title: Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients.
abstract: The clinical and histopathological distinctions between inherited versus acquired bone marrow failure and myelodysplastic syndromes are challenging. The identification of inherited bone marrow failure/myelodysplastic syndromes is critical to inform appropriate clinical management. To investigate whether a subset of pediatric and young adults undergoing transplant for aplastic anemia or myelodysplastic syndrome have germline mutations in bone marrow failure/myelodysplastic syndrome genes, we performed a targeted genetic screen of samples obtained between 1990-2012 from children and young adults with aplastic anemia or myelodysplastic syndrome transplanted at the Fred Hutchinson Cancer Research Center. Mutations in inherited bone marrow failure/myelodysplastic syndrome genes were found in 5.1% (5/98) of aplastic anemia patients and 13.6% (15/110) of myelodysplastic syndrome patients. While the majority of mutations were constitutional, a RUNX1 mutation present in the peripheral blood at a 51% variant allele fraction was confirmed to be somatically acquired in one myelodysplastic syndrome patient. This highlights the importance of distinguishing germline versus somatic mutations by sequencing DNA from a second tissue or from parents. Pathological mutations were present in DKC1, MPL, and TP53 among the aplastic anemia cohort, and in FANCA, GATA2, MPL, RTEL1, RUNX1, SBDS, TERT, TINF2, and TP53 among the myelodysplastic syndrome cohort. Family history or physical examination failed to reliably predict the presence of germline mutations. This study shows that while any single specific bone marrow failure/myelodysplastic syndrome genetic disorder is rare, screening for these disorders in aggregate identifies a significant subset of patients with inherited bone marrow failure/myelodysplastic syndrome.
authors.affiliation: Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA akiko.shimamura@childrens.harvard.edu sioban@u.washington.edu.
authors.forename: Siobán B
authors.initials: SB
authors.lastname: Keel
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Pediatric Hematology/Oncology, Seattle Children's Hospital, WA, USA.|Department of Pediatrics, University of Washington, Seattle, WA, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Scott
authors.affiliation: Boston Children's Hospital, Dana Farber Cancer Institute, and Harvard Medical School, MA, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Sanchez-Bonilla
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Pediatric Hematology/Oncology, Seattle Children's Hospital, WA, USA.|Department of Pediatrics, University of Washington, Seattle, WA, USA.
authors.forename: Phoenix A
authors.initials: PA
authors.lastname: Ho
authors.affiliation: Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Suleyman
authors.initials: S
authors.lastname: Gulsuner
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Pritchard
authors.affiliation: Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA.
authors.forename: Janis L
authors.initials: JL
authors.lastname: Abkowitz
authors.affiliation: Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.affiliation: Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.affiliation: Boston Children's Hospital, Dana Farber Cancer Institute, and Harvard Medical School, MA, USA akiko.shimamura@childrens.harvard.edu sioban@u.washington.edu.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
mesh_terms: D000293:Adolescent; D000328:Adult; D000741:Anemia, Aplastic / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D005190:Family; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human