Single-Cell Transcriptomics Supports a Role of CHD8 in Autism

Chromodomain helicase domain 8 (CHD8) is one of the most frequently mutated and most penetrant genes in the autism spectrum disorder (ASD). Individuals with CHD8 mutations show leading symptoms of autism, macrocephaly, and facial dysmorphisms. The molecular and cellular mechanisms underpinning the early onset and development of these symptoms are still poorly understood and prevent timely and more efficient therapies of patients. Progress in this area will require an understanding of when, why and how cells deviate from their normal trajectories. High-throughput single-cell RNA sequencing (sc-RNAseq) directly quantifies information-bearing RNA molecules that enact each cell's biological identity. Here, we discuss recent insights from sc-RNAseq of CRISPR/Cas9-editing of Chd8/CHD8 during mouse neocorticogenesis and human cerebral organoids. Given that the deregulation of the balance between excitation and inhibition (E/I balance) in cortical and subcortical circuits is thought to represent a major etiopathogenetic mechanism in ASD, we focus on the question of whether, and to what degree, results from current sc-RNAseq studies support this hypothesis. Beyond that, we discuss the pros and cons of these approaches and further steps to be taken to harvest the full potential of these transformative techniques.

Automated summary

CHD8 is a highly mutated gene in individuals with autism spectrum disorder, leading to symptoms such as autism, macrocephaly, and facial dysmorphisms. Understanding the molecular and cellular mechanisms underlying these symptoms is crucial for developing more effective therapies. Recent insights from high-throughput single-cell RNA sequencing studies on CRISPR/Cas9-edited Chd8/CHD8 provide valuable information on the E/I balance in cortical and subcortical circuits in ASD, showcasing the potential of these transformative techniques for future research.