KDR – Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy characterized by elevated pulmonary arterial pressure and right ventricular failure. KDR (VEGFR2) encodes the primary receptor for vascular endothelial growth factor A (VEGF-A) and is essential for endothelial cell proliferation and vascular homeostasis. Genetic disruption of KDR impairs VEGF signaling and has been implicated in heritable and idiopathic PAH.

Heterozygous, high-impact loss-of-function variants in KDR were first identified in five unrelated PAH cases from the UK NIHR BioResource (posterior probability [PP]=0.989 for reduced transfer coefficient for carbon monoxide [KCO] and PP=0.912 for older age at diagnosis) (PMID:33320693). Familial segregation of a rare nonsense KDR variant further supported dominant inheritance and co-segregation with PAH in a single pedigree (PMID:33320693).

Independent replication in the US PAH Biobank identified four additional PAH cases harboring rare, likely loss-of-function KDR variants with similar phenotypic features, including parenchymal abnormalities on high-resolution CT imaging (PMID:33320693). A multinational consortium study of 4,241 PAH cases confirmed enrichment of rare deleterious KDR variants among idiopathic PAH patients compared to controls (FDR <0.1) (PMID:33971972).

A recent ClinGen expert curation classified KDR as having definitive clinical validity for PAH based on robust genetic and experimental evidence, alongside known PAH genes such as BMPR2, GDF2, and TBX4 (PMID:37422716). This designation reflects multiple unrelated probands, familial segregation, replication across cohorts, and concordant functional data implicating haploinsufficiency of VEGFR2 in PAH pathobiology.

Mechanistically, heterozygous KDR loss-of-function reduces endothelial VEGF-A signaling, leading to impaired microvascular remodeling, decreased gas exchange capacity (KCO), and vascular pruning characteristic of PAH. Animal and in vitro studies of VEGFR2 deficiency recapitulate pulmonary vascular remodeling and right ventricular hypertrophy.

Key Take-home: Heterozygous KDR loss-of-function variants cause autosomal dominant pulmonary arterial hypertension, warranting inclusion of KDR in diagnostic gene panels and consideration for targeted surveillance and experimental VEGF-A/VEGFR2 pathway modulation.

References

• Circulation. Genomic and precision medicine • 2020 • Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension. PMID:33320693
• Genome Medicine • 2021 • Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH. PMID:33971972
• Genetics in Medicine • 2023 • Defining the clinical validity of genes reported to cause pulmonary arterial hypertension. PMID:37422716

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