Elucidating the Genetic Basis of Common Variable Immune Deficiency

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DESCRIPTION (provided by applicant): 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 five genes in which mutations can lead to CVID, but the genetic cause of the immune deficiency remains unknown in the overwhelming majority of patients (>85%). Ninety percent of patients with CVID present as sporadic cases, while the remaining are familial cases. Recently, three studies have demonstrated the feasibility of genetic diagnosis in individuals using selective sequencing of complete coding regions (i.e., "whole exomes"). Whole exome sequencing provides a new approach to identify the causative mutations in families with CVID. Sequencing of the exome, rather than just candidate genes or the entire human genome, is an efficient strategy to search for alleles underlying rare Mendelian disorders. First, this approach offers several advantages over candidate gene screening that requires locus-by-locus primer design and extensive Sanger sequencing, where the cost is proportional to the number exons to be tested. Candidate gene screening is limited and biased, and lacks the comprehensiveness of the whole exome approach. Exome sequencing utilizes generic, non gene- or disease-specific tools, thereby, decreasing cost. Second, the advantage of exome sequencing over whole genome sequencing is that the coding sequences (or exome) represent only 1.2 % of the genome, but is estimated to contain a majority of disease causing mutations, thereby, decreasing the sequencing cost while maintaining a reasonable chance of success. Thus, whole exome sequencing provides an efficient strategy to discover the genes for rare Mendelian disorders of unknown cause in small cohorts and families, not amenable to traditional genetic methods. Therefore we plan to examine several pedigrees with more than one case of CVID seen in the University of Utah Clinical Immunology/Immunodeficiency Clinic using whole exome sequencing after known genetic causes of CVID are ruled out. PUBLIC HEALTH RELEVANCE: Common variable immunodeficiency is the most common 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 (>85%) of these patients is unknown. This study aims to discover new genes responsible for disease in families with common variable immunodeficiency and to develop new, molecular based or flow cytometric based diagnostic tests in order to counsel patients and their families, and to provide new targets for therapeutic interventions.