A novel nonsense mutation in the SCN5A gene leads to Brugada syndrome and a silent gene mutation carrier state.

Background: Brugada syndrome (BS) is an electrical cardiac disorder with a right bundle branch block and ST segment elevation in leads V1 to V3 on surface electrocardiograms (ECGs), and is a syndrome that may lead to sudden cardiac death.

Purpose: The aim of the present study was to screen for mutations in the SCN5A gene in a family with BS, and to characterize the consequences of the mutation on channel function.

Results: A heterozygous nonsense SCN5A mutation (W822X) was identified in the index patient. The mutation was confirmed in the patient's asymptomatic 16-year-old brother and 48-year-old father. The mutation was absent in the index patient's sister and mother. The ECG of the index patient showed a BS type 2 ECG phenotype, which converted into a type 1 ECG phenotype in the presence of flecainide. The ECG of the patient's brother was not typical for BS, but ajmaline treatment unmasked a type 1 ECG phenotype. The ECG of the asymptomatic father was normal at baseline and in the presence of ajmaline. No Na+ currents could be measured in tsA201 cells transfected with W822X mutant channels. Heterozygote expression showed a nearly 50% reduction in Na+ current amplitude with no significant alterations of biophysical properties, indicating a loss of functional Na+ channels, obviously without any dominant-negative activity on wild type channels.

Conclusions: The haploinsufficiency of the Nav1.5 protein is the plausible explanation for the clinical BS phenotype in this family. Because the heterozygous W822X mutation theoretically leads to channel expression at one-half of the normal level, the authors suggest that a modifier gene may influence or rescue the phenotype in the asymptomatic family members.