Exome sequencing of 343 families, each with a single child on the autism
spectrum and at least one unaffected sibling, reveal de novo small
indels and point substitutions, which come mostly from the paternal line
in an age-dependent manner. We do not see significantly greater numbers
of de novo missense mutations in affected versus unaffected children,
but gene-disrupting mutations (nonsense, splice site, and frame shifts)
are twice as frequent, 59 to 28. Based on this differential and the
number of recurrent and total targets of gene disruption found in our
and similar studies, we estimate between 350 and 400 autism
susceptibility genes. Many of the disrupted genes in these studies are
associated with the fragile X protein, FMRP, reinforcing links between
autism and synaptic plasticity. We find FMRP-associated genes are under
greater purifying selection than the remainder of genes and suggest they
are especially dosage-sensitive targets of cognitive disorders.
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