High Prevalence of Long QT Syndrome–Associated SCN5A Variants in Patients With Early-Onset Lone Atrial Fibrillation

• DOI: 10.1161/circgenetics.111.962597
• Publication Date: 2012-06-09T03:59:41Z
• Authors: Morten S. Olesen; Lei Yuan; Bo Liang; Anders G. Holst; Nikolaj Nielsen; Jonas B. Nielsen; Paula L. Hedley; Michael Christiansen; Søren-Peter Olesen; Stig Haunsø; Nicole Schmitt; Thomas Jespersen; Jesper H. Svendsen
• Keywords: Proband; Nonsynonymous substitution; Minor allele frequency

Background— Atrial fibrillation (AF) is the most common cardiac arrhythmia. The sodium channel, Na V 1.5, plays a pivotal role in setting conduction velocity and initial depolarization of myocytes. We hypothesized that early-onset lone AF was associated with genetic variation SCN5A . Methods Results— coding sequence sequenced 192 patients AF. Eight nonsynonymous mutations (T220I, R340Q, T1304M, F1596I, R1626H, D1819N, R1897W, V1951M) 2 rare variants (S216L F2004L) were identified. Of 11 genopositive probands, 6 (3.2% total population) had variant previously long QT syndrome type 3 (LQTS3). prevalence LQTS3-associated much higher than expected, compared recent exome data (minor allele frequency, 1.6% versus 0.3%; P =0.003), mainly representing general population. functional effects analyzed by whole cell patch clamp HEK293 cells; for 5 LQTS3, patch-clamp experiments showed an increased sustained current, suggesting mechanistic overlap between LQTS3 In 9 10 identified variants, we observed compromised biophysical properties affecting transient peak current. Conclusions— cohort AF, high LQTS3. Functional investigations revealed both current