A Brugada syndrome proband with compound heterozygote SCN5A mutations identified from a Chinese family in Singapore

Europace. 2016 Jun;18(6):897-904. doi: 10.1093/europace/euv058. Epub 2015 Mar 31.


Aims: Brugada syndrome (BrS) is a rare heritable ventricular arrhythmia. Genetic defects in SCN5A, a gene that encodes the α-subunit of the sodium ion channel Nav1.5, are present in 15-30% of BrS cases. SCN5A remains by far, the highest yielding gene for BrS. We studied a young male who presented with syncope at age 11. This proband was screened for possible disease causing SCN5A mutations. The inheritance pattern was also examined amongst his first-degree family members.

Methods and results: The proband had a baseline electrocardiogram that showed Type 2 BrS changes, which escalated to a characteristic Type I BrS pattern during a treadmill test before polymorphic ventricular tachycardia onset at a cycle length of 250 ms. Mutational analysis across all 29 exons in SCN5A of the proband and first-degree relatives of the family revealed that the proband inherited a compound heterozygote mutation in SCN5A, specifically p.A226V and p.R1629X from each parent. To further elucidate the functional changes arising through these mutations, patch-clamp electrophysiology was performed in TSA201 cells expressing the mutated SCN5A channels. The p.A226V mutation significantly reduced peak sodium current (INa) to 24% of wild type (WT) whereas the p.R1629X mutation abolished the current. To mimic the functional state in our proband, functional expression of the compound variants A226V + R1629X resulted in overall peak INa of only 13% of WT (P < 0.01).

Conclusion: Our study is the first to report a SCN5A compound heterozygote in a Singaporean Chinese family. Only the proband carrying both mutations displayed the BrS phenotype, thus providing insights into the expression and penetrance of BrS in an Asian setting.

Keywords: Brugada syndrome; Channelopathy; Compound heterozygote; Nav1.5; SCN5A.

MeSH terms

  • Adolescent
  • Adult
  • Asian Continental Ancestry Group
  • Brugada Syndrome / genetics*
  • Cell Line
  • DNA Mutational Analysis
  • Electrocardiography
  • Exons
  • Female
  • Heterozygote*
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*
  • Pedigree
  • Phenotype
  • Singapore
  • Tachycardia, Ventricular / genetics*
  • Young Adult


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