Expanding the Genetic Basis of Common Variable Immunodeficiency

描述（由申请人提供）：常见可变免疫缺陷（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。对已知的b细胞发育和免疫球蛋白产生所需的基因进行筛选，发现了10个突变可导致CVID的基因，但绝大多数患者（bbb80 %）的免疫缺陷的遗传原因仍然未知。90%的CVID患者表现为单纯性病例，其余为家族性病例。使用全基因组测序或完整编码区（即“外显子组”）对单个个体进行遗传诊断现在是可能的。全外显子组测序提供了一种有效的策略来发现小家庭甚至单个个体中未知原因的遗传疾病的基因，这是传统遗传方法无法做到的。因此，我们计划研究20例在犹他大学临床免疫学/免疫缺陷诊所就诊的单纯性CVID患者及其父母，这些患者已排除了其他已知的CVID遗传原因。

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 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.