Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot
Doris Škorić‐Milosavljević, Najim Lahrouchi, Fernanda M. Bosada, Gregor Dombrowsky, Simon G. Williams, Robert Lesurf, Fleur V.Y. Tjong, Roddy Walsh, Ihssane El Bouchikhi, Jeroen Breckpot, Enrique Audain, Aho Ilgun, Leander Beekman, Ilham Ratbi, Alanna Strong, Maximilian Muenke, Solveig Heide, Alison M. Muir, Mariam Hababa, Laura Cross, Dihong Zhou, Tomi Pastinen, Marc‐Phillip Hitz, Hashim Abdul‐Khaliq, Felix Berger, Ingo Dähnert, Sven Dittrich, Anselm Uebing, Brigitte Stiller, Elaine H. Zackai, S. Atmani, Karim Ouldim, Najlae Adadi, Katharina Steindl, Anita Rauch, J. David Brook, Anna Wilsdon, Irene M. Kuipers, Nico A. Blom, Barbara J.M. Mulder, Heather C. Mefford, Boris Keren, Pascal Joset, Paul Kruszka, Isabelle Thiffault, Sarah E. Sheppard, Amy E. Roberts, Elisabeth M. Lodder, Bernard Keavney, Sally‐Ann B. Clur, Seema Mital, Marc‐Phillip Hitz, Vincent M. Christoffels, Alex V. Postma, Connie R. Bezzina
Abstract
PurposeRare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear.MethodsWe conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF.ResultsExome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10-11).ConclusionRare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.