Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy
Cyril Mignot
(1, 1, 2)
,
Celina von Stülpnagel
(3, 4)
,
Caroline Nava
(5, 1)
,
Dorothée Ville
(6)
,
Damien Sanlaville
(7, 8, 9)
,
Gaetan Lesca
(8, 9, 7)
,
Agnès Rastetter
(5)
,
Benoit Gachet
(5)
,
Yannick Marie
(5)
,
Christoph G. Korenke
(10)
,
Ingo Borggraefe
(11)
,
Dorota Hoffmann-Zacharska
(12)
,
Elżbieta Szczepanik
(13)
,
Mariola Rudzka-Dybała
(13)
,
Uluç Yiş
(14)
,
Hande Çağlayan
(15)
,
Arnaud Isapof
(16)
,
Isabelle Marey
(1)
,
Eleni Panagiotakaki
(17)
,
Christian Korff
(18)
,
Eva Rossier
(19)
,
Angelika Riess
(20)
,
Stefanie Beck-Woedl
(20)
,
Anita Rauch
(21)
,
Christiane Zweier
(22)
,
Juliane Hoyer
(22)
,
André Reis
(22)
,
Mikhail Mironov
(23)
,
Maria Bobylova
(23)
,
Konstantin Mukhin
(23)
,
Laura Hernandez-Hernandez
(24)
,
Bridget Maher
(24)
,
Sanjay Sisodiya
(24)
,
Marius Kuhn
(25)
,
Dieter Glaeser
(25)
,
Sarah Wechuysen
(26, 5)
,
Candace T. Myers
(27)
,
Heather C. Mefford
(27)
,
Konstanze Hörtnagel
(28)
,
Saskia Biskup
(28)
,
Johannes R Lemke
(29)
,
Delphine Heron
(1, 1, 2, 4)
,
Gerhard Kluger
(4, 3)
,
Christel Depienne
(1, 5)
1
CHU Pitié-Salpêtrière [AP-HP]
2 GRC 9 - Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)
3 PMU - Paracelsus Medizinische Privatuniversität = Paracelsus Medical University
4 Hospital for Neuropediatrics and Neurological Rehabilitation
5 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
6 Service de Neurologie Pédiatrique [CHU Lyon]
7 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
8 Service de Génétique [HCL Groupement Hospitalier Est]
9 UCBL - Université Claude Bernard Lyon 1
10 Klinikum Oldenburg [Oldenburg]
11 Dpt of Pediatric Neurology and Developmental Medicine and Epilepsy Center [Munich]
12 Department of Medical Genetics
13 Institute of Mother and Child
14 Division of Child Neurology
15 Dpt of Molecular Biology and Genetics Istanbul
16 CHU Trousseau [APHP]
17 Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques
18 Dpt de l'Enfant et de l'Adolescent, Neuropédiatrie [Genève]
19 Institute of Human Genetics [Tuebingen]
20 Institute of Medical Genetics and Applied Genomics [Tübingen]
21 Institute of Medical Genetics
22 Institute of Human Genetics [Erlangen, Allemagne]
23 Svt. Luka's Institute of Child Neurology and Epilepsy
24 Department of Clinical and Experimental Epilepsy
25 Genetikum
26 Neurogenetics Group
27 Division of Genetic Medicine [Seattle]
28 CeGaT GmbH
29 Institut für Humangenetik
2 GRC 9 - Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)
3 PMU - Paracelsus Medizinische Privatuniversität = Paracelsus Medical University
4 Hospital for Neuropediatrics and Neurological Rehabilitation
5 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
6 Service de Neurologie Pédiatrique [CHU Lyon]
7 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
8 Service de Génétique [HCL Groupement Hospitalier Est]
9 UCBL - Université Claude Bernard Lyon 1
10 Klinikum Oldenburg [Oldenburg]
11 Dpt of Pediatric Neurology and Developmental Medicine and Epilepsy Center [Munich]
12 Department of Medical Genetics
13 Institute of Mother and Child
14 Division of Child Neurology
15 Dpt of Molecular Biology and Genetics Istanbul
16 CHU Trousseau [APHP]
17 Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques
18 Dpt de l'Enfant et de l'Adolescent, Neuropédiatrie [Genève]
19 Institute of Human Genetics [Tuebingen]
20 Institute of Medical Genetics and Applied Genomics [Tübingen]
21 Institute of Medical Genetics
22 Institute of Human Genetics [Erlangen, Allemagne]
23 Svt. Luka's Institute of Child Neurology and Epilepsy
24 Department of Clinical and Experimental Epilepsy
25 Genetikum
26 Neurogenetics Group
27 Division of Genetic Medicine [Seattle]
28 CeGaT GmbH
29 Institut für Humangenetik
Cyril Mignot
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Caroline Nava
- Fonction : Auteur
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- ORCID : 0000-0003-1272-0518
Damien Sanlaville
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- ORCID : 0000-0001-9939-2849
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Yannick Marie
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Christiane Zweier
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Mikhail Mironov
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Sanjay Sisodiya
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Delphine Heron
- Fonction : Auteur
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Gerhard Kluger
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Christel Depienne
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Résumé
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.
Domaines
Neurosciences [q-bio.NC]
Origine : Fichiers produits par l'(les) auteur(s)
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