PB0337 - Identification and characterisation of ANKRD26-related thrombocytopenia in patients from the GAPP cohort.

Background: ANKRD26-related thrombocytopenia is an inherited platelet disorder characterised by mild thrombocytopenia, normal platelet size and a mild bleeding diathesis. It results from point mutations in the highly conserved 5’UTR of the ANKRD26 gene; a known binding site for transcription factors RUNX1 and FLI1. Patients have a 24-fold increased risk of developing myeloid malignancy, and knowledge of the condition may influence monitoring strategies and impact clinical management at the time of a cancer diagnosis. Although over 250 cases of ANKRD26-related thrombocytopenia have now been described, its incidence is unknown.

Aims: To identify undiagnosed cases of ANKRD26-related thrombocytopenia from a pre-defined patient cohort with unexplained bleeding diathesis or thrombocytopenia, and further characterise their protein and RNA expression.

Methods: We identified 133 patients with a documented history of bleeding diathesis, or thrombocytopenia from the GAPP cohort. Platelet DNA was assessed following Sanger sequencing. Protein analysis and RNA sequencing is currently in process.

Results: Of the 133 patients in whom samples were available for analysis, 11 patients have single point mutations in the 5’UTR which have previously been described as pathogenic. Three variants were identified amongst the cohort: C.-140C>G (7 patients), C.-116 C>T (3 patients) and C.-126 T>G (1 patient).

Conclusion(s): The C.-140 C>G mutation identified has previously been described as a pathogenic variant causing thrombocytopenia in eight patients of which one developed AML. However, given its frequency, and on comparison to population databases, it is possible that this may in fact represent a benign variant. Ongoing protein analysis may help determine the significance of this variant. The C.-116 C>T mutation lies within the RUNX1 binding site of 5’UTR and has been described in ten previous patients, with one of them going on to develop CMML. Four C.-126 T>G variants have been described previously with ANKRD26-related thrombocytopenia.