Mutations of RUNX1 in families with inherited thrombocytopenia

Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is a rare autosomal dominant disease characterized by thrombocytopenia and platelet functional defects. Although bleeding tendency is usually mild to moderate, an important hallmark of FPD/AML is the increased risk of myeloid neoplasms, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). FPD/AML is caused by dfferent, usually private, mutations of RUNX1, a gene encoding the DNA binding subunit of the core binding factor (CBF) transcription complex. The N-terminal domain of RUNX1 mediates DNA binding and heterodimerization to CBF-beta, the other subunit of the CBF complex. At the C-terminus, RUNX1 is constituted of domains involved in transcription activation and repression. We report three families with pathogenic variants of RUNX1 identified in our cohort of 274 consecutive unrelated probands with inherited thrombocytopenia (IT).