Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy

Cyril Mignot, Celina von Stülpnage, Caroline Nava, Dorothée Ville, Damien Sanlaville, Gaetan Lesca, Agnès Rastetter, Benoit Gachet, Yannick Marie, G. C. Korenke, Ingo Borggraefe, Dorota Hoffmann-Zacharska, Elzbieta Szczepanik, Mariola Rudzka-Dybala, Uluç Yiş, H. S. Caglayan, Arnaud Isapof, Isabelle Marey, Eleni Panagiotakaki, Christian KorffEva Rossier, Angelika Riess, Stefanie Beck-Woedl, Anita Rauch, C. Zweier, J. Hoyer, Andre Reis, Mikhail Mironov, Maria Bobylova, Konstantin Mukhin, Laura Hernandez-Hernandez, Bridget Maher, Sanjay M. Sisodiya, Marius Kuhn, Dieter Glaeser, Sarah Wechuysen, Candace T. Myers, Heather C. Mefford, K. Hörtnagel, Saskia Biskup, Johannes R. Lemke, Délphine Heron, Gerhard Kluger, Christel Depienne, Dana Craiu, Peter De Jonghe, Ingo Helbig, Renzo Guerrini, Anna Elina Lehesjoki, Carla Marini, H. Muhle, Rikke S. Møller, Bernd Neubauer, Deb Pal, Kaja Selmer, Ulrich Stephani, Katalin Štěrbová, Pasquale Striano, T. Talvik, Sarah Von Spiczak

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)511-522
Number of pages12
JournalJournal of Medical Genetics
Issue number8
Publication statusPublished - Aug 1 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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