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


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.
Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark. morten.salling.olesen@rh.regionh.dk
Morten S
MS
Olesen
Lei
L
Yuan
Bo
B
Liang
Anders G
AG
Holst
Nikolaj
N
Nielsen
Jonas B
JB
Nielsen
Paula L
PL
Hedley
Michael
M
Christiansen
Søren-Peter
SP
Olesen
Stig
S
Haunsø
Nicole
N
Schmitt
Thomas
T
Jespersen
Jesper H
JH
Svendsen
D017668:Age of Onset; D000595:Amino Acid Sequence; D001281:Atrial Fibrillation / Q000150:complications / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D001483:Base Sequence; D015331:Cohort Studies; D019295:Computational Biology; D004252:DNA Mutational Analysis; D003718:Denmark / Q000453:epidemiology; D005190:Family; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008133:Long QT Syndrome / Q000150:complications / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics*
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human