High prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation

Circ Cardiovasc Genet. 2012 Aug 1;5(4):450-9. doi: 10.1161/CIRCGENETICS.111.962597. Epub 2012 Jun 8.

Abstract

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia. The cardiac sodium channel, Na(V)1.5, plays a pivotal role in setting the conduction velocity and the initial depolarization of the cardiac myocytes. We hypothesized that early-onset lone AF was associated with genetic variation in SCN5A.

Methods and results: The coding sequence of SCN5A was sequenced in 192 patients with early-onset lone AF. Eight nonsynonymous mutations (T220I, R340Q, T1304M, F1596I, R1626H, D1819N, R1897W, and V1951M) and 2 rare variants (S216L in 2 patients and F2004L) were identified. Of 11 genopositive probands, 6 (3.2% of the total population) had a variant previously associated with long QT syndrome type 3 (LQTS3). The prevalence of LQTS3-associated variants in the patients with lone AF was much higher than expected, compared with the prevalence in recent exome data (minor allele frequency, 1.6% versus 0.3%; P=0.003), mainly representing the general population. The functional effects of the mutations were analyzed by whole cell patch clamp in HEK293 cells; for 5 of the mutations previously associated with LQTS3, patch-clamp experiments showed an increased sustained sodium current, suggesting a mechanistic overlap between LQTS3 and early-onset lone AF. In 9 of 10 identified mutations and rare variants, we observed compromised biophysical properties affecting the transient peak current.

Conclusions: In a cohort of patients with early-onset lone AF, we identified a high prevalence of SCN5A mutations previously associated with LQTS3. Functional investigations of the mutations revealed both compromised transient peak current and increased sustained current.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Amino Acid Sequence
  • Atrial Fibrillation / complications
  • Atrial Fibrillation / epidemiology*
  • Atrial Fibrillation / genetics*
  • Atrial Fibrillation / physiopathology
  • Base Sequence
  • Cohort Studies
  • Computational Biology
  • DNA Mutational Analysis
  • Denmark / epidemiology
  • Family
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Humans
  • Long QT Syndrome / complications
  • Long QT Syndrome / epidemiology*
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / physiopathology
  • Molecular Sequence Data
  • Mutation / genetics*
  • NAV1.5 Voltage-Gated Sodium Channel / chemistry
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*

Substances

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