Abstract 9693: Onset of Lone Atrial Fibrillation Before 40 Years is Associated with a High Prevalence of Mutations in the Cardiac Sodium Channel

Abstract

Introduction Atrial Fibrillation (AF) is the most common sustained arrhythmia. Studies screening SCN5A, the gene encoding the α-subunit of the cardiac sodium channel, have reported that around 0-2 % of general AF patients have mutations in the gene. Hypothesis We tested the hypothesis that early onset lone AF is associated with a high prevalence of genetic variation in SCN5A and CAV3, both genes encoding important components of the cardiac sodium channel. Methods We sequenced the coding region and splice-site of SCN5A and CAV3 in 192 early onset lone AF patients. Only lone AF patients with onset of disease before the age of 40 years and without traditional risk factors for AF were included; patients with structural heart disease, diabetes or metabolic diseases or other disease were excluded. For electrophysiological patch clamp studies HEK cells were transiently co-transfected with pcDNA3-hSCN5A, and pcDNA3-eGFP as a reporter gene. Results Of 192 probands with early onset lone AF, nine non-synonymous mutations were found in ten probands: eight mutations in SCN5A; T220I, R340Q, T1304M, F1596I, R1626H (novel), D1819N, R1897W (novel), V1951M and one mutation in CAV3 (T78M in two patients). None of the mutations were present in public available databases and only V1951M has previously been reported in conjunction to AF. All other mutations affected evolutionarily conserved residues. All patient caring SCN5A mutations underwent a flecainide test, without inducing any sings of Brugada ECG pattern. SCN5A, T220I, T1304M and CAV3 T78M has been electrophysiologically investigated earlier and the mutations all significantly compromises sodium current. In vitro electrophysiological studies were conducted of the remaining mutations. R340Q, R1626H and R1897W showed loss-of-function while T1304M showed gain-of-function. F1596I did not affect the electrophysiologic function while V1951 showed both loss-of-function and gain of function. Conclusions Ten out of 192 patients with early-onset lone AF had a non-synonymous mutation in SCN5A and CAV3. All ten mutations either had been or were investigated electrophysiologically and of those, seven mutations compromised the sodium current and are therefore suspected to enhance the susceptibility to AF.