Abstract

To identify candidate genes for intellectual disability, we performed a meta-analysis on 2,637 de novo mutations, identified from the exomes of 2,104 patient–parent trios. Statistical analyses identified 10 new candidate ID genes: DLG4, PPM1D, RAC1, SMAD6, SON, SOX5, SYNCRIP, TCF20, TLK2 and TRIP12. In addition, we show that these genes are intolerant to nonsynonymous variation and that mutations in these genes are associated with specific clinical ID phenotypes.

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Acknowledgements

The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. We thank all clinicians involved for referring individuals with ID for diagnostic exome sequencing. We thank J. Goeman for statistical advice and M. Hurles for discussions. We would also like to thank the participating individuals and their families. This work was in part financially supported by grants from the Netherlands Organization for Scientific Research (912-12-109 to J.A.V., A.S. and B.B.A.d.V.; 916-14-043 to C.G.; 907-00-365 to T.K. and SH-271-13 to C.G. and J.A.V.) and the European Research Council (ERC Starting Grant DENOVO 281964 to J.A.V.).

Author information

Author notes

    • Stefan H Lelieveld
    • , Margot R F Reijnders
    • , Lisenka E L M Vissers
    • , Han G Brunner
    •  & Christian Gilissen

    These authors contributed equally to this work.

Affiliations

  1. Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Stefan H Lelieveld
  2. Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Margot R F Reijnders
    • , Rolph Pfundt
    • , Helger G Yntema
    • , Erik-Jan Kamsteeg
    • , Petra de Vries
    • , Bert B A de Vries
    • , Marjolein H Willemsen
    • , Tjitske Kleefstra
    • , Ineke van der Burgt
    • , Ernie M H F Bongers
    • , Tuula Rinne
    • , Marcel R Nelen
    • , Joris A Veltman
    • , Lisenka E L M Vissers
    • , Han G Brunner
    •  & Christian Gilissen
  3. Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.

    • Katharina Löhner
    •  & Patrick Rump
  4. Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.

    • Maaike Vreeburg
    • , Servi J C Stevens
    • , Alexander P A Stegmann
    • , Joris A Veltman
    •  & Han G Brunner

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Contributions

C.G., L.E.L.M.V. and H.G.B. designed the study; S.H.L., M.R.F.R., C.G. and L.E.L.M.V. performed the analysis. R.P., H.G.Y., E.-J.K., T.R., S.J.C.S., A.P.A.S. and M.R.N. signed out initial diagnostic reports. P.d.V. performed Sanger validations. B.B.A.d.V., M.H.W., T.K., K.L., M.V., I.v.d.B., E.M.H.F.B., P.R. and M.R.F.R. collected patient phenotypes. S.H.L., M.R.F.R., J.A.V., H.G.B., L.E.L.M.V. and C.G. drafted the manuscript; all authors contributed to the final version of the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Christian Gilissen.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–13, Supplementary Tables 1, 7, 11–13, and Supplementary Note

  2. 2.

    Supplementary Methods Checklist

Excel files

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    Supplementary Table 2

    All identified de novo mutations in the RUMC cohort

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    Supplementary Table 3

    Genes significantly enriched for de novo mutations in the full RUMC cohort

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    Supplementary Table 4

    List of known ID genes

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    Supplementary Table 5

    Gene statistics for the RUMC set

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    Supplementary Table 6

    Gene statistics for the ID set

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    Supplementary Table 8

    Gene sets and corresponding pLI and RVIS

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    Supplementary Table 9

    Clustering of mutations in genes with only missense mutations

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    Supplementary Table 10

    Gene statistics for the NND set

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    Supplementary Table 14

    Gene statistics for the control set

About this article

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DOI

https://doi.org/10.1038/nn.4352

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