ClinVar

In a 53-year-old French man who presented with chest pain but had normal coronary angiography and echocardiography, in whom electrocardiogram (ECG) revealed ST segment elevation typical of Brugada syndrome (BRGDA5; 612838), Watanabe et al. (2008) identified heterozygosity for a 536G-A transition in exon 3A of the SCN1B gene, resulting in a trp179-to-ter (W179X) substitution predicted to generate a truncated protein lacking the membrane-spanning segment and intracellular portion. The proband also had conduction abnormalities, including a prolonged PR interval of 220 ms and left anterior hemiblock, and ventricular fibrillation was induced by programmed electrical stimulation in the absence of drugs. The mutation was also found in the proband's brother, who had no history of palpitations or syncope, but on baseline ECG had 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, who also carried the mutation, had a normal ECG and a negative flecainide test, but her mutation-positive son was found to have right bundle branch block and type II Brugada syndrome after flecainide challenge. There was no family history of tachyarrhythmias, syncope, sudden cardiac death, or epilepsy. The mutation was not found in 1,404 population controls. Functional studies of the W179X mutation, which occurs only in the beta-1B transcript, showed that coexpression of wildtype beta-1B with Na(v)1.5 increased sodium current density by 69%, whereas coexpression with mutant beta-1B did not increase the sodium current compared to Na(v)1.5 alone; there was no evidence of a dominant-negative effect by the mutant. In addition, wildtype beta-1B produced negative shifts in the voltage dependence of Na(v)1.5 activation and inactivation, whereas mutant beta-1B did not modulate Na(v)1.5 gating.