Elucidating the Genetic Basis of Common Variable Immune Deficiency

描述（由申请人提供）：常见的可变免疫缺陷（CVID）是最常见的原发性免疫缺陷疾病，是一种异质性疾病，其特征是免疫球蛋白产生缺陷，导致复发性感染，并伴有自身免疫性和恶性疾病的风险增加。CVID导致血清免疫球蛋白显著减少，血清免疫球蛋白是血液和其他体液中发现的可溶性蛋白质，是抵抗传染性病原体的主要防御机制之一。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。筛选已知的b细胞发育和免疫球蛋白产生所需的基因，发现了5个突变可导致CVID的基因，但绝大多数患者（>85%）的免疫缺陷的遗传原因仍然未知。90%的CVID患者为散发性病例，其余为家族性病例。最近，三项研究已经证明了使用完整编码区（即“全外显子组”）的选择性测序在个体中进行遗传诊断的可行性。全外显子组测序为识别CVID家族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背后的等位基因的有效策略。首先，与需要逐个位点设计引物和广泛的Sanger测序的候选基因筛选相比，这种方法有几个优势，Sanger测序的成本与要测试的外显子数量成正比。候选基因筛选是有限的和有偏见的，并且缺乏全外显子组方法的全面性。外显子组测序利用通用、非基因或疾病特异性工具，从而降低了成本。其次，与全基因组测序相比，外显子组测序的优势在于编码序列（或外显子组）仅占基因组的1.2%，但据估计包含了大多数引起疾病的突变，因此，在保持合理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，可以在小群体和家庭中发现罕见的未知原因孟德尔疾病的基因，而传统的遗传方法无法实现。因此，在排除已知的CVID遗传原因后，我们计划在犹他大学临床免疫学/免疫缺陷诊所使用全外显子组测序检查多个CVID病例的家系。

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.