Clinical and molecular heterogeneity in the Brugada syndrome: A novel gene locus on chromosome 3

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 impla...

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Published in:	Circulation (New York, N.Y.) Vol. 105; no. 6; pp. 707 - 713
Main Authors:	WEISS, Raul, BARMADA, M. Michael, NGUYEN, Tuduy, SEIBEL, Jolene S, CAVLOVICH, Doris, KORNBLIT, Cari A, ANGELILLI, Adam, VILLANUEVA, Flordeliza, MCNAMARA, Dennis M, LONDON, Barry
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott Williams & Wilkins 12-02-2002 American Heart Association, Inc
Subjects:	Adult Age Factors Aged Biological and medical sciences Bundle-Branch Block - diagnosis Bundle-Branch Block - epidemiology Bundle-Branch Block - genetics Bundle-Branch Block - physiopathology Cardiac dysrhythmias Cardiology. Vascular system Chromosomes, Human, Pair 3 - genetics Comorbidity Death, Sudden, Cardiac - epidemiology Disease Progression Electrocardiography Female Genetic Linkage Heart Heart Conduction System - physiopathology Humans Incidence Lod Score Male Medical sciences Middle Aged NAV1.5 Voltage-Gated Sodium Channel Pedigree Penetrance Polymorphism, Genetic Procainamide Prognosis Sex Factors Sodium Channels - genetics Syncope - epidemiology Syncope - genetics Syndrome Ventricular Fibrillation - diagnosis Ventricular Fibrillation - epidemiology Ventricular Fibrillation - genetics Ventricular Fibrillation - physiopathology Human Arrhythmia Sudden death Right Cardiovascular disease Bundle branch block Ionic channel Chromosome 3 Conduction disorder Genetic determinism Excitability disorder Ventricular fibrillation ST elevation Heart block Heart disease Sodium ion
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Summary:	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. 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, > or =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 approximately equal 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 < or =-2). 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0009-7322 1524-4539
DOI:	10.1161/hc0602.103618