Ephrin Receptor EphB4 (EPHB4; MIM#600011) is a receptor tyrosine kinase transmembrane protein that has a critical role in angiogenesis and vascular development. Regulation is complex with bidirectional signaling critical for vasculature assembly and mesenchymal cell differentiation. Autosomal dominant pathogenic variants in EPHB4 were first described in 2016 (PMID:28687708, 27400125) in association with variable vascular malformations including capillary and arteriovenous malformations (CM-AVM), and has since been described in many additional affected individuals with phenotypes including CM-AVMs, lymphatic malformations, non-immune hydrops fetalis, recurrent epistaxis and additional vascular and lymphatic phenotypes (PMID:33864021, 27400125, 29444212, others). The phenotype of EPHB4 has high intra- and interfamilial variability (PMID:33864021, 27400125) and can be associated with a spectrum of phenotypes ranging from subtle features of lymphatic dysfunction to lethal non-immune hydrops fetalis. The mechanism is loss of function, and while nonsense and frameshift variants are found throughout the coding sequence, pathogenic missense variants are found to be enriched within the Tyrosine Kinase domain (for Review; PMID:30819650) Animal models of EPHB4 demonstrate defects in vascular modeling, growth restriction, pre- and postnatal edemas, and tortuous dilated lymphatic vessels (PMID:10518221, 27400125, 29444212). EPHB4 is curated by the Prenatal Gene Curation Expert Panel as Definitive for EPHB4-associated vascular malformation spectrum.
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