Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot.
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
27
12
2020
accepted:
04
05
2021
revised:
02
05
2021
pubmed:
12
6
2021
medline:
26
10
2021
entrez:
11
6
2021
Statut:
ppublish
Résumé
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. 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. 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 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.
Identifiants
pubmed: 34113005
doi: 10.1038/s41436-021-01212-y
pii: S1098-3600(21)05126-1
pmc: PMC8486653
doi:
Substances chimiques
KDR protein, human
EC 2.7.10.1
Vascular Endothelial Growth Factor Receptor-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1952-1960Subventions
Organisme : NHLBI NIH HHS
ID : UM1 HL098162
Pays : United States
Organisme : British Heart Foundation
ID : RG/F/21/110050
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : UM1 HL098123
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL131003
Pays : United States
Organisme : British Heart Foundation
ID : RG/15/12/31616
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : UM1 HL128761
Pays : United States
Organisme : British Heart Foundation
ID : CH/13/2/30154
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : UM1 HL128711
Pays : United States
Organisme : NHLBI NIH HHS
ID : UM1 HL098147
Pays : United States
Investigateurs
Marc-Phillip Hitz
(MP)
Hashim Abdul-Khaliq
(H)
Felix Berger
(F)
Ingo Dähnert
(I)
Sven Dittrich
(S)
Anselm Uebing
(A)
Brigitte Stiller
(B)
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s).
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