PB1383 - RUNX1-mutated familial platelet disorder (RUNX1-FPD) with associated acute myeloid leukaemia – a case/family series

Background: Germline mutations in the runt-related transcription factor 1 (RUNX1) are an established cause of familial platelet disorder with predisposition to myeloid malignancy.

Aims: A case of acute myeloid leukaemia (AML) in a 34-year-old male patient with RUNX1-FPD with proven familial inheritance.

Methods: The patient, his mother and brother have FPD with thrombocytopaenia, abnormal platelet aggregometry and the non-canonical splice site RUNX1 variant NM_001754.4:c.968-4_968-3delinsAG.

Results: Three family members had pre-existing mild thrombocytopaenia of 100-110x109/l, with normal sized platelets on blood smear examination. They were registered at the local haemophilia centre with a mild platelet function defect requiring tranexamic acid and/or platelet transfusions for procedures. Platelet aggregometry showed normal response to ristocetin 1.25mg/ml, a reduced slope and disaggregation to arachidonic acid, epinephrine and collagen, with no demonstrable release to adenosine diphosphate (ADP). Total platelet nucleotides were reduced, with a significant reduction in ADP at 0.08 amol/plt (normal range 0.22-0.59) and ATP:ADP ratio 4.51 (0.86-2.26). The proband presented acutely with fever and was found to be pancytopenic with circulating blasts on blood smear. Bone marrow biopsy confirmed AML. Cytogenetic analysis showed trisomy 8 by G-banding, an IDH2 and SRSF2 mutation. A heterozygous RUNX1 mutation was found on peripheral blood platelet panel testing. The RUNX1 mutation was filtered out on bone marrow next generation sequencing due to only splice sites +/- 1 and +/-2 (exon/intron boundary) being investigated but was detected in the row data.

Conclusion(s): The non-canonical splice site variant NM_001754.4:c.968-4_968-3delinsAG has not previously been reported in the literature. Several nonsense and frameshift variants in exon 9 have been reported in FPD with/without AML. These are commonly associated with other acquired somatic mutations. This novel variant was reported as a variant of unknown significance, but the genomics panel felt it was in keeping with the platelet disorder, predisposition to myeloid malignancy and family history.