Impact of thrombocytopenia-associated c.-118C>T and c.-140C>G ANKRD26 5'UTR variants in three-generational pedigree.

Inherited thrombocytopenias (ITs) encompass a group of rare disorders characterized by diminished platelet count. Recent advancements have unveiled various forms of IT, with inherited thrombocytopenia 2 (THC2) emerging as a prevalent subtype associated with germline variants in the critical 5' untranslated region of the gene. This region is crucial in regulating the gene expression of , particularly in megakaryocytes. THC2 is an autosomal dominant disorder presenting as mild-to-moderate thrombocytopenia with minimal symptoms, with an increased risk of myeloproliferative malignancies. In our study of a family with suspected IT, three affected individuals harbored the c.-118C>T variant, while four healthy members carried the c.-140C>G variant. We performed a functional analysis by studying platelet-specific gene expression levels using quantitative real-time polymerase-chain reaction. Functional analysis of the c.-118C>T variant showed a significant increase in expression in affected individuals, supporting its pathogenicity. On the contrary, carriers of the c.-140C>G variant exhibited normal platelet counts and no significant elevation in the expression, indicating the likely benign nature of this variant. Our findings provide evidence confirming the pathogenicity of the c.-118C>T variant in THC2 and suggest the likely benign nature of the c.-140C>G variant.