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A novel ITGA2B double-cytosine frameshift variant (c.1986_1987insCC) leads to Glanzmann’s thrombasthenia in a cat

Rivas, Victor1; Stern, Joshua1

Published Jan 16, 2024 on Dryad. https://doi.org/10.25338/B8JW72

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Jan 16, 2024 version files 5.48 MB

Abstract

Glanzmann’s thrombasthenia is the most recognized congenital platelet disorder in small animals. The disorder affects ~1:1,000,000 people globally and is characterized by impaired platelet aggregation and clot retraction. Autosomal recessive, loss-of-function, variants in either ITGA2B or ITGB3 of the αIIbβ3 receptor explains the disease in humans. Physical exam and clinical pathology assessments were performed on a feline patient with idiopathic thrombocytopenia and thrombopathia. Patient blood samples were obtained for flow cytometry and platelet aggregometry analyses and patient phenotyping. Patient and validation cohort (n=20) DNA samples were extracted for Sanger sequencing of a previously identified ITGA2B (c.1986delC) variant. A novel c.1986_1987insCC autosomal recessive variant in ITGA2B was identified. This variant leads to a frameshift near the 3’ end of the gene, consequentially leading to complete truncation of the encoded protein’s calf-1, calf-2, and transmembrane domains. This variant was absent in a population of 194 unrelated cats spanning 44 different breeds. RT-PCR was performed on patient PRP samples as well as a clinically heathy sex- and age-matched control cat to verify ITGA2B variant consequence. Complete loss of ITGA2B transcript and protein expression was verified on RT-PCR and flow cytometry, explaining the underlying etiology of Glanzmann’s thrombasthenia, and likely macrothrombocytopenia, in this cat.