title: Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.
abstract: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.
  
  
  
  We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.
  
  
  
  Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping.
  
  
  
  A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays.
  
  
  
  This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Norwegian National Unit for Newborn Screening, Oslo University Hospital, Oslo, Norway; Department of Pediatrics, Oslo University Hospital, Oslo, Norway. Electronic address: astraype@ous-hf.no.
authors: Asbjørg
authors: A
authors: Stray-Pedersen
authors: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors: Hanne Sørmo
authors: HS
authors: Sorte
authors: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors: Pubudu
authors: P
authors: Samarakoon
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
authors: Tomasz
authors: T
authors: Gambin
authors: Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: Ivan K
authors: IK
authors: Chinn
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Zeynep H
authors: ZH
authors: Coban Akdemir
authors: Department of Pediatrics, Oslo University Hospital, Oslo, Norway.
authors: Hans Christian
authors: HC
authors: Erichsen
authors: Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: Lisa R
authors: LR
authors: Forbes
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Shen
authors: S
authors: Gu
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Bo
authors: B
authors: Yuan
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex.
authors: Shalini N
authors: SN
authors: Jhangiani
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex.
authors: Donna M
authors: DM
authors: Muzny
authors: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors: Olaug Kristin
authors: OK
authors: Rødningen
authors: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors: Ying
authors: Y
authors: Sheng
authors: Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: Sarah K
authors: SK
authors: Nicholas
authors: Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: Lenora M
authors: LM
authors: Noroski
authors: Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: Filiz O
authors: FO
authors: Seeborg
authors: Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: Carla M
authors: CM
authors: Davis
authors: Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: Debra L
authors: DL
authors: Canter
authors: Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: Emily M
authors: EM
authors: Mace
authors: Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: Timothy J
authors: TJ
authors: Vece
authors: Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Tex; Texas Children's Cancer and Hematology Center, Department of Pediatrics, Center for Cell and Gene Therapy, Texas Children's Hospital and Baylor College of Medicine, Houston, Tex.
authors: Carl E
authors: CE
authors: Allen
authors: Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Tex; Texas Children's Cancer and Hematology Center, Department of Pediatrics, Center for Cell and Gene Therapy, Texas Children's Hospital and Baylor College of Medicine, Houston, Tex.
authors: Harshal A
authors: HA
authors: Abhyankar
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Philip M
authors: PM
authors: Boone
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Christine R
authors: CR
authors: Beck
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Wojciech
authors: W
authors: Wiszniewski
authors: Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors: Børre
authors: B
authors: Fevang
authors: Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors: Pål
authors: P
authors: Aukrust
authors: Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Hematology, Oslo University Hospital, Oslo, Norway.
authors: Geir E
authors: GE
authors: Tjønnfjord
authors: Department of Hematology, Oslo University Hospital, Oslo, Norway.
authors: Tobias
authors: T
authors: Gedde-Dahl
authors: Department of Hematology, St Olavs Hospital, Trondheim, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors: Henrik
authors: H
authors: Hjorth-Hansen
authors: Department of Hematology, Oslo University Hospital, Oslo, Norway.
authors: Ingunn
authors: I
authors: Dybedal
authors: Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors: Ingvild
authors: I
authors: Nordøy
authors: Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors: Silje F
authors: SF
authors: Jørgensen
authors: Department of Pediatrics, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors: Tore G
authors: TG
authors: Abrahamsen
authors: Department of Pediatrics, Oslo University Hospital, Oslo, Norway.
authors: Torstein
authors: T
authors: Øverland
authors: Department of Pediatrics, Oslo University Hospital, Oslo, Norway.
authors: Anne Grete
authors: AG
authors: Bechensteen
authors: Department of Infectious Diseases, Medical Clinic, University Hospital of North-Norway, Tromsø, Norway.
authors: Vegard
authors: V
authors: Skogen
authors: Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway.
authors: Liv T N
authors: LTN
authors: Osnes
authors: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors: Mari Ann
authors: MA
authors: Kulseth
authors: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors: Trine E
authors: TE
authors: Prescott
authors: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors: Cecilie F
authors: CF
authors: Rustad
authors: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors: Ketil R
authors: KR
authors: Heimdal
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: John W
authors: JW
authors: Belmont
authors: Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: Nicholas L
authors: NL
authors: Rider
authors: Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: Javier
authors: J
authors: Chinen
authors: Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: Tram N
authors: TN
authors: Cao
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Tex.
authors: Eric A
authors: EA
authors: Smith
authors: Immunology Service, Ricardo Gutierrez Children's Hospital, Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina.
authors: Maria Soledad
authors: MS
authors: Caldirola
