Expanding the Genetic Basis of Common Variable Immunodeficiency

描述（由申请人提供）：常见变异型免疫缺陷（CVID）是最常见的原发性免疫缺陷疾病，是一组异质性疾病，其特征为免疫球蛋白产生缺陷，导致复发性感染，并伴有自身免疫和恶性疾病风险增加。CVID导致血清免疫球蛋白显著减少，血清免疫球蛋白是在血液和其他体液中发现的可溶性蛋白质，并且是对抗感染因子的主要防御机制之一。CVID的遗传原因一直在寻找，但传统的遗传方法只取得了部分成功。对已知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个基因，其中突变可导致CVID，但绝大多数患者（>80%）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。使用全基因组或完整编码区（即，“exomes”）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性疾病的基因，而这些基因不适合传统的遗传学方法。因此，我们计划研究20名单纯CVID患者及其父母，他们在犹他州大学临床免疫学/免疫缺陷诊所就诊，其中CVID的其他已知遗传原因已被排除。

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.