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Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Nature Neuroscience volume 20, pages 1043–1051 (2017)Cite this article

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Abstract

Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.

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Figure 1: Burden and recurrence of de novo missense mutations.
Figure 2: Severity of de novo missense mutations.
Figure 3: Recurrent mutations fall in or near functional domains.
Figure 4: Functional effect of recurrent GRIA1 missense mutations.
Figure 5: Proteins with excessive clustering of missense mutations in NDD cases.

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Acknowledgements

We thank the individuals and their families for participation in this study. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. Approved researchers can obtain the SSC population data set described in this study (http://sfari.org/resources/simons-simplex-collection) by applying at https://base.sfari.org/. We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to principal investigator C.M. Lajonchere. We thank J. Gerdts, S. Trinh and B. McKenna for their contributions and T. Brown for assistance in editing this manuscript. This research was supported, in part, by the following: Simons Foundation Autism Research Initiative (SFARI 303241) to E.E.E., National Institutes of Health (R01MH101221 to E.E.E., R01MH100047 to R.A.B., R01MH104450 to L.S.Z., RO1MH105527 and R01DC014489 to J.J.M.), an NHGRI Interdisciplinary Training in Genome Science Grant (T32HG00035) to H.A.F.S. and T.N.T., postdoctoral fellowship grant from the Autism Science Foundation (16-008) to T.N.T., Australian NHMRC grants 1091593 and 1041920 and Channel 7 Children's Research Foundation support to J.G., the National Basic Research Program of China (2012CB517900) and the National Natural Science Foundation of China (81330027, 81525007 and 31671114) to K.X. and H.G., the China Scholarship Council (201406370028) and the Fundamental Research Funds for the Central Universities (2012zzts110) to T.W., grants from the Jack Brockhoff Foundation and Perpetual Trustees, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS, the Swedish Brain Foundation, the Swedish Research Council, the Stockholm County Council, grants (KL2TR00099 and 1KL2TR001444) from the University of California, San Diego Clinical and Translational Research Institute to T.P., the Research Fund – Flanders (FWO) to R.F.K. and G.V., Czech Republic Grant 00064203 and Norway Grant NF-CZ11-PDP-3-003-2014 to Z.S., and the Italian Ministry of Health and '5 per mille' funding to C.R. H.P. is a Senior Clinical Investigator of The Research Foundation–Flanders (FWO). E.E.E. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Holly A F Stessman

    Present address: Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska, USA

Authors and Affiliations

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

    Madeleine R Geisheker, Bradley P Coe, Tychele N Turner, Holly A F Stessman, Kendra Hoekzema & Evan E Eichler

  2. Department of Pharmacology, University of Washington, Seattle, Washington, USA

    Gabriel Heymann & Larry S Zweifel

  3. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA

    Gabriel Heymann, Raphael A Bernier & Larry S Zweifel

  4. The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China

    Tianyun Wang, Hui Guo & Kun Xia

  5. Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    Malin Kvarnung, Britt-Marie Anderlid, Ann Nordgren, Anna Lindstrand & Magnus Nordenskjöld

  6. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden

    Malin Kvarnung, Britt-Marie Anderlid, Ann Nordgren, Anna Lindstrand & Magnus Nordenskjöld

  7. Robinson Research Institute and the University of Adelaide at the Women's and Children's Hospital, North Adelaide, South Australia, Australia

    Marie Shaw, Kathryn Friend & Jozef Gecz

  8. SA Pathology, Adelaide, South Australia, Australia

    Kathryn Friend

  9. South Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), Adelaide, South Australia, Australia

    Jan Liebelt, Christopher Barnett, Elizabeth M Thompson & Eric Haan

  10. School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia

    Christopher Barnett

  11. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    Elizabeth M Thompson & Eric Haan

