Key result
Early-onset lone atrial fibrillation was associated with a significantly higher minor allele frequency of LQTS3-associated SCN5A variants compared to the general population (1.6% vs 0.3%; P=0.003).
Why the study?
Is early-onset lone atrial fibrillation associated with genetic variation in SCN5A?
Observational (n=192)
Is early-onset lone atrial fibrillation associated with genetic variation in SCN5A?
Absolute Event Rate: 1.6% vs 0.3%
p-value: p=0.003
Early-onset lone AF is associated with a high prevalence of SCN5A mutations previously linked to LQTS3, which exhibit compromised transient peak current and increased sustained current.
May support SCN5A testing in early-onset lone AF; extends LQTS3 variant links but remains hypothesis-generating.
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. METHODS AND 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.
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Olesen et al. (2012) conducted an observational in Early-onset lone atrial fibrillation (n=192). SCN5A genetic variation vs. General population (recent exome data) was evaluated on Minor allele frequency of LQTS3-associated variants (p=0.003). Early-onset lone atrial fibrillation was associated with a significantly higher minor allele frequency of LQTS3-associated SCN5A variants compared to the general population (1.6% vs 0.3%; P=0.003).
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