Phenotypic Characterization of Gene Disrupting Mutations in ASD

描述(由申请人提供)：自闭症谱系障碍(ASD)是一种遗传和表型上的异质性障碍。根据行为和神经表型识别亚型的努力一直没有成功，而且特定遗传事件的罕见使得CNV或外显子突变水平的亚型具有挑战性，并且非常耗费资源。然而，探索常见途径中基因突变的影响有望阐明ASD的表型亚型和阐明基因-表型关系。最重要的是，确定基于途径的亚型将推进选择干预措施、定义治疗目标和预测结果的转换目标。目前的项目旨在研究通过脑电(EEG)获得的行为和神经表型，在预先确定的具有β-连环蛋白途径基因突变的ASD患者中。本项目通过阐明ASD危险基因、脑功能和行为之间的关系以及通过仔细的亚型鉴定来解决ASD中广泛的异质性的必要性，解决了理解ASD发病机制的迫切需要。我们将包括60名有β-连环蛋白途径基因突变的ASD参与者，60名有其他途径基因中断的ASD参与者，60名没有发现任何CNV或基因破坏性突变的ASD参与者以及30名典型个体。鉴于β-连环蛋白在神经元黏附、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，以及学习和记忆中行为障碍的初步证据，可能会在行为和神经生理水平上观察到β-连环蛋白功能障碍的证据。电生理测量将使我们能够具体处理与学习和记忆相关的大脑系统，以及与自闭症核心特征相关的大脑系统。这项研究有望发现基因-脑-行为关系，这是通过整合基因、脑电和行为数据获得的。

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.