Genetic characterization of Glanzmann thrombasthenia: insights from novel igta2b mutations in a Tunisian patient cohort

Glanzmann thrombasthenia is an inherited platelet disorder resulting from defects in the integrin αIIbβ3 complex due to mutations in the ITGA2B or ITGB3 genes. This study aimed to elucidate the molecular and clinical characteristics of Glanzmann thrombasthenia in a Tunisian cohort. Twelve patients from 11 unrelated families were evaluated using clinical examination, platelet function assays, and comprehensive genetic analysis. Genomic DNA was extracted from peripheral blood, and the entire coding regions along with intron-exon boundaries of ITGA2B were amplified and sequenced via Sanger sequencing. Molecular analysis identified seven likely pathogenic variants in 9 out of 12 patients, including five missense mutations, of which two were novel (p.Tyr221Asp and p.Gly929Trp), one frameshift mutation, and one large deletion spanning exons 19-29. Additionally, three benign variants were detected in five patients, while one patient exhibited no ITGA2B mutation, suggesting a potential defect in ITGB3. Three previously reported missense variants (p.Gln165His, p.Arg584Gln, and p.Ser957Leu) and an intronic splicing variant (c.2095-22_2095-19del) were also identified. Clinically, patients presented with heterogeneous bleeding phenotypes, predominantly epistaxis and gingival bleeding. Genotype-phenotype correlations underscore that mutation type and location critically influence disease severity. These findings expand the mutational spectrum of ITGA2B and emphasize the need for further functional studies to inform targeted therapies.