Genetic Mosaicism in Inborn Errors of Immunity

项目摘要 先天性免疫错误(IEI)是一组不同类型的疾病，由单基因缺陷引起 具有广泛临床范围的免疫反应，包括感染易感性、自身免疫、 炎症和癌症易感性。已经发现了450多个不同的IEI。 诊断IEI的确切遗传原因和机制(例如，功能获得或功能丧失)导致 通过改进诊断和指导临床监测来加强对患者的护理和治疗 关于基因分型和靶向治疗。虽然新的IEI的发现和对患者的测试迅速增长， 成功的基因诊断仍然只有~40%的患者被专家临床医生确定为有可能 患有单基因疾病。然而，IEI也可以由体细胞的从头突变引起，即后突变。 DNA序列中可能被当前测序方法遗漏的合子遗传变化。这 花叶病可表现为生殖系疾病，特别是具有显性表型的疾病。我们 将通过制定检测和验证马赛克遗传变异的战略来解决这一差距。在AIM 1，我们将使用一种定制的捕获测序方法来鉴定已知和预测的IEI基因中的嵌合体 尽管进行了标准检测，但仍未确诊的患者。在目标2中，我们将从功能上验证马赛克 变异体使用单细胞测序技术将基因与表达谱相关联。长期的 此应用程序的目标是改进IEI的诊断，以使诊断和靶向治疗成为可能 这些障碍。

Project Summary Inborn errors of immunity (IEI) are a heterogeneous group of disorders due to monogenic defects in the immune response that have a broad clinical spectrum including susceptibility to infection, autoimmunity, inflammation, and cancer susceptibility. There are more than 450 distinct IEI that have been discovered. Diagnosis of the precise genetic cause and mechanism (e.g., gain-of-function or loss-of-function) of IEI has led to enhanced care and treatment of patients through improved diagnosis, guidance for clinical monitoring based on genotype, and targeted therapies. While discovery of new IEI and testing for patients has rapidly grown, successful genetic diagnosis still only occurs for ~40% of the patients identified by expert clinicians as likely to have monogenic disease. However, IEI can also arise from de novo mutations in somatic cells, i.e., post- zygotic genetic changes in DNA sequence that may be missed by current sequencing approaches. This mosaic disease can phenocopy germline disease, particularly for disorders with a ‘dominant’ phenotype. We will address this gap through development of a strategy to detect and validate mosaic genetic variants. In Aim 1, we will use a custom capture sequencing assay to identify mosaicism in known and predicted IEI genes in patients who remain undiagnosed despite standard testing. In Aim 2, we will functionally validate mosaic variants using single cell sequencing techniques to correlate genotype with expression profile. The long-term goal of this application is to improve diagnosis of IEI to enable diagnosis and targeted therapy of patients with these disorders.