Astute Clinician Report: A Novel 10 bp Frameshift Deletion in Exon 2 of ICOS Causes a Combined Immunodeficiency Associated with an Enteritis and Hepatitis

• Published in: Journal of clinical immunology Vol. 35; no. 7; pp. 598 - 603
• Main Authors: Robertson, Nic, Engelhardt, Karin R, Morgan, Neil V, Barge, Dawn, Cant, Andrew J, Hughes, Stephen M, Abinun, Mario, Xu, Yaobo, Koref, Mauro Santibanez, Arkwright, Peter D, Hambleton, Sophie
• Format: Journal Article
• Language: English
• Published: Netherlands Springer Nature B.V 01.10.2015; Springer US
• Subjects: Astute Clinician Report; Child; Child, Preschool; DNA Mutational Analysis; Enteritis - diagnosis; Enteritis - etiology; Exons - genetics; Fatal Outcome; Female; Frameshift Mutation - genetics; Hepatitis - diagnosis; Hepatitis - etiology; Herpesvirus 6, Human - immunology; Human herpesvirus 6; Humans; Immunologic Deficiency Syndromes - complications; Immunologic Deficiency Syndromes - diagnosis; Inducible T-Cell Co-Stimulator Protein - genetics; Inducible T-Cell Co-Stimulator Protein - metabolism; Male; Pakistan; Pedigree; Roseolovirus Infections - diagnosis; Roseolovirus Infections - immunology; Sequence Deletion - genetics; Siblings; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - virology; Pakistan; primary immunodeficiency; CVID; common variable immunodeficiency; ICOS
• ISSN: 0271-9142; 1573-2592
• DOI: 10.1007/s10875-015-0193-x

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.