Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot

Škorić-Milosavljević D, Lahrouchi N, Bosada FM, Dombrowsky G, Williams SG, Lesurf R, Tjong FV, Walsh R, El Bouchikhi I, Breckpot J, Audain E, Ilgun A, Beekman L, Ratbi I, Strong A, Muenke M, Heide S, Muir AM, Hababa M, Cross L, Zhou D, Pastinen T, Hitz MP, Abdul-Khaliq H, Berger F, Dähnert I, Dittrich S, Uebing A, Stiller B, Zackai E, Atmani S, Ouldim K, Adadi N, Steindl K, Rauch A, Brook D, Wilsdon A, Kuipers I, Blom NA, Mulder BJ, Mefford HC, Keren B, Joset P, Kruszka P, Thiffault I, Sheppard SE, Roberts A, Lodder EM, Keavney BD, Clur SAB, Mital S, Hitz MP, Christoffels VM, Postma AV, Bezzina CR (2021)

Publication Type: Journal article

Publication year: 2021

Journal

DOI: 10.1038/s41436-021-01212-y

Abstract

Purpose: Rare 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. Methods: We 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. Results: Exome 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). Conclusion: Rare 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.

Authors with CRIS profile

Involved external institutions

Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Deutsches Herzzentrum Berlin Germany (DE) University of Washington United States (USA) (US) Veterans Affairs Healthcare System Boston and Harvard Medical School United States (USA) (US) National Human Genome Research Institute (NHGRI) United States (USA) (US) University of Nottingham United Kingdom (GB) The Hospital for Sick Children (SickKids) Canada (CA) University of Missouri–Kansas City (UMKC) United States (USA) (US) Centre Hospitalier Universitaire Hassan II / CHU de Fès Morocco (MA) Abulcasis International University of Health Sciences / Université Internationale Abulcasis des Sciences de la Santé Morocco (MA) University of Zurich / Universität Zürich (UZH) Switzerland (CH) Children's Mercy Hospital United States (USA) (US) Sidi Mohamed Ben Abdellah University / Université Sidi Mohamed Ben Abdellah de Fès (USMBA) / جامعة سيدي محمد بن عبد الله Morocco (MA) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Sorbonne Université France (FR) Children's Hospital of Philadelphia United States (USA) (US) Universitätsklinikum Leipzig Germany (DE) Universitäts-Herzzentrum Freiburg - Bad Krozingen GmbH Germany (DE) Universitätsklinikum des Saarlandes (UKS) Germany (DE)

How to cite

APA:

Škorić-Milosavljević, D., Lahrouchi, N., Bosada, F.M., Dombrowsky, G., Williams, S.G., Lesurf, R.,... Bezzina, C.R. (2021). Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot. Genetics in Medicine. https://doi.org/10.1038/s41436-021-01212-y

MLA:

Škorić-Milosavljević, Doris, et al. "Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot." Genetics in Medicine (2021).

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