Genetic Mosaicism in Inborn Errors of Immunity

项目摘要 先天性免疫缺陷（IEI）是一组异质性疾病，由于单基因缺陷， 具有广泛临床谱免疫应答，包括对感染的易感性，自身免疫， 炎症和癌症易感性。已经发现了450多种不同的IEI。 精确的遗传原因和机制的诊断（例如，功能获得或功能丧失）导致 通过改进诊断、指导临床监测， 基因型和靶向治疗。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发生在约40%的患者中，这些患者被专家临床医生确定为可能 患有单基因疾病。然而，IEI也可以由体细胞中的从头突变引起，即，后 DNA序列中的合子遗传变化可能被当前的测序方法遗漏。这 镶嵌病可以表型复制生殖系疾病，特别是具有“显性”表型的疾病。我们 将通过制定一项战略来检测和验证镶嵌遗传变异来解决这一差距。在Aim中 1，我们将使用定制的捕获测序测定来鉴定已知的和预测的IEI基因中的嵌合体， 尽管进行了标准测试但仍未确诊的患者。在目标2中，我们将在功能上验证马赛克 使用单细胞测序技术将基因型与表达谱相关联。长期 本申请的目的是改善IEI的诊断，以便能够对患有IEI的患者进行诊断和靶向治疗。 这些紊乱。

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.