Developmental Synaptopathies Associated with TSC, PTEN and SHANK3 Mutations

自闭症谱系障碍和智力残疾(ASD/ID)是严重的神经发育疾病， 童年早期发病。遗传学的进展表明，ASD/ID代表了一系列罕见的 疾病和数百个基因的突变可能导致对ASD/ID的易感性。这种异质性 代表着巨大的挑战，但同时也是研究领域的独特机会 ASD/ID。ASD/ID中涉及的许多基因似乎聚集在几个共同的途径上， 这表明可能在细胞或系统水平上存在共同的功能障碍。更深入的理解 这些疾病的共同病理生理学的研究可以作为理解这些疾病的机制的门户 ASD/ID的其他原因以及共同的治疗可能性。在这里，我们关注三个久负盛名的 与ASD/ID高外显性相关的遗传综合征：TSC1/2、PTEN和Shanks 突变。TSC的具体目标是：1)全面描述ASD和ID的发育表型 儿童TSC患者队列；2)使用先进的磁共振成像识别生物标记物；3)建立 从TSC收集和储存包括遗传物质在内的人类生物标本的基础设施 ASD患者及其家属。PTEN的具体目标是：1)确定横截面和 PTEN ASD与其他组在医学、行为和认知方面的纵向差异；2)确定 PTEN ASD的认知、神经系统和分子生物标记物；3)创建和维持 PTEN ASD的生物信息库和链接的表型数据库。尚克斯的具体目标是：1)塑造 使用标准化的医学、行为和认知测量并跟踪经前综合症的自然历史 使用重复纵向评估的证候；2)使用先进的磁共振成像识别生物标志物；S) 确定导致经前综合征患者不同表型的遗传因素。详情请参阅 资源部分，该联盟包括来自顶尖学术机构的经验丰富的医生和研究人员 拥有强大的机构支持，令人印象深刻的未来医生-研究人员培训的导师， 以及与拥有广泛招聘网络的患者权益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.