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Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy
  1. Cyril Mignot1,2,3,
  2. Celina von Stülpnagel4,5,
  3. Caroline Nava1,6,
  4. Dorothée Ville7,
  5. Damien Sanlaville8,9,10,
  6. Gaetan Lesca8,9,10,
  7. Agnès Rastetter6,
  8. Benoit Gachet6,
  9. Yannick Marie6,
  10. G Christoph Korenke11,
  11. Ingo Borggraefe12,
  12. Dorota Hoffmann-Zacharska13,
  13. Elżbieta Szczepanik14,
  14. Mariola Rudzka-Dybała14,
  15. Uluç Yiş15,
  16. Hande Çağlayan16,
  17. Arnaud Isapof17,
  18. Isabelle Marey1,
  19. Eleni Panagiotakaki18,
  20. Christian Korff19,
  21. Eva Rossier20,
  22. Angelika Riess21,
  23. Stefanie Beck-Woedl21,
  24. Anita Rauch22,
  25. Christiane Zweier23,
  26. Juliane Hoyer23,
  27. André Reis23,
  28. Mikhail Mironov24,
  29. Maria Bobylova24,
  30. Konstantin Mukhin24,
  31. Laura Hernandez-Hernandez25,
  32. Bridget Maher25,
  33. Sanjay Sisodiya25,
  34. Marius Kuhn26,
  35. Dieter Glaeser26,
  36. Sarah Wechuysen6,27,
  37. Candace T Myers28,
  38. Heather C Mefford28,
  39. Konstanze Hörtnagel29,
  40. Saskia Biskup29,
  41. EuroEPINOMICS-RES MAE working group,
  42. Johannes R Lemke30,
  43. Delphine Héron1,2,3,4,
  44. Gerhard Kluger4,5,
  45. Christel Depienne1,6
    1. 1Département de Génétique, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
    2. 2Centre de Référence “Déficiences Intellectuelles de Causes Rares, Paris, France
    3. 3Groupe de Recherche Clinique (GRC) “Déficience Intellectuelle et Autisme”, UPMC, Paris, France
    4. 4Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Vogtareuth, Germany
    5. 5Paracelsus Medical University Salzburg, Austria
    6. 6Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR S 1127, CNRS UMR 7225, ICM, Paris, France
    7. 7Service de Neurologie Pédiatrique, Hôpital Femme Mère Enfant, CHU de Lyon, Bron, France
    8. 8Service de Génétique, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
    9. 9Université Claude-Bernard Lyon 1, Villeurbanne, France
    10. 10CRNL, CNRS UMR 5292, INSERM U1028, bâtiment IMBL, Villeurbanne, France
    11. 11Klinikum Oldenburg, Zentrum für Kinder- und Jugendmedizin (Elisabeth Kinderkrankenhaus), Klinik für Neuropädiatrie u. angeborene Stoffwechselerkrankungen, Oldenburg, Germany
    12. 12Department of Pediatric Neurology and Developmental Medicine and Epilepsy Center, University of Munich, Munich, Germany
    13. 13Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
    14. 14Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland
    15. 15Division of Child Neurology, Department of Pediatrics, School of Medicine, Dokuz Eylül University, İzmir, Turkey
    16. 16Department of Molecular Biology and Genetics Istanbul, Boğaziçi University, Istanbul, Turkey
    17. 17AP-HP, Hôpital Trousseau, Service de Neuropédiatrie, Paris, France
    18. 18Epilepsy, Sleep and Pediatric Neurophysiology Department (ESEFNP), University Hospitals of Lyon (HCL), France
    19. 19Département de l'Enfant et de l'Adolescent, Neuropédiatrie—Hôpitaux Universitaires de Genève, Genève, Switzerland
    20. 20Institute of Human Genetics, University of Tuebingen, Tuebingen, Germany
    21. 21Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
    22. 22Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland
    23. 23Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
    24. 24Svt. Luka's Institute of Child Neurology and Epilepsy, Moscow, Russia
    25. 25Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK
    26. 26Genetikum, Neu-Ulm, Germany
    27. 27Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium
    28. 28Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, USA
    29. 29CeGaT GmbH, Tübingen, Germany
    30. 30Institut für Humangenetik, Universitätsklinikum Leipzig, Leipzig, Germany
    1. Correspondence to Dr Cyril Mignot, Département de Génétique, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris F-75013, France; cyril.mignot{at}psl.aphp.fr or Dr Christel depienne, Service de Cytogénétique Constitutionnelle et Prénatale, Hôpital de Hautepierre, 1 avenue Moliére, 67098 STRASBOURG Cedex, France

    Abstract

    Objective We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype–phenotype correlations.

    Methods We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.

    Results We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3′ and 5′ exons. Seizures in patients with mutations in exons 4–5 were more pharmacoresponsive than in patients with mutations in exons 8–15.

    Conclusions SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.

    • Epilepsy and seizures
    • Genetics
    • Neurology

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