Genetic variants in SCN5A promoter are associated with arrhythmia phenotype severity in patients with heterozygous loss-of-function mutation

Heart Rhythm. 2012 Jul;9(7):1090-6. doi: 10.1016/j.hrthm.2012.02.023. Epub 2012 Feb 24.


Background: Heterozygous SCN5A mutations have been associated with varied arrhythmia phenotypes; phenotype severity may range from asymptomatic electrocardiographic changes (mild phenotype) to symptomatic arrhythmias resulting in syncope, cardiac arrest, and sudden cardiac death (severe phenotype) even among family members carrying the same mutation. Risk-stratification schemes for SCN5A mutation carriers remain uncertain.

Objective: To determine the role of SCN5A promoter variants and DNA methylation by using a family-based approach in predicting phenotype severity in a kindred with loss-of-function SCN5A mutation.

Methods: In a large kindred with a heterozygous SCN5A loss-of-function mutation (1936delC, Q646RfsX5; 22 mutation carriers), we sought SCN5A promoter variants. In addition, we assessed SCN5A and genome-wide DNA methylation profiles on genomic DNA derived from blood (Illumina Human Methylation27 BeadChip).

Results: During systematic survey of the 2.8-kb SCN5A promoter region, we identified 2 single nucleotide polymorphisms in complete linkage disequilibrium (rs41310749 and rs41310239). These promoter variants were significantly associated with disease severity (mild vs severe phenotype) (P = .0007), as all 3 patients with severe phenotype carried the 2-SNP variant on both mutant and wild-type alleles. Analysis did not support a role for the methylation of SCN5A-related genes.

Conclusion: These family-based genetic findings suggest that the presence of specific promoter variants increase the risk of a severe phenotype in heterozygous carriers of an SCN5A loss-of-function mutation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Arrhythmias, Cardiac / genetics*
  • DNA Fingerprinting
  • DNA Methylation
  • Death, Sudden, Cardiac
  • Female
  • Genetic Linkage
  • Genetic Variation
  • Genome-Wide Association Study
  • Haplotypes
  • Humans
  • Linkage Disequilibrium
  • Male
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*
  • Pedigree
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic / genetics*
  • Young Adult


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