Modeling Autism and Comorbid Cancer Risk in Individuals with Germline PTEN Mutations

项目摘要/摘要 胚系PTEN突变导致PTEN错构瘤肿瘤综合征(PHTS)，一种遗传性过度生长和癌症 易感障碍。除了是与癌症相关的经典抑癌基因外，PTEN突变也是 导致神经发育障碍的最常见原因，包括自闭症谱系障碍(ASD)和发育障碍 延迟(DD)。然而，还不知道哪些特定的PHTS个体会发展为ASD/DD，更重要的是，是否所有 患有PHTS和ASD/DD的儿童长大后与非ASD/DD PHTS儿童具有相同的癌症风险。宽阔的拱顶 这项建议的目的是系统地描述PHTS患者的修复者景观，以便 最终将当前的研究和临床实践范式从总体水平的概率转向更精确的 个人水平的疾病风险概率。根据目前的知识差距和原则证明数据，中央 假设是生殖系PTEN变异与其他相关的可测量生物因素的相互作用，如 生殖系基因组修饰物或代谢差异，提供了更准确的ASD/DD风险估计，并可能， 在个体层面上，PHTS的癌症并存。这一假设将通过三个具体目标进行检验：(目标1) 在PHTS患者来源的血浆和淋巴母细胞系中确定ASD/DD的代谢标志物和癌症风险； (目的2)通过多模式表型驱动的基因组研究ASD/DD的基因组标记与PHTS的癌症风险 分析包括拷贝数变异分析、基于家族的全基因组测序和全基因组衍生 多基因风险评分；(目标3)生成ASD/DD和PHTS癌症风险的预测模型，包括翻译 方法便于临床采用，对个体患者进行风险分层。这项以患者为中心的研究将依赖于 存在一致表型的PHTS队列和携带生殖系PTEN的个体的持续预期收益 突变。拟议的研究符合NICHD优先事项和机构间自闭症协调委员会 ASD的战略计划，因为优先事项是(1)了解与ASD相关的遗传综合征及其共生 与此类疾病相关的医疗和精神健康状况；(2)确定可靠的标记物来预测自闭症 及时在PHTS内进行干预，因为早期干预会改善ASD的预后；(3)了解 通过研究代谢和基因组标记，以及重要的是，整合这些因素，研究自闭症的生物学 通过预测模型开发。这项拟议的研究具有创新性，因为除了研究单基因 (异质性较低)和深/统一表型的PTEN-ASD/DD个体组，这项建议继续 超越观察性流行病学讯问，调查潜在的代谢和基因组因素 首先导致ASD/DD改变，然后在ASD/DD患者中共患癌症风险。在结束时，在 除了发现科学，这项应用预计将导致临床医生可以在 护理点。

PROJECT SUMMARY/ABSTRACT Germline PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), a hereditary overgrowth and cancer predisposition disorder. Besides being a classical tumor suppressor gene associated with cancer, PTEN mutations are one of the most common causes of neurodevelopmental disorders, including autism spectrum disorder (ASD) and developmental delay (DD). However, it is not known which specific PHTS individual will develop ASD/DD, and importantly, whether all children with PHTS and ASD/DD grow up to have identical cancer risks as non-ASD/DD PHTS. The broad over-arching objective of this proposal is to systematically characterise the modifier landscape of individuals with PHTS in order to ultimately shift current research and clinical practice paradigms from population-level probabilities towards more precise individual-level disease risk probabilities. Based on the current knowledge gaps and proof-of-principle data, the central hypothesis is that interactions of germline PTEN variation with other pertinent measurable biological factors, such as germline genomic modifiers or metabolic differences, provide more precise risk estimates of ASD/DD and possibly, comorbid cancer in PHTS at the individual level. This hypothesis will be tested through three specific aims: (Aim 1) To identify metabolomic markers of ASD/DD and cancer risk in PHTS patient-derived plasma and lymphoblastoid cell lines; (Aim 2) To characterize genomic markers of ASD/DD and cancer risk in PHTS via multimodal phenotype-driven genomic analyses including copy number variation analysis, family-based whole-genome sequencing, and genome-wide derivation of polygenic risk scores; (Aim 3) To generate a predictive model of ASD/DD and cancer risk in PHTS including translational methods to facilitate clinical adoption for individual patient risk stratification. This patient-focused research will rely on an existing uniformly phenotyped PHTS cohort and continuing prospective accrual of individuals harboring germline PTEN mutations. The proposed research aligns with the NICHD Priorities and the Interagency Autism Coordinating Committee strategic plan for ASD in that the priority is (1) to understand genetic syndromes associated with ASD and the co-occurring medical and mental health conditions associated with such disorders; (2) to identify reliable markers to predict for ASD within PHTS in a timely manner, since earliest interventions lead to improved outcomes in ASD; (3) to understand the biology of autism through investigating metabolomic and genomic markers and importantly, integrating these factors through predictive model development. The proposed research is innovative because in addition to studying a monogenic (less heterogeneous) and deeply/uniformly phenotyped group of individuals with PTEN-ASD/DD, this proposal goes beyond observational epidemiological interrogation into investigating underlying metabolomic and genomic factors that contribute first to altered ASD/DD and then comorbid cancer risks in individuals with ASD/DD. Upon conclusion, in addition to discovery science, this application is projected to result in predictive methods that clinicians can adopt at the point-of-care.