A novel CBFA2 single-nucleotide mutation in familial platelet disorder with propensity to develop myeloid malignancies

Hereditary mutations associated with hematologic malignancies are rare. Heterozygous mutations affecting the hematopoietic transcription factor CBFA2 (also AML1/RUNX1) were recently reported to be associated with familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML, MIM 601399). A new 3-generation family with FPD/AML with a novel CBFA2 mutation is described. In this family, AML was diagnosed in a second-generation male. After allogeneic stem cell transplantation from his human leukocyte antigen-identical sister, a donor-derived, genetically identical leukemia developed in the recipient and the donor. Sequencing analysis identified a G-to-T transition within the CBFA2 gene, which involves codon 198, encoding a conserved aspartic acid within the DNA- binding Runt domain. Three of 5 siblings affected with the FPD/AML trait harbored the mutation in a heterozygous form. This experience underscores the necessity of performing mutation analysis of the CBFA2 gene before sibling allogeneic transplantation in families with FPD/AML.