Natural history of individuals with autism spectrum disorder and germline PTEN mutations

患有自闭症谱系障碍和种系 PTEN 突变的个体的自然史

• 批准号: 10701741
• 负责人: Charis Eng
• 金额: $ 34.94万
• 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: 2014-09-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10701741
• 关键词: Adolescent; Adult; Age; Behavior; Behavioral; Behavioral Symptoms; Biochemical; Biological Markers; Brain; Caring; Cell Proliferation; Characteristics; Child; Clinical Trials; Cognition; Cognitive; Comprehensive Health Care; Consensus; Consensus Development; Data; Data Collection; Development; Education; Electroencephalography; Etiology; Evaluation; FRAP1 gene; Functional disorder; Funding; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genomics; Goals; Guidelines; Heritability; Heterogeneity; Heterozygote; Human; Individual; Intervention Studies; Knockout Mice; Malignant Neoplasms; Medical; Megalencephaly; Modeling; Molecular; Mutation; National Comprehensive Cancer Network; Natural History; Neurocognitive; Neurodevelopmental Disorder; Neurons; Outcome; PI3K/AKT; PTEN Hamartoma Tumor Syndrome; PTEN autism spectrum disorder; PTEN gene; Pathway interactions; Pattern; Peripheral; Phenotype; Phosphoric Monoester Hydrolases; Practice Guidelines; Process; Proteins; Recommendation; Risk Management; Series; Signs and Symptoms; Specificity; Stratification; Subgroup; Symptoms; System; Tumor Suppressor Proteins; Validation; Variant; aged; autism spectrum disorder; biomarker identification; biomarker validation; cancer risk; cell growth; cognitive function; cohort; differential expression; frontal lobe; individuals with autism spectrum disorder; molecular marker; mouse model; neural; neural correlate; neurobehavior; neurobehavioral; neuropathology; neurophysiology; neuropsychiatric disorder; potential biomarker; precision genetics; psychologic; recruit; repetitive behavior; risk stratification; social communication; specific biomarkers; therapeutic target; transcriptome; treatment planning; white matter

Autism spectrum disorders (ASD) are an etiologically heterogeneous set of neurodevelopmental disorders marked by social communication/interaction deficits and restricted/repetitive behaviors. Genetic studies have identified a strong heritable component, yet >80% of ASD remains idiopathic. Marked heterogeneity has slowed attempts to identify pathophysiology and related therapeutic targets. One promising strategy to reduce complexity is to focus on subgroups with a specific genetic etiology, such as ASD associated with germline heterozygous PTEN mutations (PTEN-ASD, who are always macrocephalic). In the last 4 years, we characterized cross-sectional neurobehavioral and neurocognitive differences among PTEN-ASD, those with PTEN mutations but no ASD (PTEN-no ASD) and macrocephalic ASD without PTEN mutations (Macro-ASD) and begun longitudinal data collection in individuals aged 3-21. We propose a natural history study of the neurophenotypic and molecular characteristics of PTEN-ASD with the goals of understanding risk management and treatment planning as well as identifying sensitive biomarkers for intervention studies. We will recruit 170 (70 from current cohort) individuals with PTEN-ASD, Macro-ASD, and PTEN no-ASD, and expanding recruitment to aged 18 months to 45 years. Data collected will include: (a) cancer occurrence, (b) autism and other behavioral symptoms, (c) neurocognitive profiles, (d) adaptive function, (e) genomic modifiers, (f) protein levels from PI3K/AKT/mTOR/S6K pathway, and (g) EEG, in order to: (Aim 1) Determine cross-sectional and longitudinal neurobehavioral and medical differences between PTEN-ASD and other groups in an expanded age range. This aim seeks to describe initial levels and longitudinal changes in cancer occurrence, behavioral signs/symptoms, and cognitive function in PTEN-ASD; (Aim 2) Identify EEG and molecular biomarkers specific to PTEN-ASD and those shared with other groups. This aim seeks to identify biomarkers that may be treatment targets in intervention studies; and (Aim 3) Develop a comprehensive, multi-level, longitudinal model of PTEN-ASD to inform future clinical trials and the development of consensus care guidelines. We will use data from Aims 1 and 2 and from TSC Associated Neuropsychiatric Disorders (TAND) Checklist (after validation). This first comprehensive longitudinal evaluation of the phenotypic and molecular characteristics of PTEN ASD, to identify specific molecular pathway and correlated neural abnormalities responsible for ASD symptoms in these individuals, which can be ably compared to TSC and PMS. It is a crucial next step toward the development of personalized genetic treatment approaches for PTEN-ASD. Prior to initiating further clinical trials, it will be critical to identify treatment targets at the molecular, neurophysiological, and behavioral levels.

自闭症谱系障碍 (ASD) 是一组病因学异质性的神经发育障碍 以社交沟通/互动缺陷和受限/重复行为为特征。遗传学研究已 确定了一个很强的遗传因素，但超过 80% 的 ASD 仍然是特发性的。异质性明显放缓 尝试确定病理生理学和相关的治疗靶点。一项有前景的减少 复杂性是关注具有特定遗传病因的亚组，例如与种系相关的 ASD 杂合 PTEN 突变（PTEN-ASD，总是巨头型）。在过去的4年里，我们 表征了 PTEN-ASD 之间的横断面神经行为和神经认知差异， PTEN 突变但无 ASD（PTEN-no ASD）和无 PTEN 突变的巨头型 ASD（Macro-ASD） 并开始收集 3-21 岁个体的纵向数据。我们建议进行自然历史研究 PTEN-ASD 的神经表型和分子特征，旨在了解风险管理 和治疗计划以及确定干预研究的敏感生物标志物。我们将招募170名 （当前队列中的 70 名）患有 PTEN-ASD、Macro-ASD 和 PTEN no-ASD 的个体，并扩大招募范围 年龄 18 个月至 45 岁。收集的数据将包括：(a) 癌症发生情况，(b) 自闭症和其他行为 症状，(c) 神经认知特征，(d) 适应功能，(e) 基因组修饰因子，(f) 蛋白质水平 PI3K/AKT/mTOR/S6K 通路，以及 (g) EEG，以便：（目标 1）确定横截面和纵向 在扩大的年龄范围内，PTEN-ASD 与其他群体之间的神经行为和医学差异。这 目标旨在描述癌症发生、行为体征/症状的初始水平和纵向变化， 和 PTEN-ASD 的认知功能； （目标 2）识别 PTEN-ASD 特有的脑电图和分子生物标志物 与其他团体共享的内容。该目标旨在确定可能作为治疗目标的生物标志物 干预研究； （目标 3）开发一个全面的、多层次的、纵向的 PTEN-ASD 模型，以 为未来的临床试验和共识护理指南的制定提供信息。我们将使用目标 1 和 2 和 TSC 相关神经精神疾病 (TAND) 检查表（验证后）。这第一 对 PTEN ASD 的表型和分子特征进行全面纵向评估，以确定 导致这些人自闭症谱系障碍症状的特定分子途径和相关神经异常 个人，这可以很好地与 TSC 和 PMS 进行比较。这是下一步发展的关键 PTEN-ASD 的个性化基因治疗方法。在开始进一步的临床试验之前，至关重要 确定分子、神经生理学和行为水平的治疗目标。