Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

Johannes R Lemke; Dennis Lal; Eva M Reinthaler; Isabelle Steiner; Michael Nothnagel; Michael Alber; Kirsten Geider; Bodo Laube; Michael Schwake; Katrin Finsterwalder; Andre Franke; Markus Schilhabel; Johanna A Jähn; Hiltrud Muhle; Rainer Boor; Wim Van Paesschen; Roberto Caraballo; Natalio Fejerman; Sarah Weckhuysen; Peter De Jonghe; Jan Larsen; Rikke S Møller; Helle Hjalgrim; Laura Addis; Shan Tang; Elaine Hughes; Deb K Pal; Kadi Veri; Ulvi Vaher; Tiina Talvik; Petia Dimova; Rosa Guerrero López; José M Serratosa; Tarja Linnankivi; Anna-Elina Lehesjoki; Susanne Ruf; Markus Wolff; Sarah Buerki; Gabriele Wohlrab; Judith Kroell; Alexandre N Datta; Barbara Fiedler; Gerhard Kurlemann; Gerhard Kluger; Andreas Hahn; D Edda Haberlandt; Christina Kutzer; Jürgen Sperner; Felicitas Becker; Yvonne G Weber; Martha Feucht; Hannelore Steinböck; Birgit Neophythou; Gabriel M Ronen; Ursula Gruber-Sedlmayr; Julia Geldner; Robert J Harvey; Per Hoffmann; Stefan Herms; Janine Altmüller; Mohammad R Toliat; Holger Thiele; Peter Nürnberg; Christian Wilhelm; Ulrich Stephani; Ingo Helbig; Holger Lerche; Fritz Zimprich; Bernd A Neubauer; Saskia Biskup; Sarah von Spiczak

doi:10.1038/ng.2728

Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

Johannes R Lemke
, Dennis Lal
, Eva M Reinthaler
, Isabelle Steiner
, Michael Nothnagel
, Michael Alber
, Kirsten Geider
, Bodo Laube
, Michael Schwake
, Katrin Finsterwalder
, Andre Franke
, Markus Schilhabel
, Johanna A Jähn
, Hiltrud Muhle
, Rainer Boor
, Wim Van Paesschen
, Roberto Caraballo
, Natalio Fejerman
, Sarah Weckhuysen
, Peter De Jonghe

Jan Larsen, Rikke S Møller, Helle Hjalgrim, Laura Addis, Shan Tang, Elaine Hughes, Deb K Pal, Kadi Veri, Ulvi Vaher, Tiina Talvik, Petia Dimova, Rosa Guerrero López, José M Serratosa, Tarja Linnankivi, Anna-Elina Lehesjoki, Susanne Ruf, Markus Wolff, Sarah Buerki, Gabriele Wohlrab, Judith Kroell, Alexandre N Datta, Barbara Fiedler, Gerhard Kurlemann, Gerhard Kluger, Andreas Hahn, D Edda Haberlandt, Christina Kutzer, Jürgen Sperner, Felicitas Becker, Yvonne G Weber, Martha Feucht, Hannelore Steinböck, Birgit Neophythou, Gabriel M Ronen, Ursula Gruber-Sedlmayr, Julia Geldner, Robert J Harvey, Per Hoffmann, Stefan Herms, Janine Altmüller, Mohammad R Toliat, Holger Thiele, Peter Nürnberg, Christian Wilhelm, Ulrich Stephani, Ingo Helbig, Holger Lerche, Fritz Zimprich, Bernd A Neubauer, Saskia Biskup, Sarah von Spiczak

IRS - The Epilepsyhospital Filadelfia

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.

Original language	English
Journal	Nature Genetics
Volume	45
Issue number	9
Pages (from-to)	1067-1072
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2728
Publication status	Published - Sept 2013

Keywords

Amino Acid Substitution
Epilepsies, Partial
Female
Humans
Male
Models, Molecular
Mutation
Mutation, Missense
Pedigree
Protein Conformation
Receptors, N-Methyl-D-Aspartate

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Lemke, J. R., Lal, D., Reinthaler, E. M., Steiner, I., Nothnagel, M., Alber, M., Geider, K., Laube, B., Schwake, M., Finsterwalder, K., Franke, A., Schilhabel, M., Jähn, J. A., Muhle, H., Boor, R., Van Paesschen, W., Caraballo, R., Fejerman, N., Weckhuysen, S., ... von Spiczak, S. (2013). Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nature Genetics, 45(9), 1067-1072. https://doi.org/10.1038/ng.2728

