Regulatory genes and pathways disrupted in autism spectrum disorders

Abstract

Autism spectrum disorder (ASD) is a highly prevalent and complex genetic disorder. The complex genetic make-up of ASD has been extensively studied and both common and rare genetic variants in up to 1000 genes have been linked to increased ASD risk. While these studies highlight the genetic complexity and begin to provide a window for delineating pathways at risk in ASD, the pathogenicity and specific contribution of many mutations to the disorder are poorly understood. Defining the convergent pathways disrupted by this large number of ASD-associated genetic variants will help to understand disease pathogenesis and direct future therapeutic efforts for the groups of patients with distinct etiologies. Here, we review some of the common regulatory pathways including chromatin remodeling, transcription, and alternative splicing that have emerged as common features from genetic and transcriptomic profiling of ASD. For each category, we focus on one gene (CHD8, FOXP1, and RBFOX1) that is significantly linked to ASD and functionally characterized in recent years. Finally, we discuss genetic and transcriptomic overlap between ASD and other neurodevelopmental disorders.

Keywords: Autism; CHD8; FOXP1; Network; RBFOX1; Splicing; Transcription.

Figure 1:. Regulatory genes disrupted in ASD.

High confidence ASD genes regulate multiple levels of gene expression. CHD8 (purple) is a chromatin remodeler and is associated with open chromatin and active promoters. FOXP1 is a transcriptional factor (green) active or repress its transcriptional targets. RBFOX1 (red) is a RNA binding protein and regulates RNA metabolism including splicing.