Kcnq1 P.ARG231HIS–ASSOCIATED Early–onset Atrial Fibrillation With Mild Long Qt Syndrome Phenotype: A Familial Case Highlighting Opposite Atrial and Ventricular Electrophysiology

Background Early–onset isolated atrial fibrillation (AF) is often characterized by a complex genetic substrate, including rare variants with incomplete penetrance and variable expressivity, related to channelopathies or cardiomyopathies. We describe a familial case. Cases The proband is a competitive male athlete evaluated in 2012 at age 10 for asymptomatic AF detected during sports eligibility screening. Holter ECG confirmed AF with a normal QTc. Electrical cardioversion (ECV) was performed after anticoagulation and flecainide therapy, restoring sinus rhythm (QTc 400 ms). Flecainide was stopped after six months, and sports eligibility resumed. In 2016, AF recurred asymptomatically and ECV was repeated. Cardiac MRI and Brugada–lead Holter monitoring were unremarkable, and an implantable loop recorder was placed. Over the following years, three additional asymptomatic AF recurrences occurred, culminating in pulmonary vein isolation (PVI) by radiofrequency ablation in July 2022. Voltage mapping during AF showed no low–voltage areas and a very short atrial cycle length (90–100 ms). Ambulatory ECG monitoring under flecainide (100 mg bid) showed suboptimal QTc adaptation at night with T–wave notching. Genetic testing revealed the KCNQ1 p.Arg231His variant, a missense change in the S4 segment of IKs, associated with both early–onset AF and a mild LQT1 phenotype. In atrial myocardium, the variant exerts a gain–of–function effect, shortening action potential duration and atrial refractoriness, thereby promoting AF, as opposed to the conventional loss–of–function effect in the ventricular myocardium. Maximal exercise testing showed largely preserved QT behavior with transient maladaptation during early phases and after standing. Nadolol was initiated and up titrated. The proband’s father had AF onset at 16 and an asymptomatic recurrence at 42 treated with ECV. In 2025 he underwent PVI with cryoablation and ECV for tachycardiomyopathy (LVEF ∼30%, NT–proBNP 9826 pg/mL). QTc remained upper–normal to mildly prolonged at times (448 ms in AF at 130 bpm, 447 ms post–ablation in sinus rhythm). Conclusions This case underscores that early–onset AF may reveal actionable genetic etiologies. The KCNQ1 p.Arg231His variant drives opposite atrial and ventricular electrophysiology. Genetic testing in young patients with isolated AF has diagnostic, therapeutic, and familial implications, guiding rhythm management and cascade screening.