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: 9804362
• 负责人: ALEXANDER KOLEVZON
• 金额: $ 40.07万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9804362
• 关键词: 22q; Academic Medical Centers; Address; 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; Deletion Mutation; Development; Developmental Delay Disorders; Disease Outcome; Electroencephalography; Electrophysiology (science); FRAP1 gene; Foundations; Frequencies; Future; Genes; Genetic Risk; Genotype; Glutamates; Goals; Impairment; Infrastructure; Intellectual functioning disability; Intramural Research Program; Knowledge; Language; Learning; Light; Literature; Longevity; Measures; Medical; Modeling; Molecular; Monitor; Motor Skills; Mutation; National Institute of Mental Health; Natural History; Outcome Assessment; PTEN gene; Participant; Pathway interactions; Patients; Pediatric Hospitals; Penetrance; Phelan-McDermid syndrome; Phenotype; Play; Readiness; 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 protein complex; United States National Institutes of Health; Universities; Validity and Reliability; Visual evoked cortical potential; autism spectrum disorder; base; clinical practice; 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; 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 全基因组阵列和测序工作的增加已经确定了几个单基因的原因， 自闭症谱系障碍（ASD）和智力残疾（ID），包括SHANK 3，称为M-M 综合征（PMS）。SHANK 3途径的破坏也常见于多种单基因形式的ID和 ASD，如结节性硬化综合征（TSC）和PTEN错构瘤肿瘤综合征（PHTS）。PMS是 特征为重度全面发育迟缓/ID、运动技能缺陷、言语延迟或缺失，以及 自闭症在使用Shank 3缺陷模型系统的翻译方法之后，突触中的特异性缺陷， 谷氨酸信号传导中的功能和可塑性已经被证明。该项目是一个独特的 在PMS和ASD/ID领域具有公认专业知识的五个研究中心的临床和基础科学资源之间的努力： 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 大学和国家心理健康研究所。具体目标是：1）全面表征 表型和PMS的自然史使用广泛的评估电池; 2）确定生物标志物， 电生理学; 3）开发PMS的综合临床模型，以告知评估和未来的临床 审判 这个项目是在一个更广泛的发展性突触病联盟的背景下进行的。 (DSC)该研究使用了一种机制方法来治疗三种罕见的遗传性疾病， 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 提供了PMS患者的深入表型和自然史特征。现时的建议 寻求扩展我们的多站点基础设施，以在整个生命周期内表征另外100名患者。我们 将为PMS临床试验开发生物标志物和临床结局评估（COA）。我们打算展示 经前综合症中的特定神经生理学生物标志物可以在各个研究中心可靠地收集，并将评估 具有临床意义的COA。 在这个项目的结论，我们希望充分表征PMS的神经行为表型， 来追踪这种综合症的自然发展史从该项目中获得的知识将确定关键的 电生理生物标志物和关键评估实践，为开发 新疗法由于SHANK 3通路与其他形式的ASD/ID高度相关，因此获得的知识 从拟议的研究中也将提高我们对发育迟缓/ID的神经生物学的理解 并且可能有助于更广泛地开发ASD/ID的治疗。