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

摘要 遗传性视网膜疾病(IRD)是早发性失明的主要原因，严重影响数百万人 病人。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 目前正在进行许多临床试验，是治疗这种疾病的有效方法。最大限度地提高效益 在这些新兴的治疗方法中，分子诊断是关键的第一步。 在与克莱根眼科临床领域工作小组委员会的协调下，我们建议建立一个 新的变种监管专家小组(VCEP)将专注于制定疾病和基因规范以及 策划专家对7个X连锁IRD基因的变异进行评估，包括RPGR、CHM、RS1、RP2、 OFD1、NDP和CACNA1F。这些基因的突变合计占IRD患者的15%。我们有 确定了一个由世界各地杰出的科学家组成的小组，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。这些专家带来了 这项工作的补充知识和资源，包括功能实验室分析，以评估 患者变异的影响，基于基因治疗的临床试验，以及患者样本的收集 测序的变异和详细的临床病史。 与专门的生物信息学、策展和行政支持一起，X-Linked IRD变体治疗 专家小组建议将FDA批准的Clingen基础设施工具和流程与 我们建议收集、组织并提供给专家小组以制定规则规范的支持性资源 用于X连锁IRD基因管理。与我们的小组和协调的策展志愿者团队，我们将策展和 熟练地评估这些基因中的变异。这一努力的成果将是双重的。首先，规范 可用于评估这七个基因的新变异，并可适用于其他X-连锁IRD基因。 第二，7个X连锁IRD基因的精选变体，在 ClinVar数据库将改进对新患者变异的评估，并使治疗能够 基于基因的疗法。

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.