  12. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

    Geert Vandeweyer & R Frank Kooy

  13. Unit of Pediatrics & Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy

    Antonino Alberti, Emanuela Avola & Corrado Romano

  14. Laboratory of Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy

    Mirella Vinci

  15. Unit of Neurology, IRCCS Associazione Oasi Maria Santissima, Troina, Italy

    Stefania Giusto

  16. University of California, San Diego, Autism Center of Excellence, La Jolla, California, USA

    Tiziano Pramparo, Karen Pierce, Srinivasa Nalabolu & Eric Courchesne

  17. Department of Psychiatry, The University of Iowa, Iowa City, Iowa, USA

    Jacob J Michaelson

  18. Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic

    Zdenek Sedlacek

  19. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

    Gijs W E Santen

  20. Centre for Human Genetics, KU Leuven and Leuven Autism Research, Leuven, Belgium

    Hilde Peeters

  21. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Hakon Hakonarson

  22. Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Hakon Hakonarson

  23. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Hakon Hakonarson

  24. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

    Jozef Gecz

  25. Howard Hughes Medical Institute, Seattle, Washington, USA

    Evan E Eichler

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  1. Madeleine R Geisheker
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Contributions

E.E.E., L.S.Z., M.R.G., G.H., T.N.T., B.P.C., H.A.F.S. and K.X. designed the study; M.R.G., G.H., T.N.T., B.P.C., T.W. and K.H. performed the experiments; B.P.C. and T.N.T. helped with MIP design and data analysis; M.K., M.N., M.S., J.G., C.B., E.M.T., G.V., R.F.K., T.P., S.N., H.P., C.R., R.A.B., K.X. and H.H. tested inheritance and provided clinical follow-up on select patients; other authors participated in the sample collection and DNA extraction and/or preparation. M.R.G., E.E.E., L.S.Z., G.H., B.P.C. and T.N.T. wrote the manuscript with input from all authors.

Corresponding author

Correspondence to Evan E Eichler.

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Competing interests

E.E.E. is on the scientific advisory board of DNAnexus, Inc.

Integrated supplementary information

Supplementary Figure 1 Missense mutation clustering in PTPN11.

a) Linear representation of the protein (NP_002825.3) with known functional domains annotated. The top two lines show mutations in controls from the 1000 Genomes Project (1KG)79 and the Exome Aggregation Consortium (ExAC)18. The third line shows de novo missense mutations in cases in denovo-db64 v.1.2. The case mutations fall in three small clusters. b) 3D representation of the PTPN11 protein shows that the three clusters of mutations that are far apart in the linear plot are in close proximity to each other and the ligand binding site after folding34.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1, Supplementary Tables 1 and 11, and Supplementary Clinical Case Reports (PDF 499 kb)

Supplementary Methods Checklist (PDF 337 kb)

Supplementary Table 2

Genes with recurrent de novo missense mutations in individuals with neurodevelopmental disorders (XLSX 110 kb)

Supplementary Table 3

Genes with recurrent de novo missense mutations in unaffected controls (XLSX 27 kb)

Supplementary Table 4

Recurrent de novo missense mutations at specific amino acid sites (XLSX 29 kb)

Supplementary Table 5

Cohorts sequenced with smMIPs (XLSX 20 kb)

Supplementary Table 6

Regions and cohorts targeted with smMIPs (XLSX 25 kb)

Supplementary Table 7

Rare missense variants with CADD >20 identified with targeted sequencing (XLSX 58 kb)

Supplementary Table 8

All new de novo missense mutations in NDD cases (XLSX 23 kb)

Supplementary Table 9

Phenotypes in cases with GRIA1 p.A636T mutation (XLSX 18 kb)

Supplementary Table 10

All genes with significant (P < 0.05) clustering of de novo missense mutations by CLUMP (XLSX 43 kb)

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Geisheker, M., Heymann, G., Wang, T. et al. Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Nat Neurosci 20, 1043–1051 (2017). https://doi.org/10.1038/nn.4589

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