Phenotypic Characterization of Gene Disrupting Mutations in ASD

描述（由申请人提供）：自闭症谱系障碍（ASD）是一种遗传和表型异质性疾病。基于行为和神经表型鉴定亚型的努力一直不成功，并且特定遗传事件的罕见性使得在CNV或外显子突变水平上进行亚型鉴定具有挑战性并且非常耗费资源。然而，探索基因破坏在常见途径中的影响有望阐明ASD的表型亚型和阐明基因型-表型关系。最重要的是，识别基于途径的亚型将促进选择干预措施、确定治疗目标和预测结果的转化目标。目前的项目旨在通过脑电图（EEG）研究预先识别的具有β -连环蛋白通路基因突变的ASD个体的行为和神经表型。该项目通过阐明ASD风险基因、脑功能和行为之间的关系来解决了解ASD发病机制的关键需求，并通过仔细的亚型鉴定来解决ASD的广泛异质性。我们将包括60名在β -连环蛋白途径中存在基因突变的ASD参与者，60名在其他途径中存在基因破坏的ASD参与者，以及60名没有任何已确定的CNVs或基因破坏突变的ASD参与者以及30名典型个体。鉴于-catenin在神经元粘附、突触形成和与细胞生长、分化和迁移相关的靶基因转录中的作用，以及学习和记忆行为中断的初步证据，可能在行为和神经生理水平上观察到-catenin功能障碍的证据。电生理测量将使我们能够专门研究与学习和记忆有关的大脑系统，以及与自闭症的核心特征有关的大脑系统。这项研究通过整合基因型、脑电图和行为数据，有望发现基因-脑-行为关系。

DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous disorder. Efforts to identifying subtypes based on the behavioral and neural phenotypes have been unsuccessful, and the rarity of specific genetic events renders subtyping at the CNV or exonic mutation level challenging and exceedingly resource-intensive. However, exploring the impact of gene disruptions in common pathways holds promise for elucidating phenotypic subtypes and clarifying genotype-phenotype relations in ASD. Most importantly, the identification of pathway-based subtypes will advance translational goals of selecting interventions, defining treatment targets, and predicting outcomes. The current project aims to investigate the behavioral and neural phenotype, obtained through electroencephalography (EEG), in pre-identified individuals with ASD with gene mutations in the beta-catenin pathway. This project addresses the critical need to understand the pathogenesis of ASD by elucidating the relationship between ASD risk genes, brain function and behavior and the need to address the wide heterogeneity in ASD by careful subtype identification. We will include 60 participants with ASD with gene mutations in the beta-catenin pathway, 60 participants with ASD with gene disruptions falling in other pathways, and 60 participants with ASD without any identified CNVs or gene disrupting mutations along with 30 typical individuals. Given the role of beta-catenin in neuronal adhesion, synapse formation, and in the transcription of target genes linked to cell growth, differentiation, and migration, as well as preliminary evidence of behavioral disruptions in learning and memory, evidence of dysfunction of beta-catenin may be observed at both the behavioral and neurophysiological level. Electrophysiological measures will allow us to specifically address the brain systems related to learning and memory as well as those related to the core features of autism. This research holds promise for discovery of gene-brain-behavior relationships, attained through integration of genotypic, EEG, and behavioral data.