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 journalArticle

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.

Original languageEnglish
Pages (from-to)511-522
Number of pages12
JournalJournal of Medical Genetics
Volume53
Issue number8
DOIs
Publication statusPublished - Aug 1 2016

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Intellectual Disability
Epilepsy
Mutation
Exons
Seizures
Brain Diseases
Exome
Absence Epilepsy
Myoclonus
Muscle Hypotonia
Recombinant DNA
Genetic Association Studies
Eyelids
Gait
Head
Phenotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Mignot, C., von Stülpnage, C., Nava, C., Ville, D., Sanlaville, D., Lesca, G., ... Von Spiczak, S. (2016). Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. Journal of Medical Genetics, 53(8), 511-522. https://doi.org/10.1136/jmedgenet-2015-103451

Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. / Mignot, Cyril; von Stülpnage, Celina; Nava, Caroline; Ville, Dorothée; Sanlaville, Damien; Lesca, Gaetan; Rastetter, Agnès; Gachet, Benoit; Marie, Yannick; Korenke, G. C.; Borggraefe, Ingo; Hoffmann-Zacharska, Dorota; Szczepanik, Elzbieta; Rudzka-Dybala, Mariola; Yiş, Uluç; Caglayan, H. S.; Isapof, Arnaud; Marey, Isabelle; Panagiotakaki, Eleni; Korff, Christian; Rossier, Eva; Riess, Angelika; Beck-Woedl, Stefanie; Rauch, Anita; Zweier, C.; Hoyer, J.; Reis, Andre; Mironov, Mikhail; Bobylova, Maria; Mukhin, Konstantin; Hernandez-Hernandez, Laura; Maher, Bridget; Sisodiya, Sanjay M.; Kuhn, Marius; Glaeser, Dieter; Wechuysen, Sarah; Myers, Candace T.; Mefford, Heather C.; Hörtnagel, K.; Biskup, Saskia; Lemke, Johannes R.; Heron, Délphine; Kluger, Gerhard; Depienne, Christel; Craiu, Dana; De Jonghe, Peter; Helbig, Ingo; Guerrini, Renzo; Lehesjoki, Anna Elina; Marini, Carla; Muhle, H.; Møller, Rikke S.; Neubauer, Bernd; Pal, Deb; Selmer, Kaja; Stephani, Ulrich; Štěrbová, Katalin; Striano, Pasquale; Talvik, T.; Von Spiczak, Sarah.

In: Journal of Medical Genetics, Vol. 53, No. 8, 01.08.2016, p. 511-522.

Research output: Contribution to journalArticle

Mignot, C, von Stülpnage, 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, Yiş, U, Caglayan, HS, 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, SM, Kuhn, M, Glaeser, D, Wechuysen, S, Myers, CT, Mefford, HC, Hörtnagel, K, Biskup, S, Lemke, JR, Heron, D, Kluger, G, Depienne, C, Craiu, D, De Jonghe, P, Helbig, I, Guerrini, R, Lehesjoki, AE, Marini, C, Muhle, H, Møller, RS, Neubauer, B, Pal, D, Selmer, K, Stephani, U, Štěrbová, K, Striano, P, Talvik, T & Von Spiczak, S 2016, 'Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy', Journal of Medical Genetics, vol. 53, no. 8, pp. 511-522. https://doi.org/10.1136/jmedgenet-2015-103451
Mignot, Cyril ; von Stülpnage, Celina ; Nava, Caroline ; Ville, Dorothée ; Sanlaville, Damien ; Lesca, Gaetan ; Rastetter, Agnès ; Gachet, Benoit ; Marie, Yannick ; Korenke, G. C. ; Borggraefe, Ingo ; Hoffmann-Zacharska, Dorota ; Szczepanik, Elzbieta ; Rudzka-Dybala, Mariola ; Yiş, Uluç ; Caglayan, H. S. ; Isapof, Arnaud ; Marey, Isabelle ; Panagiotakaki, Eleni ; Korff, Christian ; Rossier, Eva ; Riess, Angelika ; Beck-Woedl, Stefanie ; Rauch, Anita ; Zweier, C. ; Hoyer, J. ; Reis, Andre ; Mironov, Mikhail ; Bobylova, Maria ; Mukhin, Konstantin ; Hernandez-Hernandez, Laura ; Maher, Bridget ; Sisodiya, Sanjay M. ; Kuhn, Marius ; Glaeser, Dieter ; Wechuysen, Sarah ; Myers, Candace T. ; Mefford, Heather C. ; Hörtnagel, K. ; Biskup, Saskia ; Lemke, Johannes R. ; Heron, Délphine ; Kluger, Gerhard ; Depienne, Christel ; Craiu, Dana ; De Jonghe, Peter ; Helbig, Ingo ; Guerrini, Renzo ; Lehesjoki, Anna Elina ; Marini, Carla ; Muhle, H. ; Møller, Rikke S. ; Neubauer, Bernd ; Pal, Deb ; Selmer, Kaja ; Stephani, Ulrich ; Štěrbová, Katalin ; Striano, Pasquale ; Talvik, T. ; Von Spiczak, Sarah. / Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. In: Journal of Medical Genetics. 2016 ; Vol. 53, No. 8. pp. 511-522.
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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.",
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TY - JOUR

T1 - Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy

AU - Mignot, Cyril

AU - von Stülpnage, Celina

AU - Nava, Caroline

AU - Ville, Dorothée

AU - Sanlaville, Damien

AU - Lesca, Gaetan

AU - Rastetter, Agnès

AU - Gachet, Benoit

AU - Marie, Yannick

AU - Korenke, G. C.

AU - Borggraefe, Ingo

AU - Hoffmann-Zacharska, Dorota

AU - Szczepanik, Elzbieta

AU - Rudzka-Dybala, Mariola

AU - Yiş, Uluç

AU - Caglayan, H. S.

AU - Isapof, Arnaud

AU - Marey, Isabelle

AU - Panagiotakaki, Eleni

AU - Korff, Christian

AU - Rossier, Eva

AU - Riess, Angelika

AU - Beck-Woedl, Stefanie

AU - Rauch, Anita

AU - Zweier, C.

AU - Hoyer, J.

AU - Reis, Andre

AU - Mironov, Mikhail

AU - Bobylova, Maria

AU - Mukhin, Konstantin

AU - Hernandez-Hernandez, Laura

AU - Maher, Bridget

AU - Sisodiya, Sanjay M.

AU - Kuhn, Marius

AU - Glaeser, Dieter

AU - Wechuysen, Sarah

AU - Myers, Candace T.

AU - Mefford, Heather C.

AU - Hörtnagel, K.

AU - Biskup, Saskia

AU - Lemke, Johannes R.

AU - Heron, Délphine

AU - Kluger, Gerhard

AU - Depienne, Christel

AU - Craiu, Dana

AU - De Jonghe, Peter

AU - Helbig, Ingo

AU - Guerrini, Renzo

AU - Lehesjoki, Anna Elina

AU - Marini, Carla

AU - Muhle, H.

AU - Møller, Rikke S.

AU - Neubauer, Bernd

AU - Pal, Deb

AU - Selmer, Kaja

AU - Stephani, Ulrich

AU - Štěrbová, Katalin

AU - Striano, Pasquale

AU - Talvik, T.

AU - Von Spiczak, Sarah

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

AB - 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.

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JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

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