CLINICAL AND MOLECULAR ANALYSIS OF THE BRUGADA SYNDROME

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Arrhythmias lead to considerable morbidity and mortality. Ventricular fibrillation and sudden cardiac death can occur in patients without significant structural heart disease in association with a right bundle branch block (RBBB) pattern and ST elevations (STE) in the right precordial leads of the surface EKG. This condition has come to be known as the Brugada syndrome. Mutations of the cardiac Na+ channel SCN5A have recently been shown to cause the Brugada syndrome in three small families. The optimal methods of diagnosis and treatment of the Brugada syndrome, as for most ventricular arrhythmias, remain unclear. We have identified a family with greater than 100 living members that has an inherited form of the Brugada syndrome characterized by a RBBB/STE EKG pattern, ventricular arrhythmias, and sudden death. EKGs of 52 at-risk family members identified 10 affected and 10 probable affected predominantly male individuals with an autosomal dominant inheritance pattern characterized by age- dependent penetrance. SCN5A and the other known long QT syndrome genes were excluded as candidates using linkage analysis. We hypothesize that a mutation of another cardiac ion channel is responsible for the Brugada syndrome in this family. We therefore propose to study the clinical and molecular features of this, the largest family reported with the disorder. Noninvasive (stress testing, signal averaged EKG, Holter monitoring with ST segment analysis, high resolution body surface mapping with tilt table testing and/or pharmacological manipulations) and invasive electrophysiology studies will be compared to serial EKGs for detection syndrome and prediction of arrhythmias. Echocardiography and MRI will be used to search for subtle cardiac structural abnormalities. The chromosomal locus of the gene that causes the disorder will be identified by linkage analysis. The gene and the mutation will then be determined, either by a candidate gene approach or by positionally cloning of a new cardiac ion channel subunit. The identification of cardiac K+ and Na+ channel mutations as the cause of inherited arrhythmias has led to much excitement during the last two years. These disorders, although quite rare, have provided considerable insight into cardiac electrophysiology and the mechanisms that promote ventricular arrhythmias. Identification of a second Brugada syndrome gene and characterization of the clinical syndrome that it causes will provide further insight into the role of specific ion channels in the human heart, the factors which promote ST and T-wave changes on the EKG, and the mechanisms by which these factors lead to sudden cardiac death.