Dataset Information

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

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.

SUBMITTER: Skoric-Milosavljevic D

PROVIDER: S-EPMC8486653 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Škorić-Milosavljević Doris D Lahrouchi Najim N Bosada Fernanda M FM Dombrowsky Gregor G Williams Simon G SG Lesurf Robert R Tjong Fleur V Y FVY Walsh Roddy R El Bouchikhi Ihssane I Breckpot Jeroen J Audain Enrique E Ilgun Aho A Beekman Leander L Ratbi Ilham I Strong Alanna A Muenke Maximilian M Heide Solveig S Muir Alison M AM Hababa Mariam M Cross Laura L Zhou Dihong D Pastinen Tomi T Zackai Elaine E Atmani Samir S Ouldim Karim K Adadi Najlae N Steindl Katharina K Rauch Anita A Brook David D Wilsdon Anna A Kuipers Irene I Blom Nico A NA Mulder Barbara J BJ Mefford Heather C HC Keren Boris B Joset Pascal P Kruszka Paul P Thiffault Isabelle I Sheppard Sarah E SE Roberts Amy A Lodder Elisabeth M EM Keavney Bernard D BD Clur Sally-Ann B SB Mital Seema S Hitz Marc-Philip MP Christoffels Vincent M VM Postma Alex V AV Bezzina Connie R CR

Genetics in medicine : official journal of the American College of Medical Genetics 20210610 10

<h4>Purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 34113005

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Project description:BackgroundThe aim of this study was to investigate associations of 3 common polymorphisms in the VEGF gene, -2578C>A, -634C>G, and 936C>T, with risk of tetralogy of Fallot (TOF) in Chinese Han children.Material and methodsFrom January 2010 to June 2013, a total of 400 pediatric subjects were recruited, including 160 cases with TOF (TOF group) and 240 healthy controls (control group). The genotypes of 3 common VEGF polymorphisms, -2578C>A, -634C>G, and 936C>T, were analyzed by polymerase chain reaction restriction fragment length polymorphism. All data were analyzed with SPSS 18.0 software.ResultsNo significant differences were observed in body mass index or sex between TOF patients and controls (both P>0.05), but significant differences in age and family history of TOF were observed between the 2 groups (both P<0.05). The AA genotype in -2578C>A of VEGF was correlated with a significantly increased risk of TOF, and TOF risk in A allele carrier was 1.54-fold higher than that of C allele carrier (OR=1.54, 95%CI=1.14-2.09, P=0.005); the statistical significance was still present after Bonferroni correction (Pc=0.045). GG genotype in -634C>G of VEGF gene was also associated with an increased risk of TOF, and TOF risk in patients with G allele was 1.62-fold higher compared to patients with C allele (OR=1.62, 95%CI=1.19-2.21, P=0.002); the statistical significance was still present after Bonferroni correction (Pc=0.018). Interestingly, T allele in VEGF 936C>T polymorphism is associated with a decreased TOF risk (OR=0.65, 95%CI=0.49-0.87, P=0.003, the statistical significance was still present after Bonferroni correction (Pc=0.027). The result of logistic regression analysis revealed that -2578C>A, -634C>G, and 936C>T genotypes are independently related to the prevalence of TOF (all P<0.05).ConclusionsOur results confirmed that VEGF genetic polymorphisms, -2578C>A and -634C>G, may be associated with an increased TOF risk, while 936C>T polymorphism may be associated with decreased TOF risk.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

Similar Datasets

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