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

Nature | Apr 4, 2012

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.

Pubmed ID: 22495309 RIS Download

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

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Associated grants

  • Agency: NHLBI NIH HHS, Id: RC2 HL102923
  • Agency: NHLBI NIH HHS, Id: UC2 HL102926
  • Agency: NHLBI NIH HHS, Id: HL 1029230
  • Agency: NHLBI NIH HHS, Id: RC2 HL102926
  • Agency: NHLBI NIH HHS, Id: R01 HL094976
  • Agency: NICHD NIH HHS, Id: R01 HD065285-02
  • Agency: NICHD NIH HHS, Id: R01 HD065285
  • Agency: NHLBI NIH HHS, Id: HL 102924
  • Agency: NICHD NIH HHS, Id: HD065285
  • Agency: NHLBI NIH HHS, Id: RC2 HL102924
  • Agency: NHLBI NIH HHS, Id: HL102926
  • Agency: NIEHS NIH HHS, Id: HHSN273200800010C
  • Agency: Howard Hughes Medical Institute, Id: UC2 HL102924
  • Agency: NHLBI NIH HHS, Id: HHSN273200800010C
  • Agency: PHS HHS, Id: HL 094976
  • Agency: NHLBI NIH HHS, Id:

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UCSC Genome Browser

A collection of genomes which include reference sequences and working draft assemblies, as well as a variety of tools to explore these sequences. The Genome Browser zooms and scrolls over chromosomes, showing the work of annotators worldwide. The Gene Sorter shows expression, homology and other information on groups of genes that can be related in many ways. Blat quickly maps your sequence to the genome. The Table Browser provides access to the underlying database. VisiGene lets you browse through a large collection of in situ mouse and frog images to examine expression patterns. Genome Graphs allows you to upload and display genome-wide data sets. Also provided is a portal to the Encyclopedia of DNA Elements (ENCODE) and Neandertal projects.

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Picard

Java toolset for working with next generation sequencing data in the BAM format.

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