Letter | Published:

Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

Nature Genetics volume 43, pages 585589 (2011) | Download Citation

  • A Corrigendum to this article was published on 28 March 2012

This article has been updated


Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity1,2. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk3. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.

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Change history

  • 09 March 2012

    In the version of this article initially published, the missense variant in CNTNAP2 identified in proband 12817 was incorrectly listed as p.His275Ala in the main text and Figure 1. The correct notation for this variant is p.His275Arg. In addition, the raw sequence reads have now been deposited in the National Database for Autism Research under accession number NDARCOL0001878. These errors have been corrected in the HTML and PDF versions of the article.


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We would like to thank and recognize the following ongoing studies that produced and provided exome variant calls for comparison: National Heart, Lung, and Blood Institute (NHBLI) Lung Cohort Sequencing Project (HL 1029230), NHLBI Women's Health Initiative (WHI) Sequencing Project (HL 102924), National Institute of Environmental Health Sciences (NIEHS) SNPs (HHSN273200800010C), NHLBI/National Human Genome Research Institute (NHGRI) SeattleSeq (HL 094976), NHGRI Next Generation Mendelian Genetics (HG 005608) and the Northwest Genomics Center (HL 102926). We also thank M.-C. King and S. Stray for processing and managing DNA samples, B.H. King and E. Bliss for their work in subject recruitment and phenotype collection, E. Turner, C. Igartua, I. Stanaway, M. Dennis and B. Coe for thoughtful discussions, M. State for providing SNP genotyping data and especially the families that volunteered their time to participate in this research. This work was supported by US National Institutes of Health grant HD065285 (E.E.E. and J.S.), Wellcome Trust core award 075491/Z/04 (S.E.F. and P.D.), the Max Planck Society (S.E.F.) and grants from the Simons Foundation Autism Research Initiative (SFARI) (191889, 137578 and 137593) (E.E.E., R.B., S.E.F. and P.D.). E.E.E. is an Investigator of the Howard Hughes Medical Institute.

Author information


  1. Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.

    • Brian J O'Roak
    • , Choli Lee
    • , Laura Vives
    • , Jerrod J Schwartz
    • , Santhosh Girirajan
    • , Emre Karakoc
    • , Alexandra P MacKenzie
    • , Sarah B Ng
    • , Carl Baker
    • , Mark J Rieder
    • , Deborah A Nickerson
    • , Jay Shendure
    •  & Evan E Eichler
  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Pelagia Deriziotis
    •  & Simon E Fisher
  3. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.

    • Raphael Bernier
  4. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.

    • Simon E Fisher
  5. Howard Hughes Medical Institute, Seattle, Washington, USA.

    • Evan E Eichler


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E.E.E., J.S. and B.J.O. designed the study and drafted the manuscript. E.E.E. and J.S. supervised the study. R.B. analyzed the clinical information and contributed to the manuscript. S.E.F. and P.D. designed cell-based functional experiments, analyzed data, interpreted results and contributed to the manuscript. S.G., C.B. and L.V. generated and analyzed array CGH data. C.L. performed Illumina GAIIx sequencing. B.J.O. and E.K. developed the analysis pipeline and analyzed sequence data. A.P.M. and S.B.N. designed and optimized capture protocol. B.J.O., L.V., A.P.M. and S.B.N. constructed exome libraries. B.J.O., L.V., A.P.M. and J.J.S. performed mutation validation and haplotype characterization. B.J.O. and J.J.S. performed the evaluation of 12817 lymphoblast cell lines. P.D. performed functional experiments. M.J.R. and D.A.N. performed sequencing of control samples.

Competing interests

E.E.E. is on the scientific advisory board for Pacific Biosciences. J.S. is a member of the scientific advisory boards of Tandem Technologies, Stratos Genomics, Good Start Genetics, Halo Genomics and Adaptive TCR. B.J.O. is an inventor on patent PCT/US2009/30620: Mutations in Contactin Associated Protein 2 are Associated with Increased Risk for Idiopathic Autism.

Corresponding authors

Correspondence to Jay Shendure or Evan E Eichler.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Note, Supplementary Figures 1–5 and Supplementary Tables 2–4 and 6–9.

Excel files

  1. 1.

    Supplementary Table 1

    Core descriptive clinical values on ASD probands

  2. 2.

    Supplementary Table 5

    Variant positions of 21 genes with identified de novo events from 1000 genomes pilot data, 20 HapMap, and 20 ASD probands

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