The ITGA2B gene has been associated with the autosomal recessive condition Glanzmann Thrombasthenia, using the ClinGen Clinical Validity Framework as of 01/14/2019. This association was made using case-level data only. At least 149 variants in this gene are reported in humans, including frameshifts, splicing variants, nonsense, and functionally-characterized missense variants. Glanzmann’s Thrombasthenia is characterized by a bleeding diathesis diagnosed by an increased bleeding time, reduced platelet aggregation and lack of clot retraction. ITGA2B was first associated with this disease in humans as early as 1991 (Burk et al., PMID: 1702098).
Summary of Case Level Data: 12 POINTS The association is seen in at least 11 probands in 4 publications (PMIDs: 1702098, 9473221, 20020534, 7508443). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function, with the majority of variants observed resulting in reduced or absent expression of the integrin αIIbβ3 receptor complex on the platelet surface (PMID: 2014236). Of note, this gene has also been implicated in a Glanzmann-like autosomal dominant bleeding disorder, platelet-type, 16 with the predominant observation of macrothrombocytopenia. The disease is suggested to result from activating mutations (PMIDs: 9834222, 21454453). This will be assessed separately.
Summary of Experimental Data: 3.5 POINTS This gene-disease association is supported by biochemical function, protein interactions, functional alteration, and model systems. The pathological mechanism of the disease is impaired platelet aggregation due to diminished biochemical function (fibrinogen binding) of the αIIbβ3 receptor complex (PMID: 6460044). This gene encodes glycoprotein IIb, which interacts with the protein coded by ITGB3, glycoprotein IIIa, to form the αIIbβ3 receptor complex expressed on the surface of platelets and bind fibrinogen (PMID: 6213621). Functional alteration has been validated in non-patient cells, in which CHO cells expressing variant glycoprotein IIb have inhibited binding to fibrinogen (PMID: 9473221). The null mouse recapitulates the Glanzmann’s phenotype of impaired platelet aggregation (PMID: 16103235).
Summary Statement DEFINITIVE In summary, ITGA2B is definitively associated with autosomal recessive Glanzmann’s Thrombasthenia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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