[Molecular genetics of the long QT syndrome: clinical aspects].

The long QT syndrome (LQTS) is a heart disorder which is characterised by the prolongation of the QT interval of the surface electrocardiogram and is associated with malignant arrhythmias, syncopal episodes, torsade de pointes form ventricular tachycardias and an increased risk of sudden cardiac death. There are two familial forms of LQTS, the autosomal dominant Romano-Ward syndrome and the autosomal recessive Jervell-Lange-Nielsen syndrome which is associated with congenital senzorineural deaf-mutism. Recent advances in molecular genetics have allowed to identify mutations in four genes, KvLQT1 (11p15.5), HERG (7q35), SCN5A (3p21) and minK (21q22), which cause LQTS. There is a fifth genetic locus known on chromosome 4 (4q25-27), where the disease causing gene has not been identified yet. As LQTS genes code proteins which form sodium and potassium channels of the heart, LQTS can be regarded as the disease of cardiac ion channels. The KvLQT1 and minK genes code the slowly activating, delayed rectifier (Iks) potassium channel, the HERG gene code the rapidly activating, delayed rectifier (Ikr) potassium channel of the heart, while the SCN5A gene codes a cardiac sodium channel. Mutations in KvLQT1, minK and HERG genes affects repolarising, rectifier potassium currents, while SCN5A mutations cause delayed inactivation and reopening of the cardiac sodium channel, which initiates the depolarisation of cardiac cells. Both alterations result in a prolongation of cardiac repolarisation which is represented in the elongation of the QT interval. Elucidation of the genetic base of the disease provided new tools in the clinical management of LQTS. It has been shown that changes in the repolarisation parameters on the ECG may be predictive for the causative gene and different LQTS genes are associated with different clinical picture. More importantly, it is possible to use "gene-specific" therapy in LQTS which specifically targets ion channels affected by given gene mutations.