Harnessing Clinical Genomic Characterization to Accelerate Translational Advances for Patients with IDD

利用临床基因组特征加速 IDD 患者的转化进展

• 批准号: 10388375
• 负责人: PHILIP R.O. PAYNE
• 金额: $ 123.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-06 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388375
• 关键词: Address; Affect; Award; Biological Markers; Biology; Brain; Brain Diseases; Brain imaging; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Clinical and Translational Science Awards; Data; Data Commons; Disability phenotype; Disease; Electroencephalography; Electronic Health Record; Eligibility Determination; Ensure; Etiology; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Health; Health system; Individual; Infrastructure; Institutes; Institution; Insurance Carriers; Intellectual and Developmental Disabilities Research Centers; Intellectual functioning disability; Intervention; Investigation; Joints; Laboratories; Lead; Link; Medical Genetics; Methods; Molecular Abnormality; National Center for Advancing Translational Sciences; National Institute of Child Health and Human Development; Nature; North Carolina; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmacology; Phenotype; Population Attributable Risks; Process; Protocols documentation; Registries; Research; Resources; Risk; Role; Science; Scientist; Specific qualifier value; Standardization; Technology; Testing; Translational Research; United States National Institutes of Health; Universities; Validation; Variant; Washington; base; design; effective therapy; experience; genetic disorder diagnosis; genetic variant; genomic data; improved; individual patient; innovation; loss of function; neurobehavioral; novel; open data; patient oriented; patient population; patient registry; personalized approach; personalized intervention; personalized medicine; phenotypic data; programs; resilience; response; symptomatology; treatment response

Abstract The last decade of clinical progress in intellectual and developmental disabilities (IDD)—which affect one in six individuals in the U.S.—has been characterized by unprecedented advances in understanding the nature and complexity of genetic susceptibility to IDD. Rare copy number and sequence variants are now known to account for a major share of population-attributable risk for IDD, and are being identified in over 30% of individuals who undergo clinical genomic sequencing. Clinical identification of pathogenic variants has generated major translational opportunities to accelerate discovery and improve clinical treatment, but these opportunities are constrained by serious gaps in our understanding of how to estimate the pathogenicity of a given genetic abnormality in an individual patient. This U01 Collaborative Innovation Award of the Clinical and Translational Science Award (CTSA) Program addresses this major roadblock, capitalizing upon the fact that genomic information is now commonly acquired in clinical settings and substantially subsidized by U.S. health insurers. Ensuring that clinically-acquired sequencing data of IDD patients is systematically integrated with standardized information on neurobehavioral variation and clinical course (this is currently uncommon) stands to accelerate understanding of the relationship between genetic variation and disease. The aims of this program are to establish standards for feasible neurobehavioral characterization of IDD patients in clinical health systems across the CTSA Network, to integrate phenotypic and clinical genomic characterization of patients to directly promote progress in the national agenda for IDD gene and variant curation, and to establish a dynamic, state-of-the-art IDD patient registry, as an extension of NCAT’s Center for Data To Health (CD2H) Initiative. This registry will be designed to co-register phenotypic, genotypic, and electronic health record data on brain imaging, EEG, laboratory biomarkers, and clinical course, for the purpose of specifying nuanced profiles of risk, resilience, and intervention response, and to elucidate both common and rare pathogenic mechanisms in IDD. Once established, the CTSA-IDD Registry will constitute a self-perpetuating open science platform for translational advances in IDD, by providing major new opportunity for patients affected by individually-rare IDD conditions to be identified by qualified scientists and clinicians, to be sub grouped according to genetic or phenotypic profile, and to participate in focused discovery efforts, clinical trials, and/or innovations in personalized intervention specific to their conditions.

抽象的 过去十年智力和发育障碍 (IDD) 的临床进展 影响了美国六分之一的人——其特点是在 了解 IDD 遗传易感性的本质和复杂性。稀有拷贝数和 现在已知序列变异是造成人群归因风险的主要因素 IDD，在超过 30% 接受临床基因组测序的个体中被发现。 致病变异的临床鉴定已经产生了重大的转化机会 加速发现并改善临床治疗，但这些机会受到以下因素的限制 我们对如何估计给定基因的致病性的理解存在严重差距 个别患者的异常。本次U01临床与临床协同创新奖 转化科学奖 (CTSA) 计划解决了这一主要障碍，利用 事实上，基因组信息现在通常在临床环境中获取，并且在很大程度上 由美国健康保险公司补贴。确保临床获得的 IDD 测序数据 患者与神经行为变异的标准化信息系统地整合 和临床过程（这目前并不常见）可以加速对 遗传变异与疾病的关系。该计划的目的是建立 临床卫生系统中 IDD 患者的可行神经行为特征标准 跨 CTSA 网络，整合表型和临床基因组特征 患者直接推动 IDD 基因和变异治疗国家议程的进展， 建立动态、最先进的 IDD 患者登记处，作为 NCAT 中心的延伸 数据健康 (CD2H) 倡议。该注册表旨在共同注册表型、 有关脑成像、脑电图、实验室生物标志物的基因型和电子健康记录数据 临床课程，旨在详细说明风险、恢复力和干预的细微差别 反应，并阐明 IDD 常见和罕见的致病机制。一次 CTSA-IDD 注册中心成立后，将构成一个自我延续的开放科学平台 IDD 的转化进展，为受此影响的患者提供了重大的新机会 个别罕见的 IDD 病症将由合格的科学家和临床医生识别，以亚 根据遗传或表型概况分组，并参与重点发现工作， 临床试验和/或针对其病情的个性化干预创新。