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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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.
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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.
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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.
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Supplementary Text and Figures
Supplementary Figure 1, Supplementary Tables 1 and 11, and Supplementary Clinical Case Reports (PDF 499 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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DOI: https://doi.org/10.1038/nn.4589
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