Molecular genetics of long-QT syndrome.

Recent discoveries of genes involved in long-QT syndrome (LQTS) have led to extensive progress in understanding the molecular basis for this disorder of syncope and sudden cardiac death secondary to ventricular arrhythmias. The emerging unifying theme is that all genes identified to date encode either structural or regulatory subunits for ion channels involved in cardiac repolarization. Defects have been identified in the KCNQ1, HERG, and KCNE1 genes, whose proteins form the K+ channels for the slowly and rapidly inwardly rectifying K+ currents IKs and IKr. Depending on their location and copy number, mutations of KCNQ1 and KCNE1 can cause either autosomal dominant Romano-Ward syndrome or autosomal recessive Jervell and Lange-Nielsen syndrome. The cardiac sodium channel gene, SCN5A, is also mutated in some Romano-Ward cases to produce defects in INa, the cardiac inward Na+ current. The fact that multiple genes are involved and that most LQTS mutations are "private" or "family-specific" complicates molecular diagnosis of LQTS which, currently, is limited to a small number of research laboratories. In future, genotypic determination of LQTS patients and their family members will hopefully lead to improved gene-specific prognostic determinations and therapeutic interventions.