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: 9335190
• 负责人: MUSTAFA SAHIN
• 金额: $ 124.81万
• 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/9335190
• 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; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Resources; Specimen; Standardization; Syndrome; System; TSC1/2 gene; Time; Training; advocacy organizations; autism spectrum disorder; biobank; cohort; comparative; early childhood; experience; molecular marker; pediatric patients; public health relevance; relating to nervous system; specific biomarkers; therapeutic target; tuberous sclerosis patients

DESCRIPTION (provided by applicant) 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 SHANK3 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 SHANK3 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 that 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.

描述（由申请人提供） 自闭症谱系障碍和智力残疾（ASD/ID）是儿童早期发病的严重神经发育疾病。遗传学的进展表明，ASD/ID代表了一系列罕见疾病，数百个基因的突变可能导致ASD/ID的易感性。这种异质性代表了重大挑战，但同时也为ASD/ID领域的研究提供了独特的机会。ASD/ID中涉及的许多基因似乎集中在一些共同的途径上，这表明在细胞或系统水平上可能存在共同的功能障碍。深入了解这些疾病的共同病理生理学可以作为了解ASD/ID的其他原因的机制和共同治疗可能性的门户。在这里，我们重点关注与ASD/ID高外显率相关的三种公认的遗传综合征：TSC 1/2、PTEN和SHANK 3突变。海训方案的具体目标是：1）在一个大的TSC儿科患者队列中表征ASD和ID的发育表型; 2）使用先进的MR成像识别生物标志物; 3）建立用于收集和储存来自TSC患者及其ASD家庭成员的人类生物标本（包括遗传物质）的基础设施。PTEN的具体目标是：1）确定PTEN ASD和其他组之间的横截面和纵向医学，行为和认知差异; 2）识别认知，神经系统和特定于PTEN ASD的分子生物标志物; 3）创建和维护生物储存库和关联的PTEN ASD表型数据库。SHANK 3的具体目标是：1）使用标准化的医学，行为和认知测量来表征PMS，并使用重复的纵向评估来跟踪综合征的自然史; 2）使用先进的MR成像来识别生物标志物; S）识别导致PMS患者不同表型的遗传因素。如资源部分所述，该联盟包括来自一流学术机构的经验丰富的医生研究人员，他们拥有强大的机构支持，为未来的医生培训提供令人印象深刻的导师 研究人员，以及与患者倡导组织的长期联系，这些组织拥有广泛的招聘网络。