B-AB13-02 A NOVEL VARIANT IN MANNOSE RECEPTOR C-TYPE 2 IDENTIFIED IN INDIVIDUALS WITH FAMILIAL WOLFF-PARKINSON-WHITE SYNDROME

Abstract

Wolff-Parkinson-White (WPW) syndrome is the most common arrhythmia disorder observed in patients with structurally normal hearts and affects up to 1% of the population. A common cause of supraventricular tachycardia (SVT) worldwide, WPW contributes to sudden cardiac death in otherwise healthy children and adults. The genetic basis of WPW syndrome remains to be elucidated in individuals with structurally normal hearts. Identify a novel variant causing WPW in the structurally normal heart, leading to further insight into the molecular underpinnings of re-entry bypass tract formation. Whole exome sequencing (WES) was performed on 2 members of a three-generation extended family in which multiple members were affected by SVT, WPW pattern, or WPW syndrome. Shared non-synonymous variants between these 2 family members were then tested in all other family members and demonstrated a variant in the Mannose Receptor C-type 2 (Mrc2) gene. In addition, 154 unrelated individuals with WPW syndrome underwent whole exome sequencing and of these 75 were trio pairs, for a total of 324 subjects. An Mrc2 E990G knock-in mouse model was generated and used for experimental analysis. Resting serial ECGs, electrophysiology studies, echocardiography and optical mapping studies were performed. WES revealed a novel monogenic heterozygous variant E990G in Mrc2 as the disease-causing candidate gene. In Mrc2 E990G knock-in mice, ECGs did not demonstrate a WPW pattern, but a significantly higher incidence of inducible supraventricular tachycardia, in both heterozygous and homozygous mice, was observed with in vivo electrophysiology studies, while echocardiography did not show any change in cardiac structure or function. Furthermore, optical mapping studies also demonstrated an increased burden of SVT, and an abnormal conduction patterns suggesting the presence of a re-entry bypass tract. This study identifies a novel nonsynonymous variant E990G in the gene Mrc2 in familial WPW syndrome. Furthermore, the presence of this variant in a murine model leads to increased incidence of supraventricular tachycardia and bypass tract formation in the setting of preserved cardiac structure and function.