The LQT syndromes - current status of molecular mechanisms

Our knowledge on the molecular genetics of inherited cardiac arrhythmias is very recent in comparison to the advances of genetics achieved in other in herited cardiac disorders. This is related to the high mortality and early disease onset of these arrhythmias resulting in mostly small nucleus famili es. Thus, traditional genetic linkage studies that are based on the genetic information obtained from large multi-generation families were made diffic ult. In 1991, the first chromosomal locus for congenital long-QT (LQT) syndrome was identified on chromosome 11p15.5 (LQT1 locus) by linkage analysis. Mean while, the disease-causing gene at the LQT1 locus (KCNQ1), a gene encoding a K+ channel subunit of the IKs channel, and three other, major genes, all encoding cardiac ion channel components, have been identified. Taken togeth er, LQT syndrome turned out to be a heterogeneous channelopathy. Moreover, the power of linkage studies to reveal the genetic causes of the LQT syndro me was also important to identify unknown but fundamental channel component s that contribute to the ion currents tuning ventricular repolarization. In -vitro expression of the altered ion channel genes demonstrated in each cas e that the altered ion channel function produces prolongation of the action potential and thus the increasing propensity to ventricular tachyarrhythmi as. Since these ion channels are pharmacological targets of many antiarrhyt hmic (and other) drugs, individual and potentially deleterious drug respons es may be related to genetic variation in ion channel genes. Very recently, also in acquired LQT syndrome, which is a frequent clinical disorder in ca rdiology a genetic basis has been proposed in part since mutations in LQT g enes have been specifically found. The discovery of ion channel defects in LQT syndrome represents the major a chievement in our understanding and implies potential therapeutic options. The knowledge of the genomic structure of the LQT genes now offers the poss ibility to detect the underlying genetic defect in 80-90 % of all patients. With this specific information, containing the type of ion channel (Na+ ve rsus K+ channel) and electrophysiological alteration by the mutation (loss- of-function versus change-of-function mutation), gene-directed, elective dr ug therapies have been initiated in genotyped LQT patients. Based on prelim inary data, that were supported by in vitro studies, this approach may be u seful in recompensating the characteristic phenotypes in some LQT patients. Mutation detection is a new diagnostic tool which may become of more increa sing importance in patients with a normal QTc or just a borderline prolonga tion of the QTc interval at presentation. These patients represent approxim ately 40 % of all familial cases. Moreover, LQT3 syndrome and idiopathic ve ntricular fibrillation are allelic disorders and genetically overlap. In bo th mutations in the LQT3 gene SCN5A encoding the Na+ channel alpha-subunit for I-Na have been reported, Thus, the clinical nosology of inherited arrhy thmias may be reconsidered after elucidation of the underlying molecular ba ses. Meanwhile, genotype-phenotype correlations in large families are on the way to evaluate intergene, interfamilial, and intrafamilial differences in the clinical phenotype reflecting gene specific, gene-site specific, and indiv idual consequences of a given mutation. LQT syndrome is phenotypically hete rogeneous due to the reduced penetrance and variable expressivity associate d with the mutations. This paper discusses the current data on molecular genetics and genotype-ph enotype correlations and the implications for diagnosis and treatment.