Congenital Heart Defect

Gene: KDR

Green List (high evidence)

GREEN for AD
RED for AR

PMID:30232381
5x families (6 affecteds) with ToF: 2x PTCs + 2x missense + 1x inframe del
noted that all individuals were adults at time of assessment but known to have ToF and/or other CHD

PMID: 34328347;
cohort of ToF, looking into LoF variants
4x identified + 1x classified as VUS (stop gain in penultimate exon)
1x stop gain citing PMID: 28991257

PMID:34113005;
1x family with 2 affecteds, Chet for 2x missense

Created: 26 Mar 2024, 1:39 a.m. | Last Modified: 26 Mar 2024, 1:39 a.m.

Panel Version: 0.412

Publications

• 34113005
• 30232381
• 28991257
• 30232381

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Mode of pathogenicity is LoF.
Exome sequencing performed.
Some de novo variants point to a dominant inheritance, however some inherited from unaffected parent points reduced penetrance and a more complex inheritance.
Literature available at this time is limited.

Created: 19 Nov 2023, 5:24 a.m. | Last Modified: 19 Nov 2023, 5:24 a.m.

Panel Version: 0.315

Mode of inheritance
Unknown

Phenotypes
Tetralogy of Fallot

Publications

• 34113005

I don't know

PMID 34113005: 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).

At this stage MOI unclear and insufficient evidence for either MOI.

Created: 24 Nov 2023, 12:14 a.m. | Last Modified: 24 Nov 2023, 12:14 a.m.

Panel Version: 0.367

Variants in this gene are associated with PAH and other vascular abnormalities.

Limited evidence for association with CHD.

Created: 26 Jul 2022, 4:13 a.m. | Last Modified: 26 Jul 2022, 4:13 a.m.

Panel Version: 0.249

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Tetralogy of Fallot, MONDO:0008542

Publications

• 34113005

Red List (low evidence)

Rare variants associated with ToF but lacking evidence for causality and pathogenesis.

PMID 34113005 (2021): 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).

PMID 34328347 (2021): exome sequencing data from 811 probands with ToF, four patients had novel LoF variants in KDR demonstrating enrichment in ToF compared with controls. Segregation data not available.

PMID: 30232381 (2019): KDR variants identified in four patients (two stopgain and two nonsynonymous variants) with other VUS identified in one patient. Segregation data not available.
Sources: Literature, Expert list

Created: 23 Jul 2022, 7:51 a.m.

Mode of inheritance
Unknown

Phenotypes
Tetralogy of Fallot

Publications

• 34113005
• 34328347
• 30232381

Variants in this GENE are reported as part of current diagnostic practice