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DOI: 10.1038/s41436-021-01212-y; PMCID: PMC8486653


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.

Journal Title

Genetics in medicine : official journal of the American College of Medical Genetics





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MeSH Keywords

Animals; Genetic Predisposition to Disease; HEK293 Cells; Humans; Mice; Tetralogy of Fallot; Vascular Endothelial Growth Factor Receptor-2; Whole Exome Sequencing


Animals; Genetic Predisposition to Disease; HEK293 Cells; Humans; Mice; Tetralogy of Fallot; Vascular Endothelial Growth Factor Receptor-2; Whole Exome Sequencing


Erratum in

  • Correction to: 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 FVY, 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; German Competence Network for Congenital Heart Defects, 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 SB, Mital S, Hitz MP, Christoffels VM, Postma AV, Bezzina CR.Genet Med. 2021 Oct;23(10):2013. doi: 10.1038/s41436-021-01279-7.PMID: 34522030 Free PMC article. No abstract available.

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