Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Apr 4;485(7397):246-50.
doi: 10.1038/nature10989.

Sporadic Autism Exomes Reveal a Highly Interconnected Protein Network of De Novo Mutations

Free PMC article

Sporadic Autism Exomes Reveal a Highly Interconnected Protein Network of De Novo Mutations

Brian J O'Roak et al. Nature. .
Free PMC article


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.


Figure 1
Figure 1. De novo mutation events in autism spectrum disorder
a Haplotype phasing using informative markers shows a strong parent-of-origin bias with 41/51 de novo events occurring on the paternally inherited haplotype. b and c, Box and whisker plots for 189 SSC probands. b, The paternal estimated age at conception versus the number of observed de novo point mutations (0, n = 53; 1, n = 65; 2, n = 44; 3+, n = 27). c, Decreased nonverbal IQ is significantly associated with an increasing number of “extreme” mutation events (0, n = 138; 1, n = 41; 2+, n = 10), both with and without CNVs (Supplementary Discussion). d, Browser images showing CNVs identified in del(18)(q12.2q21.1) syndrome region. Truncating point mutation in SETBP1 occurs within the critical region, identifying the likely causative locus. Each red (deletion) and green (duplication) line represents an identified CNV in cases (solid lines) versus controls (dashed lines), with arrowheads showing point mutation.
Figure 2
Figure 2. Mutations identified in protein-protein interaction (PPI) networks
a The 49-gene connected component of the PPI network formed from 126 genes with severe de novo mutations among the 209 probands. b, Proband 13844 inherits three rare gene-disruptive CNVs and carries two de novo truncating mutations. c, GeneMANIA view of three of the affected genes (b) (red labels) which encode proteins that are part of a beta-catenin linked network. This proband is macrocephalic, impaired cognitively, and has deficits in social behavior and language development (Supplementary Discussion).

Comment in

Similar articles

  • Patterns and rates of exonic de novo mutations in autism spectrum disorders.
    Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH Jr, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Neale BM, et al. Nature. 2012 Apr 4;485(7397):242-5. doi: 10.1038/nature11011. Nature. 2012. PMID: 22495311 Free PMC article.
  • De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
    Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW. Sanders SJ, et al. Nature. 2012 Apr 4;485(7397):237-41. doi: 10.1038/nature10945. Nature. 2012. PMID: 22495306 Free PMC article.
  • Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.
    O'Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, Mackenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE. O'Roak BJ, et al. Nat Genet. 2011 Jun;43(6):585-9. doi: 10.1038/ng.835. Epub 2011 May 15. Nat Genet. 2011. PMID: 21572417 Free PMC article.
  • A de novo convergence of autism genetics and molecular neuroscience.
    Krumm N, O'Roak BJ, Shendure J, Eichler EE. Krumm N, et al. Trends Neurosci. 2014 Feb;37(2):95-105. doi: 10.1016/j.tins.2013.11.005. Epub 2013 Dec 30. Trends Neurosci. 2014. PMID: 24387789 Free PMC article. Review.
  • Mutations and Modeling of the Chromatin Remodeler CHD8 Define an Emerging Autism Etiology.
    Barnard RA, Pomaville MB, O'Roak BJ. Barnard RA, et al. Front Neurosci. 2015 Dec 17;9:477. doi: 10.3389/fnins.2015.00477. eCollection 2015. Front Neurosci. 2015. PMID: 26733790 Free PMC article. Review.
See all similar articles

Cited by 886 articles

See all "Cited by" articles


    1. Schaaf CP, Zoghbi HY. Solving the autism puzzle a few pieces at a time. Neuron. 2011;70:806–808. doi: 10.1016/j.neuron.2011.05.025. - DOI - PubMed
    1. Sanders SJ, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011;70:863–885. doi: 10.1016/j.neuron.2011.05.002. - DOI - PMC - PubMed
    1. Levy D, et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron. 2011;70:886–897. doi: 10.1016/j.neuron.2011.05.015. - DOI - PubMed
    1. O’Roak BJ, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genetics. 2011;43:585–589. doi: 10.1038/ng.835. - DOI - PMC - PubMed
    1. Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichenberg A. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Molecular psychiatry. 2010 doi: 10.1038/mp.2010.121. - DOI - PubMed

Publication types

MeSH terms