Brugada Syndrome 5

A number sign (#) is used with this entry because of evidence that Brugada syndrome-5 (BRGDA5) and a nonspecific cardiac conduction defect are caused by heterozygous mutation in the SCN1B gene (600235) on chromosome 19q13.

Description

Brugada syndrome is characterized by an ST segment elevation in the right precordial electrocardiogram leads (so-called type 1 ECG) and a high incidence of sudden death in patients with structurally normal hearts. The syndrome typically manifests during adulthood, with a mean age of sudden death of 41 +/- 15 years, but also occurs in infants and children (summary by Antzelevitch et al., 2005).

For a discussion of genetic heterogeneity of Brugada syndrome, see BRGDA1 (601144).

Clinical Features

Watanabe et al. (2008) studied 3 kindreds with conduction abnormalities, 1 Turkish, 1 French, and 1 Dutch; none of the families had a history of syncope, sudden cardiac death, or epilepsy. The Turkish proband was a 50-year-old woman who presented with palpitations and dizziness and had complete left bundle branch block on electrocardiogram (ECG); echocardiogram was normal. Electrophysiologic analysis revealed a prolonged His-ventricle interval of 80 ms and inducible atrioventricular nodal reentrant tachycardia; complete atrioventricular block occurred following atrial programmed stimulation and during induced tachycardia. Her brother was found to have bifascicular block (right bundle branch block and left anterior hemiblock), whereas their mother had a normal ECG. The French proband was a 53-year-old man who presented with chest pain but had normal coronary angiography and echocardiography; ECG revealed ST segment elevation typical of Brugada syndrome as well as conduction abnormalities, including a prolonged PR interval of 220 ms and left anterior hemiblock. Ventricular fibrillation was induced by programmed electrical stimulation in the absence of drugs. A baseline ECG in his brother, who had no history of palpitations or syncope, showed left anterior hemiblock and minor ST segment elevation suggestive of Brugada syndrome (type II saddleback abnormalities); on flecainide challenge, the ST segment elevation was exacerbated but did not meet the criteria for a diagnostic (type I) pattern. Their sister had a normal ECG and a negative flecainide test, but her son was found to have right bundle branch block and type II Brugada syndrome after flecainide challenge. The Dutch proband was a 17-year-old girl who had right bundle branch block and a prolonged PR interval of 196 ms on ECG; echocardiography was normal and a flecainide test for Brugada syndrome was negative. Her father had a normal ECG and a negative flecainide test.

Molecular Genetics

Watanabe et al. (2008) analyzed the SCN1B gene in 282 probands with Brugada syndrome and 44 patients with conduction disease in whom mutation in the SCN5A gene (600163) had been excluded, and identified 3 mutations in 3 kindreds, 1 French, 1 Turkish, and 1 Dutch (600235.0003, 600235.0004, and 600235.0005, respectively). The mutations were not found in 1,404 population controls. Functional studies showed that the sodium current was lower when Na(v)1.5 was coexpressed with these mutant SCN1B subunits than with wildtype.