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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的遗传性视网膜疾病（IRD）是早发性失明的主要原因，深刻影响着数以百万计的人患者。鉴于 IRD 的临床和遗传异质性，靶向基因治疗正在成为主要的治疗方法治疗该疾病的有效方法，目前正在进行许多临床试验。为了利益最大化在这些针对患者的新兴疗法中，分子诊断是第一个关键步骤。在与 ClinGen 眼科临床领域工作组委员会的协调下，我们建议建立一个新的变异管理专家小组（VCEP）将专注于开发疾病和基因规范以及对七个 X 连锁 IRD 基因的变异进行专家评估，包括 RPGR、CHM、RS1、RP2、 OFD1、NDP 和 CACNA1F。总的来说，这些基因的突变占 IRD 患者的 15%。我们有确定了一个由世界各地杰出科学家组成的小组，他们将以不同的专业知识致力于这一努力：执业眼科医师、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补充知识和资源，包括功能实验室测定来评估患者变异的影响、基于基因的治疗的临床试验以及患者样本的收集测序的变异和详细的临床病史。加上专门的生物信息学、策展和行政支持，X-linked IRD Variant Curation 小组提议将部署 FDA 批准的 ClinGen 基础设施工具和流程，并结合我们建议收集、组织并向专家组提供用于制定规则规范的支持资源用于 X 连锁 IRD 基因管理。通过我们的小组和协调策展志愿者团队，我们将策划和专业地评估这些基因的变异。这项努力的成果将是双重的。一、规格可用于评估七个基因中的新变异，并可适用于其他 X 连锁 IRD 基因。其次，七个 X 连锁 IRD 基因的精心设计变体在以下方面具有三星级（专家小组评估）评级： ClinVar 数据库将改善对新发患者变异的评估并实现治疗基于基因的疗法。