Article Text

Download PDFPDF
Original research
De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability
  1. Audrey Schalk1,
  2. Margot A Cousin2,3,
  3. Nikita R Dsouza4,
  4. Thomas D Challman5,
  5. Karen E Wain5,
  6. Zoe Powis6,
  7. Kelly Minks6,
  8. Aurélien Trimouille7,8,
  9. Eulalie Lasseaux7,
  10. Didier Lacombe7,8,
  11. Chloé Angelini7,8,
  12. Vincent Michaud7,8,
  13. Julien Van-Gils9,
  14. Nino Spataro10,
  15. Anna Ruiz10,
  16. Elizabeth Gabau11,
  17. Elliot Stolerman12,
  18. Camerun Washington12,
  19. Ray Louie12,
  20. Brendan C Lanpher3,13,
  21. Jennifer L Kemppainen3,13,
  22. Micheil Innes14,
  23. Frank Kooy15,
  24. Marije Meuwissen15,
  25. Alice Goldenberg16,
  26. Francois Lecoquierre16,
  27. Gabriella Vera16,
  28. Karin E M Diderich17,
  29. Beth Sheidley18,
  30. Christelle Moufawad El Achkar18,
  31. Meredith Park18,
  32. Fadi F Hamdan19,
  33. Jacques L Michaud19,
  34. Ann J Lewis20,
  35. Christiane Zweier21,22,
  36. André Reis21,
  37. Matias Wagner23,24,
  38. Heike Weigand25,
  39. Hubert Journel26,
  40. Boris Keren27,28,
  41. Sandrine Passemard29,30,
  42. Cyril Mignot27,28,
  43. Koen van Gassen31,
  44. Eva H Brilstra31,
  45. Gina Itzikowitz32,
  46. Emily O'Heir33,34,
  47. Jake Allen35,
  48. Kirsten A Donald32,36,
  49. Bruce Richard Korf37,
  50. Tammi Skelton37,
  51. Michelle Thompson37,38,
  52. Nathaniel H Robin37,
  53. Natasha L Rudy37,
  54. William B Dobyns39,
  55. Kimberly Foss39,
  56. Yuri Alexander Zarate40,
  57. Katherine A Bosanko40,
  58. Yves Alembik41,
  59. Benjamin Durand41,
  60. Frederic Tran Mau-them1,
  61. Emmanuelle Ranza42,
  62. Xavier Blanc42,
  63. Stylianos E Antonarakis42,
  64. Kirsty McWalter43,
  65. Erin Torti43,
  66. Francisca Millan43,
  67. Amy Dameron43,
  68. Mari Tokita43,
  69. Michael T Zimmermann4,44,
  70. Eric W Klee2,3,13,
  71. Amelie Piton45,
  72. Benedicte Gerard1
  1. 1 Institut de génétique médicale d’Alsace (IGMA), Laboratoire de Diagnostic Génétique, Hôpitaux universitaires de Strasbourg, Strasbourg, Alsace, France
  2. 2 Department of Quantitative Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  3. 3 Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
  4. 4 Bioinformatics Research and Development Laboratory, Genomics Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
  5. 5 Autism & Developmental Medicine Institute, Geisinger-Lewistown Hospital, Lewistown, Pennsylvania, USA
  6. 6 Department of Clinical Genomics, Ambry Genetics Corp, Aliso Viejo, California, USA
  7. 7 Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, Aquitaine, France
  8. 8 Maladies rares: Génétique et Métabolisme (MRGM), INSERM U1211, Université de Bordeaux Centre de Génomique Fonctionnelle de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France
  9. 9 Département de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, Aquitaine, France
  10. 10 Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí, Sabadell, Catalunya, Spain
  11. 11 Paediatric Unit, Parc Tauli Foundation–UAB University Institute, Sabadell, Catalunya, Spain
  12. 12 106 Gregor Mendel Cir, Greenwood Genetic Center Inc, Greenwood, South Carolina, USA
  13. 13 Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA
  14. 14 Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
  15. 15 Center Medical Genetics, University Hospital Antwerp, Antwerp, Belgium
  16. 16 Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, Centre Hospitalier Universitaire de Rouen, Rouen, Normandie, France
  17. 17 Erasmus Medical Center Department of Clinical Genetics, Rotterdam, Netherlands
  18. 18 Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA
  19. 19 Division of Medical Genetics, Department of Pediatrics, Saint Justine Hospital, Montreal, Quebec, Canada
  20. 20 Pediatric Neurology, Kaiser Permanente Santa Clara Medical Center, Santa Clara, California, USA
  21. 21 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  22. 22 Department of Human Genetics, Inselspital University Hospital Bern, Bern, BE, Switzerland
  23. 23 Institute of Human Genetics, Technische Universitat Munchen, Munchen, Bayern, Germany
  24. 24 Institute of Neurogenomics, Helmholtz Zentrum Munchen Deutsches Forschungszentrum fur Umwelt und Gesundheit, Neuherberg, Bayern, Germany
  25. 25 Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr von Hauner Children's Hospital, Munich University Hospital (Ludwig Maximilians University), Munchen, Bayern, Germany
  26. 26 Service de Génétique Médicale, Hopital Chubert, Vannes, Bretagne, France
  27. 27 Département de Génétique et de Cytogénétique, Centre de Reference Déficience Intellectuelle de Causes Rares, GRC UPMC « Déficience Intellectuelle et Autisme », Hôpital Universitaire Pitié Salpêtrière, Paris, Île-de-France, France
  28. 28 INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière, Paris, Île-de-France, France
  29. 29 APHP, Hopital Universitaire Robert-Debre Departement de genetique, Paris, Île-de-France, France
  30. 30 NeuroDiderot, UMR1141, INSERM, Paris, France
  31. 31 Department of Genetics, University Medical Centre Utrecht Center for Molecular Medicine, Utrecht, The Netherlands
  32. 32 Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, Rondebosch, Western Cape, South Africa
  33. 33 Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute for Genome Research, Cambridge, Massachusetts, USA
  34. 34 Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA
  35. 35 Stanley Center for Psychiatric Research, Broad Institute Stanley Center for Psychiatric Research, Cambridge, Massachusetts, USA
  36. 36 Neuroscience Institute, University of Cape Town, Rondebosch, Western Cape, South Africa
  37. 37 Department of Genetics, The University of Alabama at Birmingham, Birmingham, Alabama, USA
  38. 38 HudsonAlpha Institute, HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA
  39. 39 Department of Pediatrics (Genetics) and Neurology, University of Washington, Seattle Children's Research Institute, Seattle, Washington, USA
  40. 40 Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
  41. 41 Institut de génétique médicale d’Alsace (IGMA), Service de Génétique Médicale, Hôpitaux universitaires de Strasbourg, Strasbourg, Alsace, France
  42. 42 Medigenome, Swiss Institute of Medicine, Bern, Bern, Switzerland
  43. 43 GeneDx, GeneDx, Gaithersburg, Maryland, USA
  44. 44 Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
  45. 45 Neurogenetics and Translational Medecine, Institut of Genetics and Molecular and Cellular Biology, Illkirch-Grafenstaden, Grand Est, France
  1. Correspondence to Amelie Piton, Neurogenetics and Translational Medicine, Institut of Genetics and Molecular and Cellular Biology, Illkirch-Grafenstaden, Grand Est, France; piton{at}


