Maintenance of Heterochromatin links Chromatin Modifiers and Neurodevelopment in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a highly heritable and highly heterogeneous neuropsychiatric condition whose cause is still unknown because there are no recurrent genes found among diagnosed individuals. One of the most common functional properties of the many reported risk-genes for autism is "chromatin modification" but it is not known how this biological process relates to neurodevelopment and autism. We recently reported frequent, recurrent genomic structural variants (SVs) in two cohorts of individuals with autism that were identified using non-Mendelian inheritance (NMI) patterns in family trios. The genes harboring the SVs participate in neurodevelopment, glutamate signaling, and chromatin modification, confirming previous reports and providing greater detail for these processes in ASD. The majority of these ASD-associated SVs (ASD-SV) were found in non-coding regions of the genome and were enriched for expression quantitative trait loci (eQTL) suggesting that gene dysregulation results from these genomic disruptions rather than alteration of proteins. Here, we intersect the ASD-SV from our earlier work with different gene regulatory and epigenetic multiomic layers to understand how they may function to produce autism. Our results indicate that the core of ASD resides in the dysregulation of a process called RNA-induced Initiation of Transcriptional gene Silencing (RITS) that is meant to maintain heterochromatin and produces SVs in the genes within these chromosomal regions, resulting in alterations in brain development. This finally links reported ASD-risk genes involved in chromatin remodeling with neurodevelopment. In addition, it may explain the role of de novo mutations in ASD and provide a framework for more accurate diagnostics and endophenotypes.