Editors' ChoiceAutism Spectrum Disorder

Swimming in Autism Mutations

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Science Translational Medicine  23 Jul 2014:
Vol. 6, Issue 246, pp. 246ec127
DOI: 10.1126/scitranslmed.3009589

Use of the word “spectrum” in the definition of autism—as in autism spectrum disorder (ASD)—implies a multiplicity of disease causes. As a consequence, the recent searches for disease mechanisms are analogous to casting a large fishing net over genomic and proteomic data sets and seeing what gets stuck in it. In the current study by Bernier et al., the fishing approach was taken to the fish—literally.

For quite some time, ASD researchers have been aware of a potential link between disruptive mutations in the CHD8 gene and ASD. The CHD8 protein belongs to a mechanistically mysterious family of chromatin remodelers. Furthermore, the precise nature of the genes whose expression is controlled by CHD8 remains unknown.

Now, a tour de force sequencing approach has revealed the presence of 15 independent mutations in more than 6000 children with developmental delay or ASD. In addition to the high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, distinct clinical characteristics enriched in this group included macrocephaly, distinct facial phenotypes, and gastrointestinal malfunction. Remarkably, most of these phenotypes can be reproduced in zebrafish that have reduced CHD8 expression or that carry 1 of the 15 CHD8 mutations found in children with ASD. In particular, deficiency in CHD8 resulted in the failure of neurons to properly innervate the zebrafish gut, thus pinpointing reduced enteric neuron colonization during gut development as a likely cause of the gastrointestinal syndrome in human ASD patients. Taking the ASD-related CHD8 mutation into the zebrafish and reproducing the ASD phenotype may spur a wave of fish-based genetic testing of other ASD mutations. Although subtleties of the behavioral ASD phenotype are likely to remain entirely human, the zebrafish approach may help to identify genes that play a crucial role in hardwiring of the neuronal network disrupted in ASD.

R. Bernier et al., Disruptive CHD8 mutations define a subtype of autism early in development. Cell, published online 17 July 2014 (10.1016/j.cell.2014.06.017). [Abstract]

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