title: Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency.
abstract: The gene PIK3CD codes for the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), and is expressed solely in leucocytes. Activating mutations of PIK3CD have been described to cause an autosomal dominant immunodeficiency that shares clinical features with common variable immunodeficiency (CVID). We screened a cohort of 669 molecularly undefined primary immunodeficiency patients for five reported mutations (four gain-of-function mutations in PIK3CD and a loss of function mutation in PIK3R1) using pyrosequencing. PIK3CD mutations were identified in three siblings diagnosed with CVID and two sporadic cases with a combined immunodeficiency (CID). The PIK3R1 mutation was not identified in the cohort. Our patients with activated PI3Kδ syndrome (APDS) showed a range of clinical and immunological findings, even within a single family, but shared a reduction in naive T cells. PIK3CD gain of function mutations are more likely to occur in patients with defective B and T cell responses and should be screened for in CVID and CID, but are less likely in patients with a pure B cell/hypogammaglobulinaemia phenotype.
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.|Faculty of Biology, Albert Ludwigs University, Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Elgizouli
authors.affiliation: Institute of Immunity and Transplantation, University College London, London, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Lowe
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.|Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Speckmann
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.|Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University, Freiburg, Germany.|Faculty of Biology, Albert Ludwigs University, Freiburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Schubert
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.|Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University, Freiburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hülsdünker
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Z
authors.initials: Z
authors.lastname: Eskandarian
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.|Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University, Freiburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Dudek
authors.affiliation: Department of Pathology, University Medical Center, Freiburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schmitt-Graeff
authors.affiliation: Institute of Immunity and Transplantation, University College London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Wanders
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, and Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: S F
authors.initials: SF
authors.lastname: Jørgensen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, and Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Fevang
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Salzer
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Nieters
authors.affiliation: Institute of Immunity and Transplantation, University College London, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Burns
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.|Institute of Immunity and Transplantation, University College London, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Grimbacher
mesh_terms: D000293:Adolescent; D000328:Adult; D000361:Agammaglobulinemia / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002648:Child; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D017074:Common Variable Immunodeficiency / Q000235:genetics* / Q000276:immunology; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D009154:Mutation; D035781:Siblings; D013601:T-Lymphocytes / Q000276:immunology; D055815:Young Adult
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human
keywords: B cells; PI3Kδ; common variable immunodeficiency; hypogammaglobulinaemia; primary immunodeficiency