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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014).

  2. 2.

    , , & The role of de novo mutations in the genetics of autism spectrum disorders. Nat. Rev. Genet. 15, 133–141 (2014).

  3. 3.

    et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158, 263–276 (2014).

  4. 4.

    , & A genotype-first approach to defining the subtypes of a complex disease. Cell 156, 872–877 (2014).

  5. 5.

    et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87, 1215–1233 (2015).

  6. 6.

    Neocortical neurogenesis and the etiology of autism spectrum disorder. Neurosci. Biobehav. Rev. 64, 185–195 (2016).

  7. 7.

    et al. Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns. Hum. Mol. Genet. 24, 5995–6002 (2015).

  8. 8.

    et al. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. Mol. Psychiatry 21, 126–132 (2016).

  9. 9.

    et al. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat. Genet. 46, 380–384 (2014).

  10. 10.

    DSM-5 and psychiatric genetics — round hole, meet square peg. Biol. Psychiatry 77, 766–768 (2015).

  11. 11.

    et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310–315 (2014).

  12. 12.

    et al. Genome sequencing of autism-affected families reveals disruption of putative noncoding regulatory DNA. Am. J. Hum. Genet. 98, 58–74 (2016).

  13. 13.

    et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).

  14. 14.

    et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014).

  15. 15.

    et al. Prevalence and architecture of de novo mutations in developmental disorders. Nature (2017).

  16. 16.

    , & Molecular subtyping and improved treatment of neurodevelopmental disease. Genome Med. 8, 22 (2016).

  17. 17.

    et al. Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. Am. J. Hum. Genet. 91, 1122–1127 (2012).

  18. 18.

    et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).

  19. 19.

    Rate, molecular spectrum, and consequences of human mutation. Proc. Natl. Acad. Sci. USA 107, 961–968 (2010).

  20. 20.

    et al. PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13. Hum. Mutat. 20, 298–304 (2002).

  21. 21.

    , & A new growth deficiency syndrome. Clin. Genet. 20, 1–5 (1981).

  22. 22.

    et al. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat. Genet. 44, 85–88 (2011).

  23. 23.

    et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 44, D1, D862–D868 (2016).

  24. 24.

    et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929 (2012).

  25. 25.

    , , & Conserved structural and functional control of N-methyl-d-aspartate receptor gating by transmembrane domain M3. J. Biol. Chem. 280, 29708–29716 (2005).

  26. 26.

    et al. Neurodegeneration in Lurcher mice caused by mutation in δ2 glutamate receptor gene. Nature 388, 769–773 (1997).

  27. 27.

    et al. GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia. Neurology 84, 1751–1759 (2015).

  28. 28.

    , & Mutation of a glutamate receptor motif reveals its role in gating and δ2 receptor channel properties. Nat. Neurosci. 3, 315–322 (2000).

  29. 29.

    et al. The Lurcher mutation of an α-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid receptor subunit enhances potency of glutamate and converts an antagonist to an agonist. J. Biol. Chem. 275, 8475–8479 (2000).

  30. 30.

    & Effects of the lurcher mutation on GluR1 desensitization and activation kinetics. J. Neurosci. 24, 4941–4951 (2004).

  31. 31.

    & Synaptic AMPA receptor plasticity and behavior. Neuron 61, 340–350 (2009).

  32. 32.

    et al. De novo SCN2A splice site mutation in a boy with autism spectrum disorder. BMC Med. Genet. 15, 35 (2014).

  33. 33.

    et al. De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013).

  34. 34.

    et al. MuPIT interactive: webserver for mapping variant positions to annotated, interactive 3D structures. Hum. Genet. 132, 1235–1243 (2013).

  35. 35.

    , & Genetic aspects of autism spectrum disorders: insights from animal models. Front. Cell. Neurosci. 8, 58 (2014).

  36. 36.

    et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 39, 25–27 (2007).

  37. 37.

    et al. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol. Psychiatry 69, 898–901 (2011).

  38. 38.

    et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147, 235–246 (2011).

  39. 39.

    et al. Neuroligins determine synapse maturation and function. Neuron 51, 741–754 (2006).

  40. 40.

    et al. Death and survival of heterozygous Lurcher Purkinje cells in vitro. Dev. Neurobiol. 69, 505–517 (2009).

  41. 41.

    , , , & Impaired regulation of synaptic strength in hippocampal neurons from GluR1-deficient mice. J. Physiol. (Lond.) 552, 35–45 (2003).

  42. 42.

    et al. Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and 'schizophrenia-related' behaviors. Mol. Psychiatry 13, 631–640 (2008).

  43. 43.

    et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat. Genet. 44, 1255–1259 (2012).

  44. 44.

    Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519, 223–228 (2015).

  45. 45.

    et al. Whole-exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome. Clin. Genet. 89, 198–204 (2016).

  46. 46.

    et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014).

  47. 47.

    et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154, 518–529 (2013).

  48. 48.

    et al. Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder. J. Hum. Genet. 61, 199–206 (2016).

  49. 49.

    et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet. Med. 18, 898–905 (2016).

  50. 50.

    et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science 350, 1262–1266 (2015).

  51. 51.

    et al. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am. J. Hum. Genet. 93, 249–263 (2013).

  52. 52.

    et al. De novo mutations from sporadic schizophrenia cases highlight important signaling genes in an independent sample. Schizophr. Res. 166, 119–124 (2015).

  53. 53.

    et al. Excess of rare, inherited truncating mutations in autism. Nat. Genet. 47, 582–588 (2015).

  54. 54.

    , , , & Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum. Mol. Genet. 23, 3481–3489 (2014).

