Developmental Synaptopathies Associated with TSC,PTEN and SHANK3 Mutations - supplement #2

资助的父母奖或项目的摘要或摘要 遗传学的进展表明，自闭症谱系障碍（ASD）和智力残疾（ID） 包括一系列罕见疾病，数百个基因的突变可能导致对 ASD/ID。这种异质性代表了重大挑战，但同时也是独特的机会， 许多与ASD/ID有关的基因似乎集中在一些常见的基因上， 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 了解这些疾病的共同病理生理学可以作为理解这些疾病的途径。 ASD/ID的其他原因的机制和共享的治疗可能性。发育 突触病变联盟（DSC）于2014年成立并获得资助，以进行 三种遗传性疾病与ASD/ID的高发病率，并阐明了分子途径， 机制为基础的治疗目标相关的ASD/ID。我们建议继续我们的重点是三个遗传 具有异常突触结构或功能的综合征，并且与高突触率相关， ASD/ID：TSC 1/2（多发性硬化症或TSC），PHTS（PTEN错构瘤肿瘤综合征或PHTS） 和SHANK 3（麦克德米德综合征或PMS）突变。海训方案的具体目标是： 在一项前瞻性、多因素、多阶段的研究中， 中心纵向设计; 2）识别突触功能和连接性的电生理学生物标志物 与TSC中ASD和ID相关;以及3）评估TAND检查表作为TSC特定检查表的适用性 研究工具，用于评估未来ASD和ID临床试验中具有临床意义的结局。具体目标 PHTS是：1）确定横截面和纵向神经行为和医疗之间的差异 PTEN-ASD和扩展年龄范围内的其他组; 2）识别EEG和特异性分子生物标志物， PTEN-ASD和那些与其他群体共享的;和3）巩固和发展一个全面的， 使用目标1和2的数据以及TAND评分的PTEN-ASD的多水平纵向模型，为未来的研究提供信息 临床试验和共识护理指南的发展。PMS的具体目标是：1） 全面描述PMS在整个生命周期中的特征，并跟踪自然史; 2） PMS的电生理生物标志物;和3）开发PMS的综合临床模型，以告知 评估和未来的临床试验。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医生-研究人员，拥有强大的机构和患者 倡导小组（PAG）的支持，沿着令人印象深刻的导师培训未来的医生研究人员， 遗传学顾问专注于神经发育障碍的转化研究。我们将继续 与PAG密切合作，参与并告知受这些疾病影响的家庭。获得的知识 该项目的研究成果将为临床实践提供信息，并刺激新疗法的发展。

Summary or Abstract of the Funded Parent Award or Project Advances in genetics have illustrated that autism spectrum disorder (ASD) and intellectual disability (ID) include 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. The Developmental Synaptopathies Consortium (DSC) was formed and funded in 2014 in order to perform mechanistic analysis of three genetic disorders with high penetrance of ASD/ID, and shed light on molecular pathways and mechanism-based therapeutic targets relevant to ASD/ID. We propose to continue our focus on three genetic syndromes with abnormal synapse structure or function and that are associated with high penetrance for ASD/ID: TSC1/2 (Tuberous Sclerosis Complex or TSC), PHTS (PTEN Hamartoma Tumor Syndrome or PHTS) and SHANK3 (Phelan McDermid Syndrome or PMS) mutations. Specific aims for TSC are: 1) Characterize the phenotype of ASD and ID in a large cohort of pediatric and adult patients with TSC in a prospective, multi- center longitudinal design; 2) Identify electrophysiological biomarkers of synaptic function and connectivity associated with ASD and ID in TSC; and 3) Evaluate the suitability of the TAND Checklist as TSC-specific research tool for assessing clinically-meaningful outcomes in future ASD and ID clinical trials. Specific aims for PHTS are: 1) Determine cross-sectional and longitudinal neurobehavioral and medical differences between PTEN-ASD and other groups in an expanded age range; 2) Identify EEG and molecular biomarkers specific to PTEN-ASD and those shared with other groups; and 3) Validate TAND and develop a comprehensive, multilevel, longitudinal model of PTEN-ASD using data from Aims 1 and 2 and TAND scores to inform future clinical trials and the development of consensus care guidelines. Specific aims for PMS are: 1) Comprehensively characterize PMS across the lifespan and track the natural history; 2) Validate electrophysiological biomarkers of PMS; and 3) Develop a comprehensive clinical model of PMS to inform assessment and future clinical trials. As detailed in the Resources sections, this Consortium involves experienced physician-researchers from premier academic institutions with strong institutional and patient advocacy group (PAG) support, along with impressive mentors for training of future physician-researchers and genetic counselors focused on translational research in neurodevelopmental disorders. We will continue to work closely with the PAGs to engage and inform the families affected with these disorders. Knowledge gained from this project will inform clinical practice and spur the development of novel treatments.