Mapping the Genotype, Phenotype, and Natural History of Phelan McDermid Syndrome

绘制费兰·麦克德米德综合征的基因型、表型和自然史图谱

• 批准号: 10701744
• 负责人: ALEXANDER KOLEVZON
• 金额: $ 32.99万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10701744
• 关键词: 22q; Academic Medical Centers; Adult; Age; Auditory Evoked Potentials; Basic Science; Behavior assessment; Biological Markers; Biological Models; Boston; Brain; Child; Chromosomes; Clinical; Clinical Practice Guideline; Clinical Sciences; Clinical Trials; Clinical Trials Design; Code; Communities; Comprehensive Health Care; Data; Development; Developmental Delay Disorders; Disease Outcome; Education; Electroencephalography; Electrophysiology (science); FRAP1 gene; Foundations; Frequencies; Future; Genes; Genetic Risk; Genotype; Glutamates; Goals; Hearing Tests; Impairment; Infrastructure; Intellectual functioning disability; Intramural Research Program; Knowledge; Language; Learning; Literature; Longevity; Maps; Measures; Medical; Modeling; Molecular; Monitor; Motor Skills; Mutation; National Institute of Mental Health; Natural History; PTEN Hamartoma Tumor Syndrome; PTEN gene; Participant; Pathway interactions; Patients; Pediatric Hospitals; Penetrance; Phelan-McDermid syndrome; Phenotype; Play; Prediction of Response to Therapy; Recommendation; Research; Resources; Risk; Role; Scaffolding Protein; Screening procedure; Sensory; Severities; Signal Transduction; Site; Speech; Symptoms; Synapses; Synaptic plasticity; Syndrome; System; Testing; Texas; Time; Tuberous Sclerosis; United States National Institutes of Health; Universities; Validity and Reliability; Visual evoked cortical potential; autism spectrum disorder; biomarker identification; clinical outcome assessment; clinical practice; clinical trial readiness; density; developmental neurobiology; genome-wide; glutamatergic signaling; improved; medical schools; neurobehavioral; neurophysiology; neuropsychiatric disorder; novel therapeutics; postsynaptic; preclinical study; psychologic; rare genetic disorder; risk variant; synaptic function; synaptogenesis; transcriptional coactivator p75; translational approach; treatment responders

Project Summary Increased use of genome-wide arrays and sequencing efforts have identified several single gene causes of autism spectrum disorder (ASD) and intellectual disability (ID), including SHANK3, known as Phelan-McDermid syndrome (PMS). Disruptions in SHANK3 pathways are also common to multiple monogenic forms of ID and ASD, such as tuberous sclerosis complex (TSC) and PTEN Hamartoma Tumor Syndrome (PHTS). PMS is characterized by severe global developmental delay/ID, motor skills deficits, delayed or absent speech, and ASD. Following a translational approach using Shank3 deficient model systems, specific deficits in synaptic function and plasticity in glutamate signaling have been documented. The proposed project represents a unique effort between clinical and basic science resources at five sites with recognized expertise in PMS and in ASD/ID: Icahn School of Medicine at Mount Sinai, Boston Children’s Hospital, Rush University Medical Center, Stanford University, and the National Institute of Mental Health. Specific aims are to: 1) comprehensively characterize the phenotype and natural history of PMS using a broad assessment battery; 2) identify biomarkers using electrophysiology; 3) develop a comprehensive clinical model of PMS to inform assessment and future clinical trials. This project is being undertaken in the context of a broader Developmental Synaptopathies Consortium (DSC) which uses a mechanistic approach to three rare genetic disorders with high penetrance of ASD/ID and aims to shed light on molecular pathways and targets relevant to ASD/ID: TSC, PHTS and PMS. Our DSC provides in-depth phenotyping and natural history characterization of patients with PMS. The current proposal seeks to extend our multi-site infrastructure to characterize an additional 100 patients across the lifespan. We will develop biomarkers and clinical outcome assessments (COAs) for clinical trials in PMS. We intend to show that specific neurophysiological biomarkers in PMS can be collected reliably across sites and will assess the relationship with clinically meaningful COAs. At the conclusion of this project, we expect to fully characterize the neurobehavioral phenotype of PMS and to track the natural history of the syndrome. Knowledge gained from this project will identify critical electrophysiological biomarkers and key assessment practices to provide a foundation for the development of novel therapies. Because the SHANK3 pathway is highly relevant to other forms of ASD/ID, knowledge gained from the proposed research will also improve our understanding of the neurobiology of developmental delay/ID and may aid in developing treatments of ASD/ID more broadly.

项目摘要 越来越多地使用全基因组阵列和测序工作已经确定了几个单基因导致 自闭症谱系障碍(ASD)和智力残疾(ID)，包括被称为费兰-麦克德米德的SHANK3 综合征(经前综合征)。SHANK3通路的中断在多种单基因形式的ID和 ASD，如结节性硬化症(TSC)和PTEN错构瘤综合征(PHTS)。经前综合症是 以严重的全球发育迟缓/发育迟缓、运动技能缺陷、说话延迟或缺席为特征，以及 ASD.遵循使用Shank3缺陷模型系统的翻译方法，突触中的特定缺陷 谷氨酸信号转导的功能和可塑性已被证实。拟议的项目代表着一个独特的 在经前综合症和ASD/ID方面拥有公认专业知识的五个地点的临床和基础科学资源之间的合作： 西奈山伊坎医学院，波士顿儿童医院，拉什大学医学中心，斯坦福 大学和国家心理健康研究所。具体目标是：1)全面描述 使用广泛的评估组合来确定经前综合症的表型和自然病史；2)使用 电生理学；3)建立经前综合征的综合临床模型，为评估和未来的临床提供参考。 审判。 该项目是在一个更广泛的发展性突触疗法联盟的背景下进行的 (DSC)使用机械方法治疗三种罕见的遗传疾病，具有高ASD/ID外显率和 旨在阐明与ASD/ID相关的分子途径和靶点：TSC、PHTS和PMS。我们的DSC 提供经前综合征患者的深入表型和自然病史特征。目前的提案 寻求扩展我们的多站点基础设施，以在整个生命周期内额外识别100名患者。我们 将为经前综合征的临床试验开发生物标记物和临床结果评估(COA)。我们打算向大家展示 经前综合症中的特定神经生理生物标记物可以跨地点可靠地收集，并将评估 与临床有意义的慢性阻塞性肺疾病的关系。 在这个项目的结论中，我们期望充分描述经前综合症的神经行为表型和 以追踪该综合症的自然病史。从该项目中获得的知识将确定关键 电生理生物标志物和关键评估实践，为发展 新奇的疗法。由于SHANK3途径与其他形式的ASD/ID高度相关，因此获得的知识 来自拟议的研究也将提高我们对发育迟缓/ID的神经生物学的理解 并可能有助于更广泛地开发ASD/ID的治疗方法。