Elucidating the Genetic Basis of Common Variable Immune Deficiency

描述(由申请人提供)：共同变量免疫缺陷(CVID)是最常见的原发免疫缺陷疾病，是一组以免疫球蛋白产生缺陷为特征的异质性疾病，导致反复感染，并伴有自身免疫和恶性疾病风险的增加。CVID导致血清免疫球蛋白显著减少，免疫球蛋白是血液和其他体液中发现的可溶性蛋白质，是抵御感染性病原体的主要机制之一。长期以来，人们一直在寻找CVID的遗传原因，但传统的遗传方法只取得了部分成功。对已知的B细胞发育和免疫球蛋白产生所需基因的筛选导致了五个基因的发现，其中突变可能导致CVID，但在绝大多数患者中，免疫缺陷的遗传原因仍然未知(&gt；85%)。90%的CVID患者为散发病例，其余为家族性病例。最近，三项研究证明了利用完整编码区(即“完整外显子”)的选择性测序对个体进行基因诊断的可行性。全外显子组测序为鉴定CVID家系的致病突变提供了一种新的方法。对外显子组进行测序，而不仅仅是对候选基因或整个人类基因组进行测序，是寻找罕见孟德尔疾病潜在等位基因的有效策略。首先，这种方法与候选基因筛选相比有几个优势，后者需要逐个位点的引物设计和广泛的Sanger测序，而Sanger测序的成本与要测试的外显子的数量成正比。候选基因的筛选是有限的和有偏见的，并且缺乏整个外显子组方法的全面性。外显子组测序使用通用的、非基因或疾病特异性的工具，从而降低了成本。第二，与全基因组测序相比，外显子组测序的优点是编码序列(或外显子组)只占基因组的1.2%，但估计包含大多数致病突变，从而在保持合理的成功机会的同时降低了测序成本。因此，全外显子组测序提供了一种有效的策略，可以在小群体和家系中发现原因不明的罕见孟德尔疾病的基因，而不是传统的遗传方法。因此，我们计划在排除了CVID的已知遗传原因后，使用完整的外显子组测序来检查犹他大学临床免疫学/免疫缺陷诊所中发现的几个CVID病例以上的家系。 公共卫生相关性：常见变量免疫缺陷是最常见的免疫系统紊乱，导致易受感染，以及自身免疫性疾病和免疫系统细胞恶性肿瘤。这些患者中的绝大多数(&gt；85%)的遗传原因未知。本研究旨在发现常见变异型免疫缺陷家系致病的新基因，开发新的基于分子或基于流式细胞术的诊断试验，为患者及其家属提供咨询，并为治疗干预提供新的靶点。

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.