De novo gene disruptions in children on the autistic spectrum

Abstract

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.

Figure 1. Exome Sequencing Family and Individual Coverage

For each individual, the proportion of the exome covered in excess of 20× (dotted green line) is plotted horizontally. For each family, the proportion of the exome jointly covered in excess of 20× (solid red line) or 40× (black circle and blue “plus sign” designating sequencing center) in all members of that family is also shown. The family data are ordered by the rank of their joint coverage in excess of 20×.