High frequency of long qt syndrome-associated genetic variants in patients with early-onset lone atrial fibrillation

Abstract

Background: Atrial fibrillation (AF) is an increasingly common cardiac arrhythmia. Evidence supports that AF has a significant genetic component, and some reports point toward a shared pathophysiology underlying AF and congenital long QT syndrome (LQTS). Purpose: To investigate the frequency of previously published LQTS-associated genetic variants in patients with early-onset lone AF (i.e., AF in the absence of traditional risk factors such as hypertension and ischemic or structural heart disease). Methods and results: We included 210 patients with onset of lone AF before the age of 40 years. Sequencing of all 13 genes so far associated with LQTS revealed 12 patients (6%) carrying a genetic variant previously associated with LQTS. Two LQTS-associated variants were identified in KCNQ1, one in KCNH2, six in SCN5A, one in KCNE2, and two in CAV3. The LQTS-associated variant frequency in the lone AF population was compared to the frequency of LQTS-associated variants in an ethnically matched population represented by recent exome data from the NHLBI GO Exome Sequencing Project (ESP). This comparison revealed that the lone AF patients had a marked overrepresentation of LQTS-associated variants (12 out of 420 alleles, 3.10%) compared with the ESP population (91 out of 6,999 alleles, 1.30%, P = 0.008). Conclusion: We found that patients with early-onset lone AF carry a high frequency of genetic variants previously associated with LQTS. Because such variants may increase the risk of life-threatening arrhythmic events, our finding could have clinical implications for future treatment and risk stratification of lone AF patients.