Clinical and Molecular Heterogeneity in the Brugada Syndrome

Abstract

Background — Brugada syndrome is a form of idiopathic ventricular fibrillation characterized by a right bundle-branch block pattern and ST elevation (STE) in the right precordial leads of the ECG. Sodium channel blockers increase STE. Mutations of the cardiac sodium channel SCN5A cause the disorder, and an implantable cardioverter-defibrillator is often recommended for affected individuals. Mutations in other genes have not been identified, and it is not known if the efficacy of drug testing or the malignancy of arrhythmias correlates to the gene defect. Methods and Results — We performed histories, physical examinations, ECGs, and drug testing on a large multigenerational family with Brugada syndrome. DNA isolated from blood samples, polymorphic genomic markers, and polymorphisms within candidate sodium channels were used for a genome-wide screen, fine mapping, and linkage analysis. We identified 12 affected individuals (right bundle-branch block, ≥1-mm STE) with an autosomal dominant inheritance pattern characterized by incomplete penetrance that appeared to be dependent on age and sex. Four affected individuals had syncope and 2 had documented ventricular arrhythmias, but there was minimal family history of sudden death. Procainamide infusions did not identify additional affected individuals. Linkage was present to an ≈15-cM region on chromosome 3p22-25 (maximum LOD score=4.00). The sodium channel genes SCN5A , SCN10A , and SCN12A on chromosome 3 were excluded as candidates (LOD scores ≤−2). Conclusions — A Brugada syndrome locus distinct from SCN5A is associated with progressive conduction disease, a low sensitivity to procainamide testing, and a relatively good prognosis in a single large pedigree.