Autism-Associated Genes and Neighboring lncRNAs Converge on Key Gene Regulatory Networks.

The diversity of genes implicated in autism spectrum disorder (ASD) creates challenges for identifying core pathophysiological mechanisms. Aggregation of seven different classes of genetic variants implicated in ASD, in a database we call , reveals shared features across distinct types of ASD variants. Functional interrogation of 19 ASD genes and 9 neighboring long non-coding RNAs (lncRNAs) using CRISPR-Cas13 strikingly revealed differential gene expression profiles that were significantly enriched for other ASD genes. Furthermore, construction of a gene regulatory network (GRN) enabled the identification of central regulators that exhibit convergently altered activity upon ASD gene disruption. Thus, this study reveals how perturbing distinct ASD-associated genes can lead to shared, broad dysregulation of GRNs with critical relevance to ASD. This provides a crucial framework for understanding how diverse genes, including lncRNAs, can play convergent roles in key neurodevelopmental processes and ultimately contribute to ASD.