Biallelic variants inPOPDC2cause a novel autosomal recessive syndrome presenting with cardiac conduction defects and variable hypertrophic cardiomyopathy
Authors: Nicastro Michele , Vermeer Alexa M.C. , Postema Pieter G. , Tadros Rafik , Bowling Forrest Z. , Aegisdottir Hildur M. , Tragante Vinicius , Mach Lukas , Postma Alex V. , Lodder Elisabeth M. , van Duijvenboden Karel , Zwart Rob , Beekman Leander , Wu Lingshuang , van der Zwaag Paul A. , Alders Mariëlle , Allouba Mona , Aguib Yasmine , Santomel J. Luis , de Una David , Monserrat Lorenzo , Miranda Antonio M. A. , Kanemaru Kazumasa , Cranley James , van Zeggeren Ingeborg E. , Aronica Eleonora M.A. , Ripolone Michela , Zanotti Simona , Sveinbjornsson Gardar , Ivarsdottir Erna V. , Hólm Hilma , Guðbjartsson Daníel F. , Skúladóttir Ástrós Th. , Stefánsson Kári , Nadauld Lincoln , Knowlton Kirk U. , Ostrowski Sisse Rye , Sørensen Erik , Vesterager Pedersen Ole Birger , Ghouse Jonas , Rand Søren , Bundgaard Henning , Ullum Henrik , Erikstrup Christian , Aagaard Bitten , Bruun Mie Topholm , Christiansen Mette , Jensen Henrik K. , Carere Deanna Alexis , Cummings Christopher T , Fishler Kristen , Tøring Pernille Mathiesen , Brusgaard Klaus , Juul Trine Maxel , Saaby Lotte , Winkel Bo Gregers , Mogensen Jens , Fortunato Francesco , Comi Giacomo Pietro , Ronchi Dario , van Tintelen J. Peter , Noseda Michela , Airola Michael V. , Christiaans Imke , Wilde Arthur A.M. , Wilders Ronald , Clur Sally-Ann , Verkerk Arie O. , Bezzina Connie R. , Lahrouchi Najim 
Published: July 2024

ABSTRACTPOPDC2encodes for the Popeye domain-containing protein 2 which has an important role in cardiac pacemaking and conduction, due in part to its cAMP-dependent binding and regulation of TREK-1 potassium channels. Loss ofPopdc2in mice results in sinus pauses and bradycardia and morpholino knockdown ofpopdc2 inzebrafish results in atrioventricular (AV) block. We identified bi-allelic variants inPOPDC2in 4 families that presented with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects and hypertrophic cardiomyopathy. Using homology modelling we show that the identifiedPOPDC2variants are predicted to diminish the ability of POPDC2 to bind cAMP. Inin vitroelectrophysiological studies we demonstrated that, while co-expression of wild-type POPDC2 with TREK-1 increased TREK-1 current density, POPDC2 variants found in the patients failed to increase TREK-1 current density. While patient muscle biopsy did not show clear myopathic disease, it showed significant reduction of the expression of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1–POPDC2 complex is impaired by pathogenic variants in any of the two proteins. Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and 2 was most prevalent in AV node, AV node pacemaker and AV bundle cells. Sinoatrial node cells expressed POPDC2 abundantly, but expression of POPDC1 was sparse. Together, these results concur with predisposition to AV node disease in humans with loss-of-function variants inPOPDC1and POPDC2 and presence of sinus node disease inPOPDC2,but not inPOPDC1related disease in human. Using population-level genetic data of more than 1 million individuals we showed 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 forPOPDC2as the cause of a novel Mendelian autosomal recessive cardiac syndrome, consistent with previous work showing that mice and zebrafish deficient in functionalPOPDC2display sinus and AV node dysfunction.GRAPHICAL ABSTRACT