Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies

Heart Rhythm. 2009 Mar;6(3):341-8. doi: 10.1016/j.hrthm.2008.11.009. Epub 2008 Nov 11.


Background: Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new tools for risk stratification are needed.

Objectives: We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype.

Methods: We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with <or=90% (M(active)) or >90% (M(inactive)) peak I(Na) reduction were analyzed separately.

Results: The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an M(active) mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak I(Na) reduction (T and M(inactive) mutants) had a significantly longer PR interval, compared with M(active) mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and M(inactive) groups than in the M(active) group.

Conclusion: In loss-of-function SCN5A channelopathies, patients carrying T and M(inactive) mutations develop a more severe phenotype than those with M(active) mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arrhythmias, Cardiac / diagnosis
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / physiopathology
  • Brugada Syndrome / diagnosis
  • Brugada Syndrome / genetics*
  • Brugada Syndrome / physiopathology
  • Codon, Terminator / genetics
  • Death, Sudden, Cardiac / etiology
  • Female
  • Heart Conduction System / physiopathology*
  • Humans
  • Male
  • Middle Aged
  • Muscle Proteins / genetics*
  • Mutation*
  • Mutation, Missense
  • NAV1.5 Voltage-Gated Sodium Channel
  • Phenotype
  • Risk Assessment
  • Sodium Channel Blockers / pharmacology
  • Sodium Channels / genetics*


  • Codon, Terminator
  • Muscle Proteins
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Sodium Channel Blockers
  • Sodium Channels