A hypomorphic recombination-activating gene 1 ( RAG1 ) mutation resulting in a phenotype resembling common variable immunodeficiency

• Published in: Journal of allergy and clinical immunology 2014-12, Vol.134 (6), p.1375-1380
• Main Authors: Abolhassani, Hassan, MD, Wang, Ning, PhD, Aghamohammadi, Asghar, MD, PhD, Rezaei, Nima, MD, PhD, Lee, Yu Nee, PhD, Frugoni, Francesco, PhD, Notarangelo, Luigi D., MD, Pan-Hammarström, Qiang, MD, PhD, Hammarström, Lennart, MD, PhD
• Format: Article
• Language: English
• Subjects: Adolescent; Allergy and Immunology; Biological and medical sciences; Chicken pox; Common variable immunodeficiency; Common Variable Immunodeficiency - genetics; Common Variable Immunodeficiency - immunology; Deoxyribonucleic acid; differential diagnosis; DNA; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genes; Genomes; Genotype & phenotype; Granuloma - genetics; Granuloma - immunology; granulomatous lesion; Homeodomain Proteins - genetics; Homeodomain Proteins - immunology; Humans; Immune system; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infections; Liver Diseases - genetics; Liver Diseases - immunology; Lymphocytes; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - immunology; Male; Medical sciences; Medicin och hälsovetenskap; mismanagement; Mutation; Neutropenia - genetics; Neutropenia - immunology; Patients; Phenotype; recombination activation genes; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Software; Viral infections
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2014.04.042

Background Recombination-activating gene 1 (RAG1) deficiency presents with a varied spectrum of combined immunodeficiency, ranging from a T− B− NK+ type of disease to a T+ B+ NK+ phenotype. Objective We sought to assess the genetic background of patients with common variable immunodeficiency (CVID). Methods A patient given a diagnosis of CVID, who was born to a consanguineous family and thus would be expected to show an autosomal recessive inheritance, was subjected to clinical evaluation, immunologic assays, homozygosity gene mapping, exome sequencing, Sanger sequencing, and functional analysis. Results The 14-year-old patient, who had liver granuloma, extranodal marginal zone B-cell lymphoma, and autoimmune neutropenia, presented with a clinical picture resembling CVID. Genetic analysis of this patient showed a homozygous hypomorphic RAG1 mutation (c.1073 G>A, p.C358Y) with a residual functional capacity of 48% of wild-type protein. Conclusion Our finding broadens the range of disorders associated with RAG1 mutations and might have important therapeutic implications.