Common variable immunodeficiency (CVID), which is the most common primary immunodeficiency disease, is a heterogeneous group of diseases characterized by defective immunoglobulin production that leads to recurrent infections and is complicated by an increased risk of autoimmune and malignant diseases. CVID results in a marked reduction in serum immunoglobulins, which are soluble proteins found in blood and other bodily fluids, and are one of the main defense mechanisms against infectious agents. The genetic causes of CVID have long been sought, but traditional genetic approaches have been only partially successful. Screening of genes known to be required for B-cell development and immunoglobulin production has led to the discovery of ten genes in which mutations can lead to CVID, but the genetic cause of the immune deficiency remains unknown in the overwhelming majority of patients (>80%). Ninety percent of patients with CVID present as simplex cases, while the remaining are familial cases. Genetic diagnosis in single individuals using sequencing of whole genomes or the complete coding regions (i.e., """"""""exomes"""""""") is now possible. Whole exome sequencing provides an efficient strategy to discover the genes for genetic disorders of unknown cause in small families and even in single individuals, not amenable to traditional genetic approaches. Therefore we plan to study 20 simplex CVID patients and their parents, seen at the University of Utah Clinical Immunology/Immunodeficiency Clinic, in whom other known genetic causes of CVID have been ruled out.

Public Health Relevance

Common variable immunodeficiency (CVID) is the most common genetic disorder of the immune system that leads to susceptibility to infections, as well as autoimmune diseases and malignancies of the cells of the immune system. The genetic cause in the overwhelming majority (>80%) of CVID patients is unknown. This study aims to discover new genes responsible for disease in CVID patients, understand their relevance to disease development, implement new, gene or flow cytometric based diagnostic tests in order to counsel patients and their families, and to provide new targets for therapeutic interventions.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Research Grants (R03)
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Special Emphasis Panel (ZRG1-IMM-N (52))
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Johnson, David R
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Kumánovics, Attila; Lee, Yu Nee; Close, Devin W et al. (2017) Estimated disease incidence of RAG1/2 mutations: A case report and querying the Exome Aggregation Consortium. J Allergy Clin Immunol 139:690-692.e3
Abdulhay, Nour; Fiorini, Claudia; Kumánovics, Attila et al. (2016) Normal hematologic parameters and fetal hemoglobin silencing with heterozygous IKZF1 mutations. Blood 128:2100-2103