Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation

Abstract

Background: Genetic studies have identified ion channel gene variants in families segregating atrial fibrillation (AF), the most common arrhythmia in clinical practice. Here, we tested the hypothesis that vulnerability to AF is associated with variation in SCN5A, the gene encoding the cardiac sodium channel.

Methods and results: We resequenced the entire SCN5A coding region in 375 subjects with either lone AF (n=118) or AF associated with heart disease (n=257). Controls (n=360) from the same population were then genotyped for the presence of mutations or rare variants identified in the AF cases. In 10 probands (2.7%), 8 novel variants not found in the control population (0%; P=0.001) were identified. All variants affect highly conserved residues in the SCN5A protein. In 6 families with >1 affected member, the novel variant cosegregated with AF. We also identified 11 rare missense variants in 12 probands (3.2%) that have previously been associated with inherited arrhythmia syndromes (eg, congenital long-QT syndrome and Brugada syndrome).

Conclusions: Mutations or rare variants in SCN5A may predispose patients with or without underlying heart disease to AF. The findings of the present study expand the clinical spectrum of disorders of the cardiac sodium channel to include AF and represent important progress toward molecular phenotyping and directed rather than empirical therapy for this common arrhythmia.

Figure 1. Novel SCN5A variants in atrial fibrillation probands

Upper panels illustrate DNA sequencing traces for each novel variant. The lower panel illustrates the locations of the novel SCN5A variants in the sodium channel protein.

Figure 2. Pedigrees of Eight Families with Atrial Fibrillation (AF) and Novel SCN5A variants

Squares indicate male and female family members respectively with slash marks indicating deceased individuals. Arrows indicate the probands. Totally solid symbols indicate the presence of AF. Open symbols indicate unaffected members, and half-shading indicates individuals with AF by history. Grey shaded symbols indicate individuals who status was indeterminate. The presence (+) or absence (−) of a SCN5A variant is indicated for persons with DNA samples available for testing. In AF406, individuals diagnosed with hypertrophic cardiomyopathy are identified by *.

Figure 3

Rare and disease-associated SCN5A variants in atrial fibrillation probands illustrated by position within the sodium channel protein topology. LQTS = long QT syndrome; SIDS = sudden infant death syndrome.