Linking Autism Risk Genes to Disruption of Cortical Development

Abstract

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. In the past few years, large-scale whole-exome sequencing and genome-wide association studies have made enormous progress in our understanding of the genetic risk architecture of ASD. While showing a complex and heterogeneous landscape, these studies have led to the identification of genetic loci associated with ASD risk. The intersection of genetic and transcriptomic analyses have also begun to shed light on functional convergences between risk genes, with the mid-fetal development of the cerebral cortex emerging as a critical nexus for ASD. In this review, we provide a concise summary of the latest genetic discoveries on ASD. We then discuss the studies in postmortem tissues, stem cell models, and rodent models that implicate recently identified ASD risk genes in cortical development.

Molecular Dysregulation in Autism Spectrum Disorder

“…The generation of a relevant disease specific knockout model for autistic traits/behaviors has been difficult because of the genetically heterogeneous nature of ASD. A number of rodent models (knockout, humanized knock-in mice, and Cre-loxP) for rare variations (de novo and CNV) detected in ASD have been used to understand the etiology of ASD [ 108 , 109 , 110 , 111 ]. Cadps2-knockout model showed decreased brain-derived neurotrophic factor (BDNF) release from neocortical and cerebellar neurons [ 112 ].…”

“…ASD is a lifelong condition, and there is no pharmaceutical intervention which can fully alleviate ASD symptoms. A disruption in cortical development [ 55 , 111 ] is common to most patients with ASD). The core feature of disrupted social communication is unlikely to protect against psychiatric illness.…”

Developmental and Behavioral Phenotypes in a Mouse Model of DDX3X Syndrome

“…Albeit complex and interlinked, the circuits subserving these behaviors require the cortex, the amygdala, and the hippocampus (50-52), all found disproportionally diminished in volume in Ddx3x +/mice. Additionally, mouse models of neurodevelopmental disorders often show similar behavioral anomalies contingent to altered balance of cortical glutamatergic populations (30,53,54). Ddx3x +/mice show an area-specific altered balance of cortical J o u r n a l P r e -p r o o f glutamatergic populations that might result from changes neurogenesis, migration and/or cell fate specification.…”

NeuroSCORE: A Genome-wide Omics-Based Model to Identify Candidate Disease Genes of the Central Nervous System

“…The Cajal body presents an interesting confluence of multiple previously discussed CNS-disease related processes as these nuclear bodies appear in fetal and neural cells to help mediate splicing, create parts of the spliceosome and ribonuclear proteins, activate transcription, and aid in chromatin and genome organization 47 . Considering that ASD and other neurodevelopmental disorders appear to begin in the fetal period 57,58 , the enrichment of Cajal body-associated genes raises an interesting target for additional study of genes related to possible “Cajalopathies”.…”