Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Patterns and rates of exonic de novo mutations in autism spectrum disorders


Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes3 as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case–control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Protein–protein interaction for genes with an observed functional de novo event.
Figure 2: Direct and indirect protein–protein interaction for genes with a functional de novo event and previous ASD genes.

Similar content being viewed by others

Accession codes

Data deposits

Data included in this manuscript have been deposited at dbGaP under accession number phs000298.v1.p1 and is available for download at


  1. Lichtenstein, P., Carlstrom, E., Rastam, M., Gillberg, C. & Anckarsater, H. The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am. J. Psychiatry 167, 1357–1363 (2010)

    Article  Google Scholar 

  2. Hallmayer, J. et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch. Gen. Psychiatry 68, 1095–1102 (2011)

    Article  Google Scholar 

  3. Betancur, C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42–77 (2011)

    Article  CAS  Google Scholar 

  4. Pinto, D. et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368–372 (2010)

    Article  CAS  ADS  Google Scholar 

  5. Sanders, S. J. et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863–885 (2011)

    Article  CAS  Google Scholar 

  6. Sebat, J., Levy, D. L. & McCarthy, S. E. Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet. 25, 528–535 (2009)

    Article  CAS  Google Scholar 

  7. Li, H. & Durbin, R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26, 589–595 (2010)

    Article  Google Scholar 

  8. DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nature Genet. 43, 491–498 (2011)

    Article  CAS  Google Scholar 

  9. McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010)

    Article  CAS  Google Scholar 

  10. Conrad, D. F. et al. Variation in genome-wide mutation rates within and between human families. Nature Genet. 43, 712–714 (2011)

    Article  CAS  Google Scholar 

  11. Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature (this issue)

  12. Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nature Methods 7, 248–249 (2010)

    Article  CAS  Google Scholar 

  13. Kryukov, G. V., Pennacchio, L. A. & Sunyaev, S. R. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am. J. Hum. Genet. 80, 727–739 (2007)

    Article  CAS  Google Scholar 

  14. Crow, J. F. The origins, patterns and implications of human spontaneous mutation. Nature Rev. Genet. 1, 40–47 (2000)

    Article  CAS  Google Scholar 

  15. Rossin, E. J. et al. Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet. 7, e1001273 (2011)

    Article  CAS  Google Scholar 

  16. Lage, K. et al. A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes. Proc. Natl Acad. Sci. USA 105, 20870–20875 (2008)

    Article  CAS  ADS  Google Scholar 

  17. O’Roak, B. J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genet. 43, 585–589 (2011)

    Article  Google Scholar 

  18. O’Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature (this issue)

  19. Wu, M. C. et al. Rare-variant association testing for sequencing data with the sequence kernel association test. Am. J. Hum. Genet. 89, 82–93 (2011)

    Article  CAS  Google Scholar 

  20. Neale, B. M. et al. Testing for an unusual distribution of rare variants. PLoS Genet. 7, e1001322 (2011)

    Article  CAS  Google Scholar 

Download references


This work was directly supported by NIH grants R01MH089208 (M.J.D.), R01 MH089025 (J.D.B.), R01 MH089004 (G.D.S.), R01MH089175 (R.A.G.) and R01 MH089482 (J.S.S.), and supported in part by NIH grants P50 HD055751 (E.H.C.), RO1 MH057881 (B.D.) and R01 MH061009 (J.S.S.). Y.K., G.C. and S.Y. are Seaver Fellows, supported by the Seaver Foundation. We thank T. Lehner, A. Felsenfeld and P. Bender for their support and contribution to the project. We thank S. Sanders and M. State for discussions on the interpretation of de novo events. We thank D. Reich for comments on the abstract and message of the manuscript. We thank E. Lander and D. Altshuler for comments on the manuscript. We acknowledge the assistance of M. Potter, A. McGrew and G. Crockett without whom these studies would not be possible, and Center for Human Genetics Research resources: Computational Genomics Core, Genetic Studies Ascertainment Core and DNA Resources core, supported in part by NIH NCRR grant UL1 RR024975, and the Vanderbilt Kennedy Center for Research on Human Development (P30 HD015052). This work was supported in part by R01MH084676 (S.S.). We acknowledge the clinicians and organizations that contributed to samples used in this study and the particular support of the Mount Sinai School of Medicine, University of Illinois-Chicago, Vanderbilt University, the Autism Genetics Resource Exchange and the institutions of the Boston Autism Consortium. We acknowledge A. Estes and G. Dawson for patient collection/characterization. We acknowledge partial support from U54 HG003273 (R.A.G.) and U54 HG003067 (E. Lander). J.D.B., B.D., M.J.D., R.A.G., A.S., G.D.S. and J.S.S. are lead investigators in the Autism Sequencing Consortium (ASC). The ASC is comprised of groups sharing massively parallel sequencing data in autism. Finally, we are grateful to the many families, without whose participation this project would not have been possible.

Author information

Authors and Affiliations



Laboratory work: A.S., C.St., G.C., O.J., Z.P., J.D.B., D.M., I.N., Y.W., L.L., Y.H., S.G., E.L.C., N.G.C. and E.T.G. Data processing: B.M.N., K.E.S., E.L., A.K., J.F., M.F., K.S., T.F., K.G., E.Ba., R.P., M.DeP., S.G., S.Y., V.M., J.L., J.D.B., A.S., C.St., U.N., J.G.R., J.R.W., B.E.B., S.E.L., C.F.L., L.S.W. and O.V. Statistical analysis: B.M.N., L.L., K.E.S., C.Sh., B.F.V., J.M., E.R., S.S., P.P., Y.K., A.M., R.D., C.-F.L., L.-S.W., H.L., T.Z., E.Bo., R.A.G., J.D.B., C.B., E.H.C., J.S.S., G.D.S., B.D., K.R. and M.J.D. Principal Investigators/study design: E.Bo., R.A.G., E.H.C., J.D.B., K.R., B.D., G.D.S., J.S.S. and M.J.D. Y.K., L.L., A.M., K.E.S., A.S. and C.-F.L. contributed equally to this work. E.Bo., J.D.B., E.H.C., B.D., R.A.G., K.R., G.D.S., J.S.S. and M.J.D. are lead investigators of the ARRA Autism Sequencing Collaboration.

Corresponding authors

Correspondence to Joseph D. Buxbaum, Kathryn Roeder or Mark J. Daly.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data, Supplementary Figures 1-4, Supplementary Tables 1-10 and additional references. (PDF 1221 kb)

Supplementary Data

This file contains Supplementary Data. (XLS 96 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Neale, B., Kou, Y., Liu, L. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research