title: Hereditary leukemia due to rare RUNX1c splice variant (L472X) presents with eczematous phenotype.
abstract: Deleterious mutations in theRUNX1gene 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.
authors.affiliation: Department of Pediatrics, City Hope National Medical Center, Duarte, CA ; Division of Clinical Cancer Genetics, City Hope National Medical Center, Duarte; CA.
authors.forename: A
authors.initials: A
authors.lastname: Sorrell
authors.affiliation: Division of Clinical Cancer Genetics, City Hope National Medical Center, Duarte; CA.
authors.forename: C
authors.initials: C
authors.lastname: Espenschied
authors.affiliation: Division of Population Sciences, City Hope National Medical Center, Duarte, CA.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Clinical Cancer Genetics, City Hope National Medical Center, Duarte; CA.
authors.forename: J
authors.initials: J
authors.lastname: Weitzel
authors.affiliation: Division of Hematology and Transplantation, City Hope National Medical Center, Duarte, CA.
authors.forename: S
authors.initials: S
authors.lastname: Chu
authors.affiliation: Division of Hematology and Transplantation, City Hope National Medical Center, Duarte, CA.
authors.forename: P
authors.initials: P
authors.lastname: Parker
authors.affiliation: Department of Molecular Genetics, City Hope National Medical Center, Duarte, CA.
authors.forename: S
authors.initials: S
authors.lastname: Saldivar
authors.affiliation: Division of Hematology and Transplantation, City Hope National Medical Center, Duarte, CA.
authors.forename: R
authors.initials: R
authors.lastname: Bhatia
keywords: FPDMM; L472X; RUNX1c isoform; eczema; hereditary leukemia