In 2018, the EPHB2 gene was first reported in association with a recessive bleeding disorder characterized by excessive spontaneous subcutaneous bleeding, heavy bleeding after minor wounds, chronic gastrointestinal bleeding leading to anemia, and a mild decrease in platelet count observed later in life (Berrou E, et al., 2018, PMID: 30213874). Platelet function tests revealed decreased responses to various agonists except ristocetin, with normal ATP/ADP content and dense granule numbers. Both the patient and the affected sibling, who are homozygous for the NM_017449.5 :c.2233C>T (p.Arg745Cys) variant in the tyrosine kinase domain of EPHB2, displayed significant defects in platelet function with similar abnormalities (PMID: 30213874).
Further experimental evidence supports the pathogenicity of this variant, indicating that the p.R745C variant in EPHB2 causes significant platelet dysfunction, including structural abnormalities, reduced aggregation, impaired activation, and enhanced clustering under stimulated conditions, suggesting disrupted signaling pathways. The EPHB2-R745C mutation impairs autophosphorylation by 50% without affecting clustering behavior, disrupting early cell activation steps independently of cell-cell contact (PMID: 30213874). Additionally, there is evidence of EphB2 interaction with ITGB3 in platelet function, as well as EphB2 signaling's role in thrombus stability (PMID: 25370417). EPHB2 truncation studies in mice (PMID: 25370417) and the expression of EPHB2 in platelets provide further support (PMID: 30213874).
For the genetic evidence, only one consanguineous family with two similarly affected individuals has been identified. Currently, both the genetic and experimental evidence suggest a borderline classification between limited and moderate. However, due to the limited genetic data, we will maintain the final classification as limited until more genetic evidence becomes available.
Gene Clinical Validity Standard Operating Procedures (SOP) - SOP 10
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