  55. 55.

    et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat. Neurosci. 19, 1194–1196 (2016).

  56. 56.

    et al. De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. Mol. Psychiatry 19, 652–658 (2014).

  57. 57.

    et al. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151, 1431–1442 (2012).

  58. 58.

    et al. Recurrent de novo mutations implicate novel genes underlying simplex autism risk. Nat. Commun. 5, 5595 (2014).

  59. 59.

    et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380, 1674–1682 (2012).

  60. 60.

    et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am. J. Hum. Genet. 90, 502–510 (2012).

  61. 61.

    et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia 54, 1270–1281 (2013).

  62. 62.

    et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat. Med. 21, 185–191 (2015).

  63. 63.

    et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 498, 220–223 (2013).

  64. 64.

    et al. Denovo-db: a compendium of human de novo variants. Nucleic Acids Res. 45, D1, D804–D811 (2017).

  65. 65.

    Genome of the Netherlands Consortium. Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nat. Genet. 46, 818–825 (2014).

  66. 66.

    Social Responsiveness Scale (SRS-2). West. Psychol. Serv. (2012).

  67. 67.

    et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–276 (2009).

  68. 68.

    et al. Multiple evidence strands suggest that there may be as few as 19,000 human protein-coding genes. Hum. Mol. Genet. 23, 5866–5878 (2014).

  69. 69.

    et al. SynaptomeDB: an ontology-based knowledgebase for synaptic genes. Bioinformatics 28, 897–899 (2012).

  70. 70.

    et al. The chromatin remodeller CHD8 is required for E2F-dependent transcription activation of S-phase genes. Nucleic Acids Res. 42, 2185–2196 (2014).

  71. 71.

    et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011).

  72. 72.

    , , , & Single molecule molecular inversion probes for targeted, high-accuracy detection of low-frequency variation. Genome Res. 23, 843–854 (2013).

  73. 73.

    , , , & MIPgen: optimized modeling and design of molecular inversion probes for targeted resequencing. Bioinformatics 30, 2670–2672 (2014).

  74. 74.

    et al. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat. Genet. 42, 483–485 (2010).

  75. 75.

    & Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

  76. 76.

    et al. Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am. J. Hum. Genet. 92, 221–237 (2013).

  77. 77.

    et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat. Genet. 46, 1063–1071 (2014).

  78. 78.

    , , , & Whole-exome sequencing in a south American cohort links ALDH1A3, FOXN1 and retinoic acid regulation pathways to autism spectrum disorders. PLoS One 10, e0135927 (2015).

  79. 79.

    et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).

  80. 80.

    et al. CRAVAT: cancer-related analysis of variants toolkit. Bioinformatics 29, 647–648 (2013).

Download references

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

    • Holly A F Stessman

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

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

Authors

  1. Search for Madeleine R Geisheker in:

  2. Search for Gabriel Heymann in:

  3. Search for Tianyun Wang in:

  4. Search for Bradley P Coe in:

  5. Search for Tychele N Turner in:

  6. Search for Holly A F Stessman in:

  7. Search for Kendra Hoekzema in:

  8. Search for Malin Kvarnung in:

  9. Search for Marie Shaw in:

  10. Search for Kathryn Friend in:

  11. Search for Jan Liebelt in:

  12. Search for Christopher Barnett in:

  13. Search for Elizabeth M Thompson in:

  14. Search for Eric Haan in:

  15. Search for Hui Guo in:

  16. Search for Britt-Marie Anderlid in:

  17. Search for Ann Nordgren in:

  18. Search for Anna Lindstrand in:

  19. Search for Geert Vandeweyer in:

  20. Search for Antonino Alberti in:

  21. Search for Emanuela Avola in:

  22. Search for Mirella Vinci in:

  23. Search for Stefania Giusto in:

  24. Search for Tiziano Pramparo in:

  25. Search for Karen Pierce in:

  26. Search for Srinivasa Nalabolu in:

  27. Search for Jacob J Michaelson in:

  28. Search for Zdenek Sedlacek in:

  29. Search for Gijs W E Santen in:

  30. Search for Hilde Peeters in:

  31. Search for Hakon Hakonarson in:

  32. Search for Eric Courchesne in:

  33. Search for Corrado Romano in:

  34. Search for R Frank Kooy in:

  35. Search for Raphael A Bernier in:

  36. Search for Magnus Nordenskjöld in:

  37. Search for Jozef Gecz in:

  38. Search for Kun Xia in:

  39. Search for Larry S Zweifel in:

  40. Search for Evan E Eichler in:

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.

Competing interests

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

Corresponding author

Correspondence to Evan E Eichler.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figure 1, Supplementary Tables 1 and 11, and Supplementary Clinical Case Reports

  2. 2.

    Supplementary Methods Checklist

Excel files

  1. 1.

    Supplementary Table 2

    Genes with recurrent de novo missense mutations in individuals with neurodevelopmental disorders

  2. 2.

    Supplementary Table 3

    Genes with recurrent de novo missense mutations in unaffected controls

  3. 3.

    Supplementary Table 4

    Recurrent de novo missense mutations at specific amino acid sites

  4. 4.

    Supplementary Table 5

    Cohorts sequenced with smMIPs

  5. 5.

    Supplementary Table 6

    Regions and cohorts targeted with smMIPs

  6. 6.

    Supplementary Table 7

    Rare missense variants with CADD >20 identified with targeted sequencing

  7. 7.

    Supplementary Table 8

    All new de novo missense mutations in NDD cases

  8. 8.

    Supplementary Table 9

    Phenotypes in cases with GRIA1 p.A636T mutation

  9. 9.

    Supplementary Table 10

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

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nn.4589

Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing