Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy

POPDC2 encodes the Popeye domain-containing protein 2, which has an important role in cardiac pacemaking and conduction, due in part to its cyclic AMP (cAMP)-dependent binding and regulation of TREK-1 potassium channels. Loss of Popdc2 in mice results in sinus pauses and bradycardia, and morpholino-mediated knockdown of popdc2 in zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in POPDC2 in four families with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects, and hypertrophic cardiomyopathy. Using homology modeling, we show that the identified variants are predicted to diminish the ability of POPDC2 to bind cAMP. In in vitro electrophysiological studies, we demonstrated that, in contrast with wild-type POPDC2, variants found in affected individuals failed to increase TREK-1 current density. While muscle biopsy of an affected individual did not show clear myopathic disease, it showed significantly reduced abundance of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1-POPDC2 complex is impaired by pathogenic variants in either protein. Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and POPDC2 was most prevalent in AV node, AV node pacemaker, and AV bundle cells. Using population-level genetic data of more than 1 million individuals, we show that none of the familial variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up. Our findings provide evidence for bi-allelic variants in POPDC2 causing a Mendelian autosomal recessive cardiac syndrome.