Background High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).

Methods This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28).

Results A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.

Conclusion Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.

  • microRNA
  • genetics
  • medical
  • mutation
  • missense
  • nervous system diseases

Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. The variants have been submitted to Clinvar. All other data are available on request.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. The variants have been submitted to Clinvar. All other data are available on request.

View Full Text


  • AP and BG are joint senior authors.

  • Twitter @ZoePowis

  • AS and MAC contributed equally.

  • Correction notice This article has been correcred since it published Online First. Funding information have been added to the article.

  • Contributors AS, MAC, AP and BG compiled the molecular and clinical data; TDC, KEW, ZP, KM, AT, EL, DL, CA, VM, JV-G, NS, AR, EG, ES, CW, RJL, BCL, JLK, MI, FK, MM, AG, FL, GV, KEMD, BRS, CMEA, MP, FFH, JLM, AJL, CZ, AR, MW, HW, HJ, BK, SP, CM, KLIVG, EHB, GI, EOH, JA, KAD, BRK, TS, NHR, NR, WBD, KF, YAZ, KAB, YA, BD, FTMT, ER, XB, SEA, KM, ET, FM, AD, MJT, MTZ and NRD contributed to clinical and molecular data and reviewed the manuscript; NRD and MTZ performed the 3D modelling analyses; EWK, AP and BG conceived, coordinated and supervised the study; AS, MAC, AP and BG wrote the manuscript. AP acts as a guarantor.

  • Funding Research reported in this publication was supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number U01MH119689. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also thank the CREGEMES for its financial support.

  • Competing interests KMW, ET, FM, AD and MJT are employees of GeneDx. ZP and KM are employees of Ambry Genetics.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.