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

Can J Cardiol. 2005 Sep;21(11):925-31.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Ajmaline
  • Anti-Arrhythmia Agents
  • Bundle-Branch Block / diagnosis
  • Bundle-Branch Block / genetics
  • Bundle-Branch Block / physiopathology
  • Cell Line
  • Codon, Nonsense*
  • Death, Sudden, Cardiac / prevention & control
  • Electrocardiography
  • Female
  • Heart Diseases / diagnosis
  • Heart Diseases / genetics*
  • Heart Diseases / physiopathology
  • Humans
  • Male
  • Microscopy, Fluorescence
  • Middle Aged
  • Molecular Biology
  • Muscle Proteins / genetics*
  • Mutagenesis
  • NAV1.5 Voltage-Gated Sodium Channel
  • Patch-Clamp Techniques
  • Pedigree
  • Phenotype
  • Sodium Channels / genetics*
  • Sodium Channels / physiology
  • Syndrome
  • Transfection


  • Anti-Arrhythmia Agents
  • Codon, Nonsense
  • Muscle Proteins
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Sodium Channels
  • Ajmaline