Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

Nature. 2012 Apr 4;485(7397):246-50. doi: 10.1038/nature10989.


It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autistic Disorder / genetics*
  • DNA-Binding Proteins / genetics
  • Exome / genetics*
  • Exons / genetics*
  • GPI-Linked Proteins / genetics
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Laminin / genetics
  • NAV1.1 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins / genetics
  • Netrins
  • Parents
  • Point Mutation / genetics*
  • Protein Interaction Maps / genetics*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Reproducibility of Results
  • Siblings
  • Signal Transduction
  • Sodium Channels / genetics
  • Stochastic Processes
  • Transcription Factors / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • beta Catenin / metabolism


  • CHD8 protein, human
  • DNA-Binding Proteins
  • GPI-Linked Proteins
  • LAMC3 protein, human
  • Laminin
  • NAV1.1 Voltage-Gated Sodium Channel
  • NR2B NMDA receptor
  • NTNG1 protein, human
  • Nerve Tissue Proteins
  • Netrins
  • Receptors, N-Methyl-D-Aspartate
  • SCN1A protein, human
  • Sodium Channels
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • beta Catenin