title: Astute Clinician Report: A Novel 10 bp Frameshift Deletion in Exon 2 of ICOS Causes a Combined Immunodeficiency Associated with an Enteritis and Hepatitis.
abstract: ICOS encodes the Inducible T-cell Co-Stimulator (ICOS). Deficiency of this receptor in humans causes a common variable immunodeficiency (CVID) characterised by an absence of class-switched memory B cells and hypogammaglobulinemia. Three pathogenic mutations in ICOS have been described to date in a total of 13 cases. Here we report a novel homozygous 10 base pair frameshift deletion in exon 2 discovered by whole exome sequencing of two siblings from a family of Pakistani origin. Both patients presented in early childhood with diarrhea, colitis and transaminitis and one showed defective handling of human herpesvirus 6. Activated patient CD3(+)CD4(+) T lymphocytes demonstrated a complete absence of ICOS expression and, consistent with previous reports, we detected a reduction in circulating T follicular helper cells. Findings in this kindred emphasise the phenotypic variability of ICOS deficiency and, in particular, the variably impaired antiviral immunity that is a poorly understood facet of this rare disorder.
authors.affiliation: Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.|Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: Nic
authors.initials: N
authors.lastname: Robertson
authors.affiliation: Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Karin R
authors.initials: KR
authors.lastname: Engelhardt
authors.affiliation: Centre for Cardiovascular Sciences, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.affiliation: Blood Sciences Flow Cytometry Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: Dawn
authors.initials: D
authors.lastname: Barge
authors.affiliation: Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cant
authors.affiliation: Paediatric Immunology, Royal Manchester Children's Hospital, Manchester, UK.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hughes
authors.affiliation: Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: Mario
authors.initials: M
authors.lastname: Abinun
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Yaobo
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Mauro Santibanez
authors.initials: MS
authors.lastname: Koref
authors.affiliation: Paediatric Immunology, Royal Manchester Children's Hospital, Manchester, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.affiliation: Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. sophie.hambleton@ncl.ac.uk.|Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. sophie.hambleton@ncl.ac.uk.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hambleton
mesh_terms: D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004751:Enteritis / Q000175:diagnosis* / Q000209:etiology; D005091:Exons / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D006505:Hepatitis / Q000175:diagnosis* / Q000209:etiology; D015654:Herpesvirus 6, Human / Q000276:immunology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000175:diagnosis*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010154:Pakistan; D010375:Pedigree; D019349:Roseolovirus Infections / Q000175:diagnosis* / Q000276:immunology; D017384:Sequence Deletion / Q000235:genetics; D035781:Siblings; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000821:virology
chemical_list: C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein
keywords: CVID; ICOS; common variable immunodeficiency; primary immunodeficiency