Developmental Synaptopathies Associated with TSC, PTEN and SHANK3 Mutations

自闭症谱系障碍和智力残疾（ASD/ID）是严重的神经发育状况， 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 这些基因突变可能导致ASD/ID的易感性。这种异质性 代表着重大的挑战，但同时也是研究领域的独特机会。 ASD/ID中涉及的许多基因似乎在一些共同的途径上会聚， 这表明在细胞或系统水平上可能存在共同的功能障碍。更深刻的认识 这些疾病的共同病理生理学可能作为理解这些疾病的机制的门户。 ASD/ID的其他原因和共享治疗的可能性。在这里，我们重点介绍三个行之有效的 与ASD/ID高发病率相关的遗传综合征：TSC 1/2、PTEN和SHANKS 突变。TSC的具体目标是：1）在大的细胞中表征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 从TSC收集和储存人类生物标本（包括遗传物质）的基础设施 ASD患者及其家属。PTEN的具体目标是：1）确定横截面和 PTEN ASD和其他组之间的纵向医疗、行为和认知差异; 2）识别 认知、神经系统和对PTEN ASD特异性的分子生物标志物; 3）产生和维持 用于PTEN ASD的生物储存库和连接的表型数据库。SHANKS的具体目标是：1）表征 使用标准化的医学，行为和认知措施，并跟踪PMS的自然历史， 使用重复的纵向评估来识别综合征; 2）使用先进的MR成像来识别生物标志物; S） 确定导致PMS患者不同表型的遗传因素。细目见 资源部分，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， 拥有强大机构支持的机构，为未来的医生研究人员提供培训的令人印象深刻的导师， 以及与拥有广泛招募网络的患者倡导组织的长期联系。

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.