PO-04-124 ARRHYTHMIAS INCLUDING ATRIAL FIBRILLATION IN KLEEFSTRA SYNDROME: A POSSIBLE EPIGENETIC LINK

Abstract

Kleefstra syndrome (KS), often diagnosed in early childhood, is a rare genetic disorder (EHMT1 gene: an important epigenetic modulator) that is characterized by hypotonia, developmental delay and distinct facial features. Although congenital heart disease (CHD) is frequently reported, there is a paucity of data on the prevalence of CHD subtypes and arrhythmias in KS; no known reports of Atrial Fibrillation (AF). To systematically assess the prevalence of CHD and arrhythmias in KS. Cross-sectional analysis of the two largest known KS registries: Radboudumc (50 patients, median/IQR age: 13.5/13 years) based on health record review at Radboud University Medical Center in Netherlands, and GenIDA (163 patients, median/IQR age: 10/12 years) based on surveys of patient families from around the world. Case series of 3 additional patients with KS and atrial tachyarrhythmias. Both registries independently report 40% (20 patients in Radboudumc and 65 in GenIDA) prevalence of a cardiovascular system abnormality and 2-8% prevalence of arrhythmias (4 in Radboudumc and 3 in GenIDA). Radboudumc registry included 14% patients with atrial septal defect (ASD), 12% with ventricular septal defect (VSD), 4% patients each with Tetralogy of Fallot and pulmonary valve stenosis, and none with left ventricular dysfunction. The 8% patients with arrhythmias in this registry did not report significant CHD and included one patient with AF, two with supraventricular tachycardias (SVTs), and one with ventricular tachycardia (VT). GenIDA registry reported 1% patients with cardiomyopathy, 10% with VSD, 13% with ASD, 16% with valvular disease, and 9% with vascular malformations. This registry also included one patient with AF and another with chronic ectopic atrial tachycardia with neither patient reporting CHD. A case series of 3 additional KS patients not included in these registries with atrial tachyarrhythmias reveals two patients with AF and one with atrial tachycardia, in the absence of CHD. One patient with symptomatic AF refractory to medications underwent successful pulmonary vein isolation (first known report) at age 23 without recurrence at 16 months. The largest database of KS patients compiled to-date reveals a high prevalence of CHD and early-onset atrial tachyarrhythmias including AF, even in the absence of structural heart disease. These findings suggest a role for regular electrocardiograms and ambulatory rhythm monitoring as well as a possible novel epigenetic mechanism for AF.