Exome Sequencing Identifies POPDC2 as a Candidate Gene for Familial Congenital Junctional Ectopic Tachycardia

Background: Congenital junctional ectopic tachycardia (cJET) is a rare, potentially life-threatening arrhythmia suspicious for a genetic basis, yet its molecular underpinnings remain incompletely defined. The POPDC2 gene, involved in cardiac pacemaking and membrane trafficking of interacting ion channels, has not previously been conclusively linked to human tachyarrhythmias. This study investigates a novel POPDC2 variant (p.Leu245Pro) identified in a family with autosomal dominant cJET. Methods: Exome sequencing was performed to identify co-segregating variants in the affected family. Functional analysis of the POPDC2 p.Leu245Pro variant was conducted by molecular dynamics (MD) simulations, a membrane targeting assay, and a bimolecular fluorescence complementation assay. Additionally, the impact of the variant on Nav1.5 and TREK-1 currents was characterized in Xenopus oocytes. Results: The p.Leu245Pro POPDC2 variant showed a destabilization of the POPDC1-POPDC2 dimer interface, resulting in impaired heterodimer formation and membrane localization. Electrophysiological studies in Xenopus oocytes demonstrated that the mutant protein significantly affected Nav1.5 and TREK-1 currents. These findings support a functional impact of the POPDC2 p.Leu245Pro variant relevant to cardiac conduction. Conclusions: Our results provide the first functional evidence implicating POPDC2 in cJET and support its role as a novel candidate gene in tachyarrhythmic disease. This study enhances the understanding of genetic contributions to cJET and suggests further investigation of POPDC2 in other forms of supraventricular tachyarrhythmias.