Thrombocytopenia Caused By Inherited Haematopoietic Transcription Factor Mutation: Clinical Phenotypes and Diagnostic Considerations

Inherited thrombocytopenias comprise a heterogeneous group of blood disorders with abnormalities in genes related to glycoproteins and adhesion molecules, signalling pathways, cytoskeletal components, granule formation, and transcription factor complexes. Recent improvements in sequencing technology have increased the number of transcription factor mutations that have been implicated as causative for these platelet disorders. Mutations in RUNX1, GATA1, GFI1B, FLI1, and ETV6 share common features, including a variable bleeding history often associated with abnormal but non-specific changes in platelet morphology and platelet function testing. The phenotype of the underlying platelet disorder is often variable despite mutations in the same transcription factor, suggesting that the site of mutation and the protein domain that is perturbed is an important determinant of the clinical syndrome. Importantly, some of these transcription factor mutations are associated with other physical abnormalities, including an increased risk of acute leukaemia as well as solid organ malignancies. Genetic diagnosis of these disorders allows rational medical management to prevent bleeding, as well as providing an opportunity for family screening in order to reduce disease burden.