Editors' ChoiceAutism

“Brain-Critical” Exons in Autism

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Science Translational Medicine  04 Jun 2014:
Vol. 6, Issue 239, pp. 239ec99
DOI: 10.1126/scitranslmed.3009417

A number of genes have been implicated in autism spectrum disorder (ASD), yet mutations in these genes explain only a small fraction of cases. As a result, finding the genetic cause of ASD in an affected individual’s genome can be likened to finding a needle in a haystack.

We have some good pitchforks to make the haystack smaller, such as excluding the genetic or genomic changes that don’t affect genes, variants within genes that do not result in a protein change, or variants that are found in an appreciable fraction (such as >5%) of the general population. A new study by Uddin and colleagues provides one more tool that highlights specific regions of the genome that might be more likely to be associated with disease when altered.

The authors first showed that genes in which affected individuals have de novo mutations are more likely to be highly expressed in brain tissue. They then showed that these genes have a low burden of rare missense mutations in healthy control individuals. On the basis of this result, the authors went on to use publicly available gene expression and population sequencing data to identify a total of 3955 “brain-critical” exons from 1744 genes that are highly expressed in brain and have a low mutation burden in control individuals but do not show the same pattern in other tissues. They found an enrichment of brain-critical exons in genes associated with ASD risk, genes encoding fragile-X mental retardation protein targets, and genes encoding components of the postsynaptic proteome. Thus, these 1744 genes represent high-priority candidate genes for further study.

Notably, the associations were stronger for specific exons than for whole genes, which may be related to brain-specific isoforms. Rare mutations or de novo mutations in critical exons should be scrutinized further. It will also be useful to examine whether mutations elsewhere in these genes confer disease risk.

M. Uddin et al., Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder. Nat. Genet. 10.1038/ng.2980 (2014). [Abstract]

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