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

Mignot C, Von Stuelpnagel C, Nava C, Ville D, Sanlaville D, Lesca G, Rastetter A, Gachet B, Marie Y, Korenke GC, Borggraefe I, Hoffmann-Zacharska D, Szczepanik E, Rudzka-Dybala M, Yis U, Caglayan H, Isapof A, Marey I, Panagiotakaki E, Korff C, Rossier E, Riess A, Beck-Woedl S, Rauch A, Zweier C, Hoyer J, Reis A, Mironov M, Bobylova M, Mukhin K, Hernandez-Hernandez L, Maher B, Sisodiya S, Kuhn M, Glaeser D, Wechuysen S, Myers CT, Mefford HC, Hoertnagel K, Biskup S, Lemke JR, Heron D, Kluger G, Depienne C (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 53

Pages Range: 511-22

Journal Issue: 8

DOI: 10.1136/jmedgenet-2015-103451

Abstract

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

Authors with CRIS profile

Involved external institutions

University of Zurich / Universität Zürich (UZH) Switzerland (CH) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) Hospices Civils de Lyon (CHU) France (FR) University of Paris 6 - Pierre et Marie Curie / Université Paris VI Pierre et Marie Curie (UPMC) France (FR) Schön Kliniken Germany (DE) Klinikum Oldenburg Germany (DE) Ludwig-Maximilians-Universität (LMU) Germany (DE) Institute of Mother and Child / Instytut Matki I Dziecka Poland (PL) Dokuz Eylül Üniversitesi (DEU) Turkey (TR) Bogazici University Turkey (TR) Hôpital Armand-Trousseau (AP-HP) France (FR) Geneva University Hospitals / Hôpitaux universitaires de Genève (HUG) Switzerland (CH) Eberhard Karls Universität Tübingen Germany (DE) University College London (UCL) United Kingdom (GB) genetikum – Genetische Beratung & Diagnostik Germany (DE) University of Washington United States (USA) (US) CeGaT GmbH Germany (DE) Universitätsklinikum Leipzig Germany (DE)

How to cite

APA:

Mignot, C., Von Stuelpnagel, C., Nava, C., Ville, D., Sanlaville, D., Lesca, G.,... Depienne, C. (2016). Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. Journal of Medical Genetics, 53(8), 511-22. https://doi.org/10.1136/jmedgenet-2015-103451

MLA:

Mignot, Cyril, et al. "Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy." Journal of Medical Genetics 53.8 (2016): 511-22.

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