Multiple studies have confirmed the contribution of rare de novo copy number variations
to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants
have been identified in affected individuals, their contribution to risk has yet to
be clarified. Specifically, the frequency and distribution of these mutations have
not been well characterized in matched unaffected controls, and such data are vital
to the interpretation of de novo coding mutations observed in probands. Here we show,
using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant
sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations
in brain-expressed genes are associated with autism spectrum disorders and carry large
effects. On the basis of mutation rates in unaffected individuals, we demonstrate
that multiple independent de novo single nucleotide variants in the same gene among
unrelated probands reliably identifies risk alleles, providing a clear path forward
for gene discovery. Among a total of 279 identified de novo coding mutations, there
is a single instance in probands, and none in siblings, in which two independent nonsense
variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit),
a result that is highly unlikely by chance.