Integrative Curation of Clinically Relevant Variants in X-Linked Inherited Retinal Disease Genes

X连锁遗传性视网膜疾病基因临床相关变异的综合治疗

• 批准号: 10661508
• 负责人: KIM C WORLEY
• 金额: $ 34.37万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661508
• 关键词: Acceleration; Address; Affect; Benign; Bioinformatics; Biological Assay; Blindness; Board Certification; Certification; Classification; ClinVar; Clinical; Clinical Trials; Collection; Country; Data; Dedications; Diagnosis; Diagnostic; Disease; Education; Eligibility Determination; Ensure; Eye diseases; FDA approved; Fright; Gene therapy trial; Genes; Genetic Heterogeneity; Genomics; Guidelines; Individual; Infrastructure; Inherited; Institution; Investigation; Knowledge; Laboratories; Lead; Link; Maintenance; Medical; Modification; Molecular; Molecular Diagnosis; Mutate; Mutation; National Human Genome Research Institute; Ophthalmologist; Pathogenicity; Patients; Phenotype; Physicians; Privatization; Procedures; Process; RPGR gene; Recording of previous events; Reporting; Research; Research Personnel; Resources; Retina; Retinal Diseases; Sampling; Scientist; Sorting; Specific qualifier value; Subgroup; Technology; Testing; Training; Variant; Work; X Chromosome; autosome; clinical diagnostics; clinical heterogeneity; clinically relevant; early onset; experience; gene therapy; gene therapy clinical trial; genetic variant; genome resource; improved; informatics infrastructure; laboratory experience; member; personalized medicine; public repository; recruit; tool; translational scientist; volunteer; webinar; working group

Abstract Inherited retinal diseases (IRD) are a major cause of early-onset blindness, profoundly affecting millions of patients. Given the clinical and genetic heterogeneity of IRD, targeted gene therapy is emerging as the main effective approach for treating the disease with many clinical trials currently underway. To maximize the benefit of these emerging therapies to patients, molecular diagnosis is the first critical step. In coordinating with the ClinGen Ocular Clinical Domain Working Group committee, we propose to establish a new variant curation expert panel (VCEP) that will focus on developing disease and gene specifications and curating expert assessment of variants in the seven X-linked IRD genes, including RPGR, CHM, RS1, RP2, OFD1, NDP, and CACNA1F. Collectively, mutations in these genes account for 15% of IRD patients. We have identified a distinguished panel of scientists across the world who will commit to this effort with diverse expertise: practicing ophthalmologic physicians, clinical diagnostic laboratory directors, and world-leading researchers studying the function of the X-linked IRD genes in the clinical and research domains. These experts bring complementary knowledge and resources to this effort including functional laboratory assays to assess the impact of patient variants, clinical trials for gene-based treatments, and collections of patient samples with sequenced variants and a detailed clinical history. Together with dedicated bioinformatics, curatorial, and administrative support, the X-linked IRD Variant Curation Panel proposed will deploy the FDA approved ClinGen infrastructure tools and processes in combination with the supportive resources we propose to collect, organize and provide to the panel to develop rule specifications for X-linked IRD gene curation. With our panel and team of coordinated curation volunteers, we will curate and expertly assess the variants in these genes. The products of this effort will be two-fold. First, specifications that can be applied to assess new variants in the seven genes and can be adapted for other X-linked IRD genes. And second, curated variants in the seven X-linked IRD genes with three-star (expert panel assessed) ratings in the ClinVar databasethat will improve the assessment of de novo patient variants and enable treatments with gene-based therapies.

抽象的 继承的视网膜疾病（IRD）是早期失明的主要原因，深刻影响数百万 患者。鉴于IRD的临床和遗传异质性，靶向基因疗法已成为主要的 通过目前正在进行的许多临床试验治疗该疾病的有效方法。最大化利益 在这些新兴疗法中，分子诊断是第一个关键步骤。 在与Clingen Ocular临床领域工作组委员会协调时，我们建议建立一个 新的变体策展专家小组（VCEP）将着重于发展疾病和基因规格以及 策划七个X连锁IRD基因的变体的专家评估，包括RPGR，CHM，RS1，RP2， OFD1，NDP和CACNA1F。这些基因中的突变占IRD患者的15％。我们有 确定了全球杰出的科学家小组，他们将以各种专业知识致力于这一努力： 执业眼科医生，临床诊断实验室主任和世界领先的研究人员 研究X连锁IRD基因在临床和研究领域的功能。这些专家带来 这项工作的互补知识和资源包括功能实验室测定法以评估 患者变体的影响，基于基因治疗的临床试验以及与患者样本的收集 测序变体和详细的​​临床病史。 连同专用的生物信息学，策展和管理支持，X连锁的IRD变体策展 提议的面板将部署FDA批准的克林根基础架构工具和流程 我们建议的支持资源收集，组织和提供给小组以制定规则规格 用于X连锁的IRD基因策展。与我们的小组和协调的策展志愿者团队一起，我们将策划和 熟练评估这些基因的变体。这项工作的产品将是两个方面。首先，规格 可以应用于评估七个基因中的新变体，并可以适用于其他X连锁IRD基因。 其次，在七个X连锁IRD基因中具有三星级（专家小组评估）评级的策划变体 Clinvar DatabaseThat将改善对从头患者变体的评估，并启用使用 基于基因的疗法。