Genetic Causes and Genetic Modifiers of Inherited Retinal Degenerations

遗传性视网膜变性的遗传原因和遗传修饰因素

• 批准号: 10200051
• 负责人: Kinga Bujakowska
• 金额: $ 50.87万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200051
• 关键词: Affect; Alleles; Benign; Blindness; Blood; Catalogs; Clinical; Clinical Data; Complex; Copy Number Polymorphism; DNA Sequence Rearrangement; Data; Data Set; Databases; Defect; Deposition; Diagnostic tests; Disease; Disease Progression; Disease model; Etiology; Evaluation; Exons; Eye diseases; Family; Family member; Fibroblasts; Genes; Genetic; Genetic study; Genomics; Goals; Hereditary Disease; Human; Human Characteristics; Human Genome; Introns; Lead; Libraries; Mendelian disorder; Messenger RNA; Mitochondria; Modeling; Mutate; Mutation; Pathogenicity; Pathway interactions; Patients; Phenotype; Prognosis; RNA; RPGR gene; Research; Resources; Retina; Retinitis Pigmentosa; Risk; SNP array; Severities; Severity of illness; Siblings; Source; Syndrome; Techniques; Testing; Therapeutic; Time; USH2A gene; Untranslated RNA; Validation; Variant; Zebrafish; base; clinical Diagnosis; clinical phenotype; cohort; comparative genomics; diagnostic accuracy; disease phenotype; disease-causing mutation; early phase clinical trial; gene augmentation therapy; gene discovery; genetic analysis; genetic disorder diagnosis; genetic testing; improved; inherited retinal degeneration; insertion/deletion mutation; loss of function; mouse model; neuroprotection; next generation sequencing; novel; patient variability; prevent; proband; segregation; therapy development; transcriptome

Project Summary/Abstract The long-term objectives of the proposed research are to improve our ability to identify the genetic cause of disease for patients with inherited retinal degenerations (IRDs), and to identify genetic modifiers of the severity of IRDs. Accurate genetic diagnosis for patients affected by IRDs is desirable for multiple reasons, including provision of information about potential therapies, disease prognosis, and risk to other family members. This is especially true now that gene augmentation therapy for two genetic forms of IRD has been shown to be safe and effective in early clinical trials. Next-generation sequencing (NGS) based approaches make it possible to sequence all 250+ known IRD disease genes at the same time. Interpretation of the NGS data, and accurate identification of the genetic cause of disease for IRD patients remains difficult, due in part to the highly variable nature of the human genome, and the practice of focusing genetic analyses on genes associated with specific clinical diagnoses, which is sub-optimal due to highly variable and overlapping clinical phenotypes of IRDs. It is hypothesized that the accuracy of genetic diagnoses for IRD patients could be improved through the unbiased assessment of variants in all IRD genes. To make this possible, in Aim 1 it is proposed to perform genetic diagnostic testing of all known IRD genes for a cohort of 4,278 genetically unsolved patients with IRDs for whom longitudinal clinical data is available. The genetic testing will include the analysis of large insertions and deletions. The focus of Aim 2 is discovery and validation of genetic modifiers of IRD disease phenotypes. A consistent observation is that patients with the same genetic cause of IRD can have notably different disease severity. It is hypothesized that variants in other IRD disease genes are the most likely source of influence on disease severity. For these studies, gene-based association testing will be performed using the sequence variants identified in IRD disease genes by the studies in Aim 1 to identify modifiers of disease phenotype. These efforts will be focused initially on patients with selected primary mutations in the three genes that are the most common causes of IRD, RHO, USH2A and RPGR. Preliminary data confirm notable variation in the severity of disease in patients already known to have disease caused by mutations in these genes. Through the proposed genetic studies, we expect to identify at least five separate gene-defect groups, each with 100 patients or more to search for disease modifiers. The activity of candidate modifier alleles identified by these studies will then be tested in zebrafish and on mRNA obtained from patient’s blood or fibroblasts. The proposed research is an essential step toward complete understanding of the complex genetic basis of IRDs that cannot be accomplished by identifying new disease genes alone. The results obtained in these studies will lead to improved diagnostic accuracy, and facilitate development of treatments to limit vision loss from these disorders through identification of pathways that modulate disease severity.

项目摘要/摘要 拟议研究的长期目标是提高我们确定遗传原因的能力 遗传残留变性（IRD）患者的疾病，并确定严重程度的遗传修饰剂 irds。对于受IRD影响的患者的准确遗传诊断是出于多种原因，包括 提供有关其他家庭成员的潜在疗法，疾病进展和风险的信息。这是 尤其是现在，已经证明针对两种遗传形式的IRD的基因增强疗法是安全的 在早期临床试验中有效。下一代测序（NGS）方法使得 序列同时所有250多个已知的IRD疾病基因。 NGS数据的解释和准确 鉴定IRD患者疾病遗传原因的鉴定仍然很困难，部分原因是高度可变 人类基因组的性质以及将遗传分析集中在与特定相关的基因上的实践 临床诊断，由于IRD的高度可变和重叠的临床表型，这是优化的。 假设可以通过 所有IRD基因中变体的无偏评估。为了实现这一可能，在AIM 1中，建议执行 所有已知IRD基因的遗传诊断测试，用于4,278例未解决的IRDS患者 为此提供纵向临床数据。基因测试将包括大插入的分析 和删除。 AIM 2的重点是发现和验证IRD疾病表型的遗传修饰剂。 一个一致的观察结果是，具有相同遗传原因IRD遗传原因的患者可能具有明显不同的疾病 严重程度。假设其他IRD疾病基因中的变体是对 疾病的严重程度。对于这些研究，将使用序列进行基于基因的关联测试 AIM 1中的研究在IRD疾病基因中鉴定出的变体以鉴定疾病表型的修饰符。 这些努力最初将集中在三个基因中选定原发突变的患者上 IRD，RHO，USH2A和RPGR的最常见原因。初步数据证实了明显的变化 这些基因突变引起的已知患者疾病的严重程度。通过 提出的遗传研究，我们期望至少识别五个单独的基因缺陷组，每个基因100群 患者或更多以寻找疾病修饰剂。这些候选修饰符等位基因的活性 然后，将在斑马鱼和从患者的血液或成纤维细胞获得的mRNA中进行研究。 拟议的研究是完全理解IRD的复杂遗传基础的重要一步 这不能通过单独识别新的疾病基因来实现。这些研究中获得的结果将 导致提高诊断准确性，并维持治疗的发展，以限制这些视力丧失 通过鉴定调节疾病严重程度的途径来疾病。