Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome

J Am Coll Cardiol. 2014 Jul 8;64(1):66-79. doi: 10.1016/j.jacc.2014.04.032.


Background: BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Nav1.8, in the electrical function of the heart.

Objectives: The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS).

Methods: Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations.

Results: We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Nav1.8 and Nav1.5 in the plasma membrane.

Conclusions: Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.

Keywords: Brugada syndrome; cardiac arrhythmias; cardiac conduction disease; electrophysiology; genetics; sudden cardiac death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Brugada Syndrome / diagnosis*
  • Brugada Syndrome / genetics*
  • Female
  • Genetic Variation / genetics*
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense / genetics*
  • NAV1.8 Voltage-Gated Sodium Channel / genetics*
  • Young Adult


  • NAV1.8 Voltage-Gated Sodium Channel
  • SCN10A protein, human