Publication
Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.
Ruzzo Elizabeth K, Pérez-Cano Laura, Jung Jae-Yoon, Wang Lee-Kai, Kashef-Haghighi Dorna, Hartl Chris, Singh Chanpreet, Xu Jin, Hoekstra Jackson N, Leventhal Olivia, Leppä Virpi M, Gandal Michael J, Paskov Kelley, Stockham Nate, Polioudakis Damon, Lowe Jennifer K, Prober David A, Geschwind Daniel H, Wall Dennis P
# Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks
This study analyzed whole-genome sequences from 2,308 individuals in multiplex autism families to identify rare genetic variants contributing to autism spectrum disorder (ASD). The researchers implicated 69 genes in ASD risk, including 24 with genome-wide significance and 16 newly identified genes, predominantly supported by rare inherited variants. Notably, inherited and de novo variants converge on a common protein-protein interaction network despite enriching distinct biological pathways—inherited variants primarily involved cytoskeletal organization and ion transport.
The analysis revealed structural variants affecting non-coding regions, particularly recurrent deletions in promoters of DLG2 and NR3C2. Functional validation in zebrafish demonstrated that nr3c2 loss disrupts sleep and social behaviors, phenotypes relevant to ASD. These findings underscore the importance of studying multiplex families and highlight shared molecular networks connecting different classes of genetic variation in autism risk. The results are accessible through the Hartwell Autism Research and Technology portal for continued investigation.
Abstract
We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.