Barnard Rebecca A, Pomaville Matthew B, O'Roak Brian J
Department of Molecular & Medical Genetics, Oregon Health & Science University Portland, OR, USA.
Department of Molecular & Medical Genetics, Oregon Health & Science UniversityPortland, OR, USA; Department of Biology, California State UniversityFresno, CA, USA.
Front Neurosci. 2015 Dec 17;9:477. doi: 10.3389/fnins.2015.00477. eCollection 2015.
Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder with a strong but complex genetic component. Recent family based exome-sequencing strategies have identified recurrent de novo mutations at specific genes, providing strong evidence for ASD risk, but also highlighting the extreme genetic heterogeneity of the disorder. However, disruptions in these genes converge on key molecular pathways early in development. In particular, functional enrichment analyses have found that there is a bias toward genes involved in transcriptional regulation, such as chromatin modifiers. Here we review recent genetic, animal model, co-expression network, and functional genomics studies relating to the high confidence ASD risk gene, CHD8. CHD8, a chromatin remodeling factor, may serve as a "master regulator" of a common ASD etiology. Individuals with a CHD8 mutation show an ASD subtype that includes similar physical characteristics, such as macrocephaly and prolonged GI problems including recurrent constipation. Similarly, animal models of CHD8 disruption exhibit enlarged head circumference and reduced gut motility phenotypes. Systems biology approaches suggest CHD8 and other candidate ASD risk genes are enriched during mid-fetal development, which may represent a critical time window in ASD etiology. Transcription and CHD8 binding site profiles from cell and primary tissue models of early development indicate that CHD8 may also positively regulate other candidate ASD risk genes through both direct and indirect means. However, continued study is needed to elucidate the mechanism of regulation as well as identify which CHD8 targets are most relevant to ASD risk. Overall, these initial studies suggest the potential for common ASD etiologies and the development of personalized treatments in the future.
自闭症谱系障碍（ASD）是一种常见的神经发育障碍，具有强大但复杂的遗传成分。最近基于家系的外显子组测序策略已在特定基因中鉴定出反复出现的新生突变，这为ASD风险提供了有力证据，但同时也凸显了该疾病极端的遗传异质性。然而，这些基因的破坏在发育早期汇聚于关键分子通路。特别是，功能富集分析发现，存在偏向于参与转录调控的基因的倾向，例如染色质修饰因子。在这里，我们综述了最近与高可信度ASD风险基因CHD8相关的遗传、动物模型、共表达网络和功能基因组学研究。CHD8是一种染色质重塑因子，可能作为常见ASD病因的“主调节因子”。携带CHD8突变的个体表现出一种ASD亚型，包括相似的身体特征，如巨头畸形和长期的胃肠道问题，包括反复便秘。同样，CHD8破坏的动物模型表现出头围增大和肠道蠕动减少的表型。系统生物学方法表明，CHD8和其他候选ASD风险基因在胎儿中期发育过程中富集，这可能代表了ASD病因中的一个关键时间窗口。来自早期发育的细胞和原代组织模型的转录和CHD8结合位点图谱表明，CHD8也可能通过直接和间接方式正向调节其他候选ASD风险基因。然而，仍需要继续研究以阐明调控机制，并确定哪些CHD8靶点与ASD风险最相关。总体而言，这些初步研究表明了未来存在常见ASD病因及个性化治疗发展的可能性。
