ITGA2B was first reported in relation to autosomal dominant platelet-type bleeding disorder 16 in 1998 (Peyruchaud et al., 1998, PMID: 9834222). At least 5 unique variants (4 missense variants and 1 single amino acid deletion in the highly conserved GFFKR sequence of the cytoplasmic domain) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 29 probands in 10 publications (PMIDs: 29090484, 24498605, 21454453, 9834222, 31119735, 31064749, 33276370, 32581362, 34355501, 36430862). Variants in this gene segregated with disease in 27 additional family members. The mechanism for disease is thought to be heterozygous gain of function, or activating, mutations (PMIDs: 9834222, 21454453). Of note, this gene has also been implicated in autosomal recessive Glanzmann’s Thrombasthenia due to loss of function variants. This has been assessed separately. This gene-disease association is supported by its shared biochemical function (PMID: 6460044) and protein interaction with ITG3B (PMID: 6213621), and functional alteration in both patient (PMID: 29090484) and non-patient (PMID: 21454453) cells, indicating a defect in proplatelet formation. Additionally, a knock-in mouse model recapitulated the macrothrombocytopenia phenotype due to constuative activation (PMID: 31691484). In summary, there is definitive evidence supporting the relationship between ITGA2B and autosomal dominant platelet-type bleeding disorder 16. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This gene-disease pair was originally evaluated by the HT GCEP on 06/25/2021. It was reevaluated on 10/23/2023. As a result of this reevaluation 9 additional patients were identified (PMIDs: 32581362, 34355501, 36430862) and increased the classification from Moderate to Definitive (SOP Version 9).
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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