The Molecular Ggenetics of the Long QT Syndrome: Genes Causing Fainting and Sudden Death

The congenital long QT syndrome is an autosomal-dominant genetic disorder of cardiac electrical repolarization. It is caused by mutations of at least six genes, of which four, all encoding for cardiac ion channels, have been identified: KVLQT1, HERG, and Min K encode for cardiac potassium ion channels, and SCN5A encodes for the cardiac sodium ion channel. In each case the altered ion channel function produces prolongation of the action potential and propensity to torsade de pointes ventricular tachycardia. A fifth gene locus is known to be on chromosome 4, but the gene has not been isolated. At least one other gene must exist, and there may be several more. Long QT syndrome is a frequent but often overlooked cause of unexpected syncope and sudden death in children and young adults. Characteristic findings are prolongation of the QT interval and T wave abnormalities on the electrocardiogram. However, the QT interval at presentation is normal about 10% of the time and just borderline prolonged another 30%, so diagnosis may be difficult. Symptoms are syncope and sudden death, typically occurring during exercise or emotional upset. The manifestations vary, depending on the genotype present. The phenotype also probably varies, depending on the specific mutation involved. Phenotypic heterogeneity is also caused by variable penetrance and expressivity.