Abstract 357: Novel Gain of Function SCN5A Mutation Causes Familial Atrial Fibrillation

Abstract

Background : Few genetic etiologies are known for familial or sporadic cases of atrial fibrillation, which is the most common arrhythmia in older adults. We report a mother and son, both with atrial fibrillation, who were found to have a novel mutation in the sodium channel gene, SCN5A. Case History: The proband, a 50 year old male, first developed paroxysmal atrial fibrillation following orthopedic surgery. At age 57, he presented with increasing fatigue and shortness of breath and was found to have chronic atrial fibrillaion. Cardiac testing found no evidence of ischemia, normal left ventricular function and mild left atrial dilation. His mother had paroxysmal atrial fibrillation, diagnosed at age 63, and a history of well-controlled hypertension and palpitations. Her atrial fibrillation was initially controlled by sotalol, but worsening symptoms led to a change to amiodarone at age 83. Her echo showed mild biatrial enlargement. ECGs for the proband and his mother have never demonstrated conduction system disease, long QT, or a Brugada pattern. Methods and Results: Genomic DNA isolated from blood lymphocytes was screened using direct sequencing techniques. Genes previously reported to be associated with atrial fibrillation, KCNA5, GJA5 and KCNQ1, were screened and no mutations were found. In the sodium channel gene, SCN5A, a novel missense mutation was identified (c. 1493K>R) in both the proband and his mother, but not in an unaffected sibling or in the proband’s 2 asymptomatic offspring. The mutation is in a highly conserved lysine residue in the voltage-gated sodium channel gene family. Functional studies recorded macroscopic sodium currents from tsA201 cells expressing both the wild-type (Nav1.5/WT) and mutant channel (Nav1.5/K1493R). The mutant channel exhibited fast activation and inactivation kinetics and an increase in current density. No effect on steady-state activation and inactivation were observed, however, current deactivation was faster in mutant Nav1.5/K1493R as compared to the WT channels. Conclusions: This is the first report of an inherited SCN5A mutation in familial atrial fibrillation. Functional studies suggest a ’gain-of-function’ effect of the identified Nav1.5/K1493R mutation.