Cyril Mignot1, Celina von Stülpnagel2, Caroline Nava3, Dorothée Ville4, Damien Sanlaville5, Gaetan Lesca5, Agnès Rastetter6, Benoit Gachet6, Yannick Marie6, G Christoph Korenke7, Ingo Borggraefe8, Dorota Hoffmann-Zacharska9, Elżbieta Szczepanik10, Mariola Rudzka-Dybała10, Uluç Yiş11, Hande Çağlayan12, Arnaud Isapof13, Isabelle Marey14, Eleni Panagiotakaki15, Christian Korff16, Eva Rossier17, Angelika Riess18, Stefanie Beck-Woedl18, Anita Rauch19, Christiane Zweier20, Juliane Hoyer20, André Reis20, Mikhail Mironov21, Maria Bobylova21, Konstantin Mukhin21, Laura Hernandez-Hernandez22, Bridget Maher22, Sanjay Sisodiya22, Marius Kuhn23, Dieter Glaeser23, Sarah Weckhuysen24, Candace T Myers25, Heather C Mefford25, Konstanze Hörtnagel26, Saskia Biskup26, Johannes R Lemke26, Delphine Héron27, Gerhard Kluger2, Christel Depienne3. 1. Département de Génétique, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Centre de Référence "Déficiences Intellectuelles de Causes Rares, Paris, France Groupe de Recherche Clinique (GRC) "Déficience Intellectuelle et Autisme", UPMC, Paris, France. 2. Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Vogtareuth, Germany Paracelsus Medical University Salzburg, Austria. 3. Département de Génétique, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR S 1127, CNRS UMR 7225, ICM, Paris, France. 4. Service de Neurologie Pédiatrique, Hôpital Femme Mère Enfant, CHU de Lyon, Bron, France. 5. Service de Génétique, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France Université Claude-Bernard Lyon 1, Villeurbanne, France CRNL, CNRS UMR 5292, INSERM U1028, bâtiment IMBL, Villeurbanne, France. 6. Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR S 1127, CNRS UMR 7225, ICM, Paris, France. 7. Klinikum Oldenburg, Zentrum für Kinder- und Jugendmedizin (Elisabeth Kinderkrankenhaus), Klinik für Neuropädiatrie u. angeborene Stoffwechselerkrankungen, Oldenburg, Germany. 8. Department of Pediatric Neurology and Developmental Medicine and Epilepsy Center, University of Munich, Munich, Germany. 9. Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. 10. Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland. 11. Division of Child Neurology, Department of Pediatrics, School of Medicine, Dokuz Eylül University, İzmir, Turkey. 12. Department of Molecular Biology and Genetics Istanbul, Boğaziçi University, Istanbul, Turkey. 13. AP-HP, Hôpital Trousseau, Service de Neuropédiatrie, Paris, France. 14. Département de Génétique, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. 15. Epilepsy, Sleep and Pediatric Neurophysiology Department (ESEFNP), University Hospitals of Lyon (HCL), France. 16. Département de l'Enfant et de l'Adolescent, Neuropédiatrie-Hôpitaux Universitaires de Genève, Genève, Switzerland. 17. Institute of Human Genetics, University of Tuebingen, Tuebingen, Germany. 18. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. 19. Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland. 20. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 21. Svt. Luka's Institute of Child Neurology and Epilepsy, Moscow, Russia. 22. Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK. 23. Genetikum, Neu-Ulm, Germany. 24. Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR S 1127, CNRS UMR 7225, ICM, Paris, France Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium. 25. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, USA. 26. CeGaT GmbH, Tübingen, Germany. 27. Département de Génétique, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Centre de Référence "Déficiences Intellectuelles de Causes Rares, Paris, France Groupe de Recherche Clinique (GRC) "Déficience Intellectuelle et Autisme", UPMC, Paris, France Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Vogtareuth, Germany.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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:SYNGAP1encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Entities:
Keywords:
Epilepsy and seizures; Genetics; Neurology
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