Developmental Synaptopathies Associated with TSC, PTEN and SHANK3 Mutations

与 TSC、PTEN 和 SHANK3 突变相关的发育性突触病

• 批准号: 9127366
• 负责人: MUSTAFA SAHIN
• 金额: $ 123.5万
• 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: 2014-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127366
• 关键词: Behavioral; Biological Markers; Cognitive; Collection; Databases; Development; Disease; Family member; Functional disorder; Future; Genes; Genetic; Genetic Materials; Hereditary Disease; Heterogeneity; Human; Institution; Intellectual functioning disability; Link; Magnetic Resonance Imaging; Measures; Medical; Mentors; Mutation; Natural History; PTEN gene; Pathway interactions; Patient advocacy; Patients; Penetrance; Phenotype; Physicians; Predisposition; Rare Diseases; Research; Research Infrastructure; Research Personnel; Resources; Specimen; Syndrome; System; TSC1/2 gene; Time; Training; advocacy organizations; autism spectrum disorder; biobank; cohort; comparative; early childhood; experience; molecular marker; pediatric patients; relating to nervous system; therapeutic target

Autism spectrum disorder and intellectual disability (ASD/ID) are severe neurodevelopmental conditions with early childhood onset. Advances in genetics have illustrated that ASD/ID represent a spectrum of rare disorders and that mutations in hundreds of genes may result in susceptibility to ASD/ID. This heterogeneity represents significant challenges but at the same time unique opportunities for research in the field of ASD/ID. Many of the genes implicated in ASD/ID appear to converge on a few common pathways, suggesting that there may be a common dysfunction at the cellular or systems level. Deeper understanding of the shared pathophysiology of these diseases may serve as gateways for understanding mechanisms of other causes of ASD/ID and for shared treatment possibilities. Here we focus of three well-established genetic syndromes that are associated with high penetrance for ASD/ID: TSC1/2, PTEN and SHANKS mutations. Specific aims for TSC are: 1) characterize the developmental phenotype of ASD and ID in a large cohort of pediatric patients with TSC; 2) identify biomarkers using advanced MR imaging; 3) establish infrastructure for the collection and storage of human bio-specimens, including genetic material, from TSC patients and their family members with ASD. Specific aims for PTEN are: 1) determine cross-sectional and longitudinal medical, behavioral, and cognitive differences between PTEN ASD and other groups; 2) identify cognitive, neural systems, and molecular biomarkers specific to PTEN ASD; 3) create and maintain a biorepository and linked phenotypic database for PTEN ASD. Specific aims for SHANKS are: 1) characterize PMS using standardized medical, behavioral, and cognitive measures and to track the natural history of the syndrome using repeated longitudinal assessments; 2) identify biomarkers using advanced MR imaging; S) identify genetic factors which contribute to diverse phenotypes in patients with PMS. As detailed in the Resources sections, this Consortium involves experienced physician-researchers from premier academic institutions with strong institutional support, impressive mentors for training of future physician-researchers, and long-standing connections to patient advocacy organizations with extensive recruitment networks.

自闭症谱系障碍和智力障碍 (ASD/ID) 是严重的神经发育疾病， 儿童早期发病。遗传学的进展表明，ASD/ID 代表了一系列罕见的疾病。 数百个基因的突变可能导致 ASD/ID 的易感性。这种异质性 代表着重大挑战，但同时也是该领域研究的独特机会 ASD/ID。许多与 ASD/ID 相关的基因似乎集中在一些常见的途径上， 表明细胞或系统水平上可能存在常见的功能障碍。更深入的了解 这些疾病共有的病理生理学的研究可能成为理解这些疾病机制的门户 ASD/ID 的其他原因以及共同治疗的可能性。这里我们重点关注三个成熟的 与 ASD/ID 高外显率相关的遗传综合征：TSC1/2、PTEN 和 SHANKS 突变。 TSC 的具体目标是：1）在大范围内表征 ASD 和 ID 的发育表型 TSC 儿科患者队列； 2) 使用先进的 MR 成像识别生物标志物； 3）建立 用于从 TSC 收集和储存人类生物样本（包括遗传物质）的基础设施 患有 ASD 的患者及其家人。 PTEN 的具体目标是： 1) 确定横截面和 PTEN ASD 与其他群体之间的纵向医学、行为和认知差异； 2）识别 PTEN ASD 特有的认知、神经系统和分子生物标志物； 3）创建并维护 PTEN ASD 的生物储存库和关联表型数据库。 SHANKS 的具体目标是：1) 表征 PMS 使用标准化的医疗、行为和认知测量并追踪自然史 使用重复纵向评估的综合征； 2) 使用先进的 MR 成像识别生物标志物； ） 确定导致经前综合症患者不同表型的遗传因素。正如详细的 资源部分，该联盟包括来自顶级学术界的经验丰富的医生研究人员 拥有强大机构支持的机构，令人印象深刻的导师，用于培训未来的医生研究人员， 与拥有广泛招募网络的患者权益组织的长期联系。