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: 10629203
• 负责人: PHILIP R.O. PAYNE
• 金额: $ 119.33万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629203
• 关键词: Acceleration; 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; Dedications; 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; Institution; Insurance Carriers; Intellectual and Developmental Disabilities Research Centers; Intellectual functioning disability; Intervention; Investigation; Joints; Laboratories; Lead; Link; Medical Genetics; Methods; Molecular Abnormality; National Institute of Child Health and Human Development; Nature; North Carolina; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Population Attributable Risks; Process; Protocols documentation; Qualifying; 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; pharmacologic; phenotypic data; programs; resilience; response; symptomatology; translational potential; 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 智力和发育障碍（IDD）临床进展的最后十年（IDD） 影响美国六分之一的人，其特征是前所未有的进步 了解遗传易感性IDD的性质和复杂性。稀有副本号码和 众所周知，序列变体可以占人群征收风险的主要份额 IDD，并且在30％的接受临床基因组测序的个体中被鉴定出来。 致病性变异的临床鉴定已产生了主要的转化机会 加速发现并改善临床治疗，但这些机会受到限制 我们对如何估计给定遗传的致病性的理解严重差距 个别患者异常。这项U01临床合作创新奖和 转化科学奖（CTSA）计划涉及这一主要障碍，资本化 基因组信息现在通常是在临床环境中获得的，并且大量获得 由美国卫生保险进行补贴。确保IDD临床上获得的测序数据 患者系统地与有关神经行为变异的标准化信息集成了 和临床课程（目前很少），可以加速对 遗传变异与疾病之间的关系。该计划的目的是建立 IDD患者在临床卫生系统中可行的神经行为表征的标准 整个CTSA网络，整合表型和临床基因组表征 患者直接促进国家议程的IDD基因和变体策划的患者， 并建立动态的，最先进的IDD患者注册表，作为NCAT中心的扩展 有关健康的数据（CD2H）倡议。该注册表将旨在共同注册表型， 基因型和电子健康记录大脑成像，脑电图，实验室生物标志物和 临床课程，目的是指定风险，弹性和干预的细微差别 响应，并阐明IDD中的常见和罕见的致病机制。一次 CTSA-IDD注册表成立，将构成一个自我延续的开放科学平台 IDD的翻译进展，为受影响的患者提供主要的新机会 合格的科学家和临床医生将确定的个人稀有IDD条件， 根据遗传或表型概况进行分组，并参与重点的发现工作， 针对其条件的个性化干预措施进行临床试验和/或创新。