations in one the two genes ( KVLQT1 and KCNE1) encoding channel subunits cause both RWS at the hete rozygous state and JLNS at the homozygous state. These two genes are e xpressed in the cardiac cells and in the marginal cells of the stria v ascularis where they regulate the endolymph homeostasis, thus explaini ng the deafness in JLNS patients. Ongoing studies are evaluating the f unction of the mutant channels and the relationship between individual mutations and the clinical manifestations of the syndrome.