Developmental Synaptopathies Associated with TSC, PTEN and SHANK3 Mutations

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。这种异质性代表着巨大的挑战，但同时也为ASD/ID领域的研究提供了独特的机会。ASD/ID涉及的许多基因似乎聚集在几个共同的途径上，这表明可能存在细胞或系统水平的共同功能障碍。更深入地了解这些疾病的共同病理生理学可能成为了解ASD/ID的其他原因的机制和共享治疗可能性的门户。在这里，我们关注与ASD/ID高外显率相关的三种公认的遗传综合征：TSC1/2、PTEN和SHANK3突变。TSC的具体目标是：1)确定大量TSC患者ASD和ID的发育表型；2)使用先进的磁共振成像识别生物标记物；3)建立收集和存储来自TSC患者及其ASD家庭成员的人类生物标本的基础设施。PTEN的具体目标是：1)确定PTEN ASD与其他组之间的横断面和纵向医学、行为和认知差异；2)确定PTEN ASD的认知、神经系统和分子生物标记物；3)创建和维护PTEN ASD的生物库和链接的表型数据库。SHANK3的具体目标是：1)使用标准化的医疗、行为和认知措施来确定经前综合征的特征，并通过重复的纵向评估来追踪综合征的自然病史；2)使用先进的磁共振成像来识别生物标记物；S)识别导致经前综合症患者不同表型的遗传因素。如参考资料部分所述，这个联盟包括来自一流学术机构的经验丰富的内科研究人员，他们拥有强大的机构支持，以及令人印象深刻的未来医生培训导师 研究人员，以及与拥有广泛招聘网络的患者倡导组织的长期联系。

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.