Stephan J. Sanders, et al., De novo mutations revealed by whole-exome sequencing are strongly associated with autism, doi:10.1038/nature10945
Highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects.
Among a total of 279 identified de novo coding mutations, there is a single instance in pro bands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, a subunit), a result that is highly unlikely by chance.
We found that the rate of de novo SNVs indeed increases with paternal age and that paternal and maternal ages are highly correlated. However, although the mean paternal age of probands in our sample was 1.1 years higher than their unaffected siblings, re-analysis accounting for age did not substantively alter any of the significant results reported here. Similarly, no significant relationship was observed between the rate of de novo SNVs and proband IQ or proband sex.
Overall, our results substantially clarify the genomic architecture of ASD, demonstrate significant association of three genes-SCN2A, KATNAL2 and CHD8-and predict that approximately 25-50 additional ASD-risk genes will be identified as sequencing of the 2,648 SSC families is completed.