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      De novo gene disruptions in children on the autistic spectrum.

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          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.

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          Author and article information

          Journal
          Neuron
          Neuron
          Elsevier BV
          1097-4199
          0896-6273
          Apr 26 2012
          : 74
          : 2
          Affiliations
          [1 ] Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
          Article
          NIHMS374246 S0896-6273(12)00340-6
          10.1016/j.neuron.2012.04.009
          3619976
          22542183
          ee4b56eb-327e-4ce2-817d-677089567fc2
          Copyright © 2012 Elsevier Inc. All rights reserved.
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