High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations

J Am Coll Cardiol. 2005 Dec 6;46(11):2100-6. doi: 10.1016/j.jacc.2005.08.043. Epub 2005 Nov 4.


Objectives: We carried out a complete screening of the SCN5A gene in 38 Japanese patients with Brugada syndrome to investigate the genotype-phenotype relationship.

Background: The gene SCN5A encodes the pore-forming alpha-subunit of voltage-gated cardiac sodium (Na) channel, which plays an important role in heart excitation/contraction. Mutations of SCN5A have been identified in 15% of patients with Brugada syndrome.

Methods: In 38 unrelated patients with clinically diagnosed Brugada syndrome, we screened for SCN5A gene mutations using denaturing high-performance liquid chromatography and direct sequencing, and conducted a functional assay for identified mutations using whole-cell patch-clamp in heterologous expression system.

Results: Four heterozygous mutations were identified (T187I, D356N, K1578fs/52, and R1623X) in 4 of the 38 patients. All of them had bradyarrhythmic complications: three with sick sinus syndrome (SSS) and the other (D356N) with paroxysmal complete atrioventricular block. SCN5A-linked Brugada patients were associated with a higher incidence of bradyarrhythmia (4 of 4) than non-SCN5A-linked Brugada patients (2 of 34). Families with T187I and K1578fs/52 had widespread penetrance of SSS. Notably, the patient with K1578fs/52, who had been diagnosed as having familial SSS without any clinical signs of Brugada syndrome, showed a Brugada-type ST-segment elevation after intravenous administration of pilsicainide and programmed electrical stimulation-induced ventricular tachycardia. All of the mutations encoded non-functional Na channels, and thus were suggested to cause impulse propagation defect underlying bradyarrhythmias.

Conclusions: Our findings suggest that loss-of-function SCN5A mutations resulting in Brugada syndrome are distinguished by profound bradyarrhythmias.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Asian People / genetics
  • Bradycardia / complications*
  • Bradycardia / genetics*
  • Bundle-Branch Block / complications*
  • Bundle-Branch Block / genetics*
  • Chromatography, High Pressure Liquid
  • Codon, Nonsense
  • DNA Mutational Analysis
  • Female
  • Frameshift Mutation
  • Humans
  • Male
  • Middle Aged
  • Mutagenesis, Site-Directed
  • NAV1.5 Voltage-Gated Sodium Channel
  • Patch-Clamp Techniques
  • Sodium Channels / genetics*
  • Syndrome


  • Codon, Nonsense
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Sodium Channels