title: Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies.
abstract: Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine and Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL;
authors.forename: Maya
authors.initials: M
authors.lastname: Lewinsohn
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia; School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia;
authors.forename: Anna L
authors.identifier: http://orcid.org/0000-0002-9023-0138
authors.initials: AL
authors.lastname: Brown
authors.affiliation: Department of Genetics and Molecular Pathology, School of Medicine, University of Adelaide, Adelaide, SA, Australia;
authors.forename: Luke M
authors.initials: LM
authors.lastname: Weinel
authors.affiliation: Section of Hematology/Oncology, Department of Medicine and Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL;
authors.forename: Connie
authors.initials: C
authors.lastname: Phung
authors.affiliation: Section of Hematology/Oncology, Department of Medicine and Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL;
authors.forename: George
authors.initials: G
authors.lastname: Rafidi
authors.affiliation: Division of Medical Genetics, 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: School of Molecular and Biological Sciences, University of Adelaide, Adelaide, SA, Australia; Australian Cancer Research Foundation Cancer Genomics Facility, Centre for Cancer Biology.
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Schreiber
authors.affiliation: Australian Cancer Research Foundation Cancer Genomics Facility, Centre for Cancer Biology.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Genetics and Molecular Pathology.
authors.forename: Milena
authors.initials: M
authors.lastname: Babic
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia;
authors.forename: Chan-Eng
authors.initials: CE
authors.lastname: Chong
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia;
authors.forename: Young
authors.initials: Y
authors.lastname: Lee
authors.affiliation: School of Medicine, University of Adelaide, Adelaide, SA, Australia; Department of Haematology.
authors.forename: Agnes
authors.initials: A
authors.lastname: Yong
authors.affiliation: SA Clinical Genetics Service, Directorate of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, Australia;
authors.forename: Graeme K
authors.initials: GK
authors.lastname: Suthers
authors.affiliation: SA Clinical Genetics Service, Directorate of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, Australia;
authors.forename: Nicola
authors.initials: N
authors.lastname: Poplawski
authors.affiliation: SA Clinical Genetics Service, Directorate of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia;
authors.forename: Meryl
authors.initials: M
authors.lastname: Altree
authors.affiliation: SA Clinical Genetics Service, Directorate of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia;
authors.forename: Kerry
authors.initials: K
authors.lastname: Phillips
authors.affiliation: SA Clinical Genetics Service, Directorate of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia;
authors.forename: Louise
authors.initials: L
authors.lastname: Jaensch
authors.affiliation: SA Clinical Genetics Service, Directorate of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia;
authors.forename: Miriam
authors.initials: M
authors.lastname: Fine
authors.affiliation: Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia; School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia; Department of Haematology.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: D'Andrea
authors.affiliation: School of Medicine, University of Adelaide, Adelaide, SA, Australia; Department of Haematology.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Lewis
authors.affiliation: Stanford University School of Medicine, Stanford, CA;
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Medeiros
authors.affiliation: University of Colorado School of Medicine and University of Colorado Cancer Center, Aurora, CO; and.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pollyea
authors.affiliation: Division of Medical Genetics, 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: Division of Medical Genetics, Department of Medicine, and Department of Genome Sciences, University of Washington, Seattle, WA;
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.affiliation: Division of Hematology, Department of Medicine, and.
authors.forename: Siobán
authors.initials: S
authors.lastname: Keel
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
authors.affiliation: Section of Hematology/Oncology, Department of Medicine and Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL;
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia; School of Medicine, University of Adelaide, Adelaide, SA, Australia;
authors.forename: Christopher N
authors.identifier: http://orcid.org/0000-0001-5105-2554
authors.initials: CN
authors.lastname: Hahn
authors.affiliation: Section of Hematology/Oncology, Department of Medicine and Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL;
authors.forename: Jane E
authors.initials: JE
authors.lastname: Churpek
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia; School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia; School of Medicine, University of Adelaide, Adelaide, SA, Australia; School of Molecular and Biological Sciences, University of Adelaide, Adelaide, SA, Australia; Australian Cancer Research Foundation Cancer Genomics Facility, Centre for Cancer Biology.
authors.forename: Hamish S
authors.identifier: http://orcid.org/0000-0002-5813-631X
authors.initials: HS
authors.lastname: Scott
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: C501226:DDX41 protein, human; D053487:DEAD-box RNA Helicases