title: Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype.
abstract: BACKGROUND
  Autosomal recessive loss-of-function mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency characterized by atopy, recurrent infections, and cancer susceptibility. A genotype-phenotype explanation for the variable disease expression is lacking.
  
  
  OBJECTIVE
  We investigated whether reversions contributed to the variable disease expression.
  
  
  METHODS
  Patients followed at the National Institutes of Health's Clinical Center were studied. We performed detailed genetic analyses and intracellular flow cytometry to detect DOCK8 protein expression within lymphocyte subsets.
  
  
  RESULTS
  We identified 17 of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion caused by somatic repair. Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover. Higher degrees of reversion were associated with recombination-mediated repair. DOCK8 expression was restored primarily within antigen-experienced T cells or natural killer cells but less so in naive T or B cells. Several patients exhibited multiple different repair events. Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation.
  
  
  CONCLUSIONS
  In patients with DOCK8 deficiency, only certain combinations of germline mutations supported secondary somatic repair. Those patients had an ameliorated disease course with longer survival but still had fatal complications or required hematopoietic cell transplantation. These observations support the concept that some DOCK8-immunodeficient patients have mutable mosaic genomes that can modulate disease phenotype over time.
authors.affiliation: Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
authors.forename: Huie
authors.initials: H
authors.lastname: Jing
authors.affiliation: Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
authors.forename: Brenna J
authors.initials: BJ
authors.lastname: Hill
authors.affiliation: Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Dove
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Division of Cell Biology, National Jewish Health, Denver, Colo.
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Ala.
authors.forename: T Prescott
authors.initials: TP
authors.lastname: Atkinson
authors.affiliation: Laboratory of Clinical Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.affiliation: Laboratory of Immunology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
authors.forename: Helen F
authors.initials: HF
authors.lastname: Matthews
authors.affiliation: Division of Infectious Diseases and Immunology, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mustillo
authors.affiliation: Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Stanford University, Stanford, Calif.
authors.forename: David B
authors.initials: DB
authors.lastname: Lewis
authors.affiliation: Section of Clinical Immunology and Allergy, Department of Pediatrics, Alberta Children's Hospital and University of Calgary, Calgary, Alberta, Canada.
authors.forename: Fotini D
authors.initials: FD
authors.lastname: Kavadas
authors.affiliation: Section of Allergy and Immunology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Tex.
authors.forename: I Celine
authors.initials: IC
authors.lastname: Hanson
authors.affiliation: Cancer and Blood Diseases Institute, Division of Bone Marrow Transplantation and Immune Deficiency and Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio.
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Kumar
authors.affiliation: Division of Immunology and Department of Pediatrics, Children's Hospital and Harvard Medical School, Boston, Mass.
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.affiliation: Laboratory of Clinical Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Laboratory of Clinical Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.affiliation: Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md. Electronic address: hsu@niaid.nih.gov.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Su
mesh_terms: D000293:Adolescent; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004260:DNA Repair; D005838:Genotype; D018095:Germ-Line Mutation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors
keywords: Dedicator of cytokinesis 8; T cell; allergy; gene conversion; immunodeficiency; intragenic single crossover; natural killer cell; recombination; reversion; somatic repair