authors: Immunology Service, Ricardo Gutierrez Children's Hospital, Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina.
authors: Liliana
authors: L
authors: Bezrodnik
authors: Immunodeficiencies Research Unit, National Institute of Pediatrics, Coyoacan, Mexico City, Mexico.
authors: Saul Oswaldo
authors: SO
authors: Lugo Reyes
authors: Immunodeficiencies Research Unit, National Institute of Pediatrics, Coyoacan, Mexico City, Mexico.
authors: Francisco J
authors: FJ
authors: Espinosa Rosales
authors: Universidad San Francisco de Quito, Quito, Ecuador.
authors: Nina Denisse
authors: ND
authors: Guerrero-Cursaru
authors: Universidad San Francisco de Quito, Quito, Ecuador.
authors: Luis Alberto
authors: LA
authors: Pedroza
authors: Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Hospital Roberto del Rio, Universidad de Chile, Santiago, Chile.
authors: Cecilia M
authors: CM
authors: Poli
authors: Grupo de Inmunodeficiencias Primarias, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad de Antioquia UdeA, Medellin, Colombia.
authors: Jose L
authors: JL
authors: Franco
authors: Grupo de Inmunodeficiencias Primarias, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad de Antioquia UdeA, Medellin, Colombia.
authors: Claudia M
authors: CM
authors: Trujillo Vargas
authors: Allergy and Clinical Immunology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru.
authors: Juan Carlos
authors: JC
authors: Aldave Becerra
authors: Alberta Children's Hospital, Calgary, Alberta, Canada.
authors: Nicola
authors: N
authors: Wright
authors: Department of Pediatrics, Dalhousie University, Izaak Walton Killam Health Centre, Halifax, Nova Scotia, Canada.
authors: Thomas B
authors: TB
authors: Issekutz
authors: Department of Pediatrics, Dalhousie University, Izaak Walton Killam Health Centre, Halifax, Nova Scotia, Canada.
authors: Andrew C
authors: AC
authors: Issekutz
authors: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors: Jordan
authors: J
authors: Abbott
authors: Section of Pulmonary, Critical Care, Allergic and Immunological Diseases, Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC.
authors: Jason W
authors: JW
authors: Caldwell
authors: Department of Pediatrics, Division of Pediatric Allergy/Immunology and Pulmonology, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors: Diana K
authors: DK
authors: Bayer
authors: Department of Pediatrics, University of California, San Francisco, Calif.
authors: Alice Y
authors: AY
authors: Chan
authors: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), and Vita-Salute San Raffaele University, Milan, Italy.
authors: Alessandro
authors: A
authors: Aiuti
authors: University Department of Pediatrics, DPUO, Bambino Gesù Children's Hospital, and Tor Vergata University, Rome, Italy.
authors: Caterina
authors: C
authors: Cancrini
authors: Department of Clinical Genetics, University Hospital of Umeå, Umeå, Sweden.
authors: Eva
authors: E
authors: Holmberg
authors: Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden.
authors: Christina
authors: C
authors: West
authors: Department of Clinical Genetics, University Hospital of Umeå, Umeå, Sweden.
authors: Magnus
authors: M
authors: Burstedt
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Ender
authors: E
authors: Karaca
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Medical Genetics, Bezmi Alem Vakif University Faculty of Medicine, Istanbul, Turkey.
authors: Gözde
authors: G
authors: Yesil
authors: Department of Pediatric Immunology and Allergy, Selcuk University Medical Faculty, Alaeddin Keykubat Kampusu, Konya, Turkey.
authors: Hasibe
authors: H
authors: Artac
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Yavuz
authors: Y
authors: Bayram
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Mehmed Musa
authors: MM
authors: Atik
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Mohammad K
authors: MK
authors: Eldomery
authors: Department of Pediatrics, Section of Pediatric Allergy and Immunology, Hamad Medical Corporation, Doha, Department of Paediatrics, Weill Cornell Medical College, Ar-Rayyan, Qatar.
authors: Mohammad S
authors: MS
authors: Ehlayel
authors: Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, Wales.
authors: Stephen
authors: S
authors: Jolles
authors: Department of Rheumatology, Oslo University Hospital, Oslo, Norway.
authors: Berit
authors: B
authors: Flatø
authors: Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Tex.
authors: Alison A
authors: AA
authors: Bertuch
authors: Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: I Celine
authors: IC
authors: Hanson
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Victor W
authors: VW
authors: Zhang
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Lee-Jun
authors: LJ
authors: Wong
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex.
authors: Jianhong
authors: J
authors: Hu
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Magdalena
authors: M
authors: Walkiewicz
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Yaping
authors: Y
authors: Yang
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
authors: Christine M
authors: CM
authors: Eng
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex; Human Genetics Center, University of Texas School of Public Health, Houston, Tex.
authors: Eric
authors: E
authors: Boerwinkle
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex.
authors: Richard A
authors: RA
authors: Gibbs
authors: Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
authors: William T
authors: WT
authors: Shearer
authors: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors: Robert
authors: R
authors: Lyle
authors: Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex. Electronic address: orange@bcm.edu.
authors: Jordan S
authors: JS
authors: Orange
authors: Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex. Electronic address: jlupski@bcm.tmc.edu.
authors: James R
authors: JR
authors: Lupski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D005260:Female; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007223:Infant; D008297:Male; D008875:Middle Aged; D055815:Young Adult
keywords: Primary immunodeficiency disease; copy number variants; whole-exome sequencing