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Deleterious mutations in the RUNX1 gene cause hereditary leukemia due
to a rare syndrome called Familial platelet Disorder with Associated Myeloid
Malignancy (FPDMM). We describe the characteristics of a family with FPDMM due
to a novel RUNX1 mutation (L472X),
located in the most 3-prime end of the gene reported to date. Our 36-year-old proband presented with incidentally detected thrombocytopenia
and a family history suggestive of FPDMM. Contrary to previously described
families, affected members of our kindred express an eczematous phenotype,
reportedly most severe in members who develop leukemia. Pedigree analysis shows that the L472X mutation tracks with thrombocytopenia, acute leukemia, and eczema.
The L472X mutation produces a stably
expressed RUNX1 protein product with a corresponding decrease in wild type RUNX1 expression. Our data supports the
inclusion of eczema in the FPDMM phenotype and suggests the possibility that
the RUNX1 L472X mutant causes the
type of dominant negative affect that is associated with an elevated risk of
leukemia in FPDMM families.