title: Hypomorphic function and somatic reversion of DOCK8 cause combined immunodeficiency without hyper-IgE.
abstract: Loss-of-function mutations in DOCK8 are linked to hyper-IgE syndrome. Patients typically present with recurrent sinopulmonary infections, severe cutaneous viral infections, food allergies and elevated serum IgE. Although patients may present with a spectrum of disease-related symptoms, molecular mechanisms explaining phenotypic variability in patients are poorly defined. Here we characterized a novel compound heterozygous mutation in DOCK8 in a patient diagnosed with primary combined immunodeficiency which was not typical of classical DOCK8 deficiency. In contrast to previously identified mutations in DOCK8 which result in complete loss of function, the newly identified single nucleotide insertion results in expression of a truncated DOCK8 protein. Functional evaluation of the truncated DOCK8 protein revealed its hypomorphic function. In addition we found somatic reversion of DOCK8 predominantly in T cells. The combination of somatic reversion and hypomorphic DOCK8 function explains the milder and atypical phenotype of the patient and further broadens the spectrum of DOCK8-associated disease.
authors.affiliation: Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, UK; Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK. Electronic address: anne-kathrin.kienzler@ndm.ox.ac.uk.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Kienzler
authors.affiliation: Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, UK; Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Pauline A
authors.initials: PA
authors.lastname: van Schouwenburg
authors.affiliation: Oxford NHS Regional Molecular Genetics Laboratory, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: John
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, UK; Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Ishita
authors.initials: I
authors.lastname: Marwah
authors.affiliation: Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, UK; Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Richa U
authors.initials: RU
authors.lastname: Sharma
authors.affiliation: Oxford NHS Regional Molecular Genetics Laboratory, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Noakes
authors.affiliation: Oxford NHS Regional Molecular Genetics Laboratory, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Thomson
authors.affiliation: Department of Clinical Laboratory Immunology, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Sadler
authors.affiliation: Department of Paediatrics, Children's Hospital, Oxford University NHS Hospitals Trust, Oxford, UK.
authors.forename: Shelley
authors.initials: S
authors.lastname: Segal
authors.affiliation: Department of Clinical Laboratory Immunology, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Berne
authors.initials: B
authors.lastname: Ferry
authors.affiliation: Oxford Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Taylor
authors.affiliation: Department of Clinical Genetics, Churchill Hospital, Oxford University NHS Hospitals Trust, Oxford, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Blair
authors.affiliation: Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, UK; Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Chapel
authors.affiliation: Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, UK; Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Smita Y
authors.initials: SY
authors.lastname: Patel
mesh_terms: D001987:Bronchiectasis / Q000209:etiology / Q000276:immunology; D002648:Child; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology*; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000235:genetics / Q000276:immunology*; D009154:Mutation; D012008:Recurrence; D012141:Respiratory Tract Infections / Q000209:etiology / Q000276:immunology
chemical_list: C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007073:Immunoglobulin E
keywords: Combined immunodeficiency; DOCK8; Hyper-IgE syndrome; Phenotypic variability; Whole exome sequencing