title: Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity.
abstract: Accurate and timely diagnosis of inherited bone marrow failure and inherited myelodysplastic syndromes is essential to guide clinical management. Distinguishing inherited from acquired bone marrow failure/myelodysplastic syndrome poses a significant clinical challenge. At present, diagnostic genetic testing for inherited bone marrow failure/myelodysplastic syndrome is performed gene-by-gene, guided by clinical and laboratory evaluation. We hypothesized that standard clinically-directed genetic testing misses patients with cryptic or atypical presentations of inherited bone marrow failure/myelodysplastic syndrome. In order to screen simultaneously for mutations of all classes in bone marrow failure/myelodysplastic syndrome genes, we developed and validated a panel of 85 genes for targeted capture and multiplexed massively parallel sequencing. In patients with clinical diagnoses of Fanconi anemia, genomic analysis resolved subtype assignment, including those of patients with inconclusive complementation test results. Eight out of 71 patients with idiopathic bone marrow failure or myelodysplastic syndrome were found to harbor damaging germline mutations in GATA2, RUNX1, DKC1, or LIG4. All 8 of these patients lacked classical clinical stigmata or laboratory findings of these syndromes and only 4 had a family history suggestive of inherited disease. These results reflect the extensive genetic heterogeneity and phenotypic complexity of bone marrow failure/myelodysplastic syndrome phenotypes. This study supports the integration of broad unbiased genetic screening into the diagnostic workup of children and young adults with bone marrow failure and myelodysplastic syndromes.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Division of Hematology, University of Washington, Seattle, WA.
authors.forename: Siobán B
authors.initials: SB
authors.lastname: Keel
authors.affiliation: Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA.
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.affiliation: Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA.
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA.
authors.forename: Suleyman
authors.initials: S
authors.lastname: Gulsuner
authors.affiliation: Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Watts
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Pritchard
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Salipante
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jeng
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA.
authors.forename: Inga
authors.initials: I
authors.lastname: Hofmann
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA Harvard Stem Cell Institute, Boston, MA.
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.affiliation: Department of Pathology, Boston Children's Hospital, MA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.affiliation: Department of Medicine, Division of Hematology, University of Washington, Seattle, WA.
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.
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA Department of Pediatric Hematology/Oncology, Seattle Children's Hospital, WA Department of Pediatrics, University of Washington, Seattle, WA, USA ashimamu@fhcrc.org.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D019046:Bone Marrow Neoplasms / Q000145:classification / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D023281:Genomics / Q000379:methods*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000145:classification / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor