title: Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism.
abstract: Primary immunodeficiency disease (PID) is caused by mutations of more than two hundred immunity-related genes. In addition to the heterogeneity of the diseases, the atypical presentation of each disease caused by hypomorphic mutations or somatic mosaicism makes genetic diagnosis challenging. Next-generation sequencing tests all genes simultaneously and has proven its innovative efficacy in genomics. We describe a male PID patient without any family history of immunodeficiency. This patient suffered from recurrent infections from 1 year of age. Laboratory analysis showed hypogammaglobulinemia. T, B, and NK cells were present, but the T cell proliferative response decreased. Whole-exome sequencing analysis identified an IL2RG p.P58T missense mutation. CD8(+) and CD56(+) cells showed revertant somatic mosaicism to the wild-type allele. A late-onset and atypical presentation of the X-linked severe combined immunodeficiency (X-SCID) phenotype might be associated with revertant somatic mosaicism in T and NK cells. This patient is the seventh reported case of X-SCID with revertant somatic mosaicism. His classical clinical management did not result in a molecular diagnosis because of the atypical presentation. The coverage that is provided by whole-exome sequencing of most PID genes effectively excluded differential diagnoses other than X-SCID. As next-generation sequencing becomes available in clinical practice, it will enhance our knowledge of PID and rescue currently undiagnosed patients.
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, University of Toyama, Toyama, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hoshino
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Muramatsu
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Kawashima
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Xinan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Taizo
authors.initials: T
authors.lastname: Wada
authors.affiliation: Department of Pathology, Japanese Red Cross Nagoya first Hospital, Nagoya, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Gunji
authors.affiliation: Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toma
authors.affiliation: Department of Pediatrics, National Defense Medical College, Saitama, Japan.
authors.forename: Tamaki
authors.initials: T
authors.lastname: Kato
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Iwata
authors.affiliation: Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hori
authors.affiliation: Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kitoh
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Pediatrics, National Defense Medical College, Saitama, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.affiliation: Department of Pathology, Japanese Red Cross Nagoya first Hospital, Nagoya, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, University of Toyama, Toyama, Japan. hkanegane.ped@tmd.ac.jp.|Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. hkanegane.ped@tmd.ac.jp.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kanegane
mesh_terms: D001230:Aspergillus / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D006084:Graft Rejection / Q000175:diagnosis* / Q000209:etiology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000175:diagnosis*; D007223:Infant; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism*; D055744:Invasive Pulmonary Aspergillosis / Q000175:diagnosis* / Q000209:etiology; D007564:Japan; D008297:Male; D009030:Mosaicism; D020125:Mutation, Missense / Q000235:genetics; D055611:Natural Killer T-Cells / Q000502:physiology*; D010375:Pedigree
chemical_list: C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit
keywords: Combined immunodeficiency; Revertant somatic mosaicism; Whole-exome sequencing; X-linked severe combined immunodeficiency