Abstract
Original language | English |
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Pages (from-to) | 1952-1960 |
Number of pages | 9 |
Journal | Genetics in medicine |
Volume | 23 |
Issue number | 10 |
Early online date | 2021 |
DOIs | |
Publication status | Published - Oct 2021 |
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In: Genetics in medicine, Vol. 23, No. 10, 10.2021, p. 1952-1960.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot
AU - Škorić-Milosavljević, Doris
AU - Lahrouchi, Najim
AU - Bosada, Fernanda M.
AU - Dombrowsky, Gregor
AU - Williams, Simon G.
AU - Lesurf, Robert
AU - Tjong, Fleur V. Y.
AU - Walsh, Roddy
AU - el Bouchikhi, Ihssane
AU - Breckpot, Jeroen
AU - Audain, Enrique
AU - Ilgun, Aho
AU - Beekman, Leander
AU - Ratbi, Ilham
AU - Strong, Alanna
AU - Muenke, Maximilian
AU - Heide, Solveig
AU - Muir, Alison M.
AU - Hababa, Mariam
AU - Cross, Laura
AU - Zhou, Dihong
AU - Pastinen, Tomi
AU - Hitz, Marc-Phillip
AU - Abdul-Khaliq, Hashim
AU - Berger, Felix
AU - Dähnert, Ingo
AU - Dittrich, Sven
AU - Uebing, Anselm
AU - German Competence Network for Congenital Heart Defects
AU - Stiller, Brigitte
AU - Zackai, Elaine
AU - Atmani, Samir
AU - Ouldim, Karim
AU - Adadi, Najlae
AU - Steindl, Katharina
AU - Rauch, Anita
AU - Brook, David
AU - Wilsdon, Anna
AU - Kuipers, Irene
AU - Blom, Nico A.
AU - Mulder, Barbara J.
AU - Mefford, Heather C.
AU - Keren, Boris
AU - Joset, Pascal
AU - Kruszka, Paul
AU - Thiffault, Isabelle
AU - Lodder, Elisabeth M.
AU - Clur, Sally-Ann B.
AU - Christoffels, Vincent M.
AU - Postma, Alex V.
AU - Bezzina, Connie R.
N1 - Funding Information: This work has been funded by research grants from the DHF (CVON project 2014-18 CONCOR-genes, to C.R.B. and V.M.C.), the CHF (to C.R.B.) and the PROCEED project, ERA PerMed Joint Translational Call Initiative (to S.M., C.R.B., and M.-P.H.). C.R.B. is funded by research grants from NWO (VICI fellowship, 016.150.610) and the Leducq Foundation (17CVD02). V.M.C. is funded by the Leducq Foundation (14CVD01). The work of E.M.L. is partly financed by the NWO (VIDI-91718361) and the CVON RESCUED project. S.M. holds the Heart and Stroke Foundation of Canada/Robert M Freedom Chair in Cardiovascular Science. The work of P.K. and M.M. was supported in part by the Division of Intramural Research of the NHGR. The work of I.T. and T.P. was supported by GA4K at Children’s Mercy hospital. This work was supported by the CNCHD with funding from the Federal Ministry of Education and Research (01GI0601 until 2014) and the DZHK (German Centre for Cardiovascular Research; as of 2015). The work of F.V.Y.T. is financed by a research grant from the DHF (E. Dekker grant 2014T053). Research reported in this publication was supported by the NCATS of the NIH (TL1TR001880) and by the ITMT of the Perelman School of Medicine, University of Pennsylvania (S.E.S). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. B.D.K. is supported by a BHF personal chair. S.G.W. is supported by the BHF. R.W. is supported by an ACS fellowship. J.B. is funded by a senior clinical investigator fellowship of the FWO-Flanders. H.C.M. was supported by a grant from NIH/NINDS (NS069605). Funding Information: We gratefully acknowledge the patients and their families for participation. The authors thank Sylvia Mantels and Lia C.J.M. Engelfriet-Rijk for their valuable work recruiting patients and managing the CONCOR registry. We acknowledge the Labatt Family Heart Centre Biobank, Hospital for Sick Children, funded by the Ted Rogers Centre for Heart Research, for access to sequencing data. A subset of data used in this study was generated by the Pediatric Cardiac Genomics Consortium (PCGC), under the auspices of the National Heart, Lung, and Blood Institute (NHLBI)’s Bench to Bassinet Program (dbGaP study accession: phs001194.v2.p2). The PCGC program is funded by the NHLBI, National Institutes of Health, US Department of Health and Human Services through grants UM1HL128711, UM1HL098162, UM1HL098147, UM1HL098123, UM1HL128761, U01HL131003. This paper was not prepared in collaboration with investigators of the PCGC, has not been reviewed and/or approved by the PCGC, and does not necessarily reflect the opinions of the PCGC investigators or the NHLBI. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85107718572&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41436-021-01212-y
DO - https://doi.org/10.1038/s41436-021-01212-y
M3 - Article
C2 - 34113005
SN - 1098-3600
VL - 23
SP - 1952
EP - 1960
JO - Genetics in medicine
JF - Genetics in medicine
IS - 10
ER -