@article{7b44525e486a444c9538eda721c8b96b,

title = "Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes",

abstract = "Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5\%; P = 4.83 {\texttimes} 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9\%) in individuals with BECTS to 9/51 (17.6\%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0\%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.",

keywords = "Amino Acid Substitution, Epilepsies, Partial, Female, Humans, Male, Models, Molecular, Mutation, Mutation, Missense, Pedigree, Protein Conformation, Receptors, N-Methyl-D-Aspartate",

author = "Lemke, \{Johannes R\} and Dennis Lal and Reinthaler, \{Eva M\} and Isabelle Steiner and Michael Nothnagel and Michael Alber and Kirsten Geider and Bodo Laube and Michael Schwake and Katrin Finsterwalder and Andre Franke and Markus Schilhabel and J{\"a}hn, \{Johanna A\} and Hiltrud Muhle and Rainer Boor and \{Van Paesschen\}, Wim and Roberto Caraballo and Natalio Fejerman and Sarah Weckhuysen and \{De Jonghe\}, Peter and Jan Larsen and M{\o}ller, \{Rikke S\} and Helle Hjalgrim and Laura Addis and Shan Tang and Elaine Hughes and Pal, \{Deb K\} and Kadi Veri and Ulvi Vaher and Tiina Talvik and Petia Dimova and \{Guerrero L{\'o}pez\}, Rosa and Serratosa, \{Jos{\'e} M\} and Tarja Linnankivi and Anna-Elina Lehesjoki and Susanne Ruf and Markus Wolff and Sarah Buerki and Gabriele Wohlrab and Judith Kroell and Datta, \{Alexandre N\} and Barbara Fiedler and Gerhard Kurlemann and Gerhard Kluger and Andreas Hahn and Haberlandt, \{D Edda\} and Christina Kutzer and J{\"u}rgen Sperner and Felicitas Becker and Weber, \{Yvonne G\} and Martha Feucht and Hannelore Steinb{\"o}ck and Birgit Neophythou and Ronen, \{Gabriel M\} and Ursula Gruber-Sedlmayr and Julia Geldner and Harvey, \{Robert J\} and Per Hoffmann and Stefan Herms and Janine Altm{\"u}ller and Toliat, \{Mohammad R\} and Holger Thiele and Peter N{\"u}rnberg and Christian Wilhelm and Ulrich Stephani and Ingo Helbig and Holger Lerche and Fritz Zimprich and Neubauer, \{Bernd A\} and Saskia Biskup and \{von Spiczak\}, Sarah",

year = "2013",

month = sep,

doi = "10.1038/ng.2728",

language = "English",

volume = "45",

pages = "1067--1072",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

Lemke, JR, Lal, D, Reinthaler, EM, Steiner, I, Nothnagel, M, Alber, M, Geider, K, Laube, B, Schwake, M, Finsterwalder, K, Franke, A, Schilhabel, M, Jähn, JA, Muhle, H, Boor, R, Van Paesschen, W, Caraballo, R, Fejerman, N, Weckhuysen, S, De Jonghe, P, Larsen, J, Møller, RS, Hjalgrim, H, Addis, L, Tang, S, Hughes, E, Pal, DK, Veri, K, Vaher, U, Talvik, T, Dimova, P, Guerrero López, R, Serratosa, JM, Linnankivi, T, Lehesjoki, A-E, Ruf, S, Wolff, M, Buerki, S, Wohlrab, G, Kroell, J, Datta, AN, Fiedler, B, Kurlemann, G, Kluger, G, Hahn, A, Haberlandt, DE, Kutzer, C, Sperner, J, Becker, F, Weber, YG, Feucht, M, Steinböck, H, Neophythou, B, Ronen, GM, Gruber-Sedlmayr, U, Geldner, J, Harvey, RJ, Hoffmann, P, Herms, S, Altmüller, J, Toliat, MR, Thiele, H, Nürnberg, P, Wilhelm, C, Stephani, U, Helbig, I, Lerche, H, Zimprich, F, Neubauer, BA, Biskup, S & von Spiczak, S 2013, 'Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes', Nature Genetics, vol. 45, no. 9, pp. 1067-1072. https://doi.org/10.1038/ng.2728

TY - JOUR

T1 - Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

AU - Lemke, Johannes R

AU - Lal, Dennis

AU - Reinthaler, Eva M

AU - Steiner, Isabelle

AU - Nothnagel, Michael

AU - Alber, Michael

AU - Geider, Kirsten

AU - Laube, Bodo

AU - Schwake, Michael

AU - Finsterwalder, Katrin

AU - Franke, Andre

AU - Schilhabel, Markus

AU - Jähn, Johanna A

AU - Muhle, Hiltrud

AU - Boor, Rainer

AU - Van Paesschen, Wim

AU - Caraballo, Roberto

AU - Fejerman, Natalio

AU - Weckhuysen, Sarah

AU - De Jonghe, Peter

AU - Larsen, Jan

AU - Møller, Rikke S

AU - Hjalgrim, Helle

AU - Addis, Laura

AU - Tang, Shan

AU - Hughes, Elaine

AU - Pal, Deb K

AU - Veri, Kadi

AU - Vaher, Ulvi

AU - Talvik, Tiina

AU - Dimova, Petia

AU - Guerrero López, Rosa

AU - Serratosa, José M

AU - Linnankivi, Tarja

AU - Lehesjoki, Anna-Elina

AU - Ruf, Susanne

AU - Wolff, Markus

AU - Buerki, Sarah

AU - Wohlrab, Gabriele

AU - Kroell, Judith

AU - Datta, Alexandre N

AU - Fiedler, Barbara

AU - Kurlemann, Gerhard

AU - Kluger, Gerhard

AU - Hahn, Andreas

AU - Haberlandt, D Edda

AU - Kutzer, Christina

AU - Sperner, Jürgen

AU - Becker, Felicitas

AU - Weber, Yvonne G

AU - Feucht, Martha

AU - Steinböck, Hannelore

AU - Neophythou, Birgit

AU - Ronen, Gabriel M

AU - Gruber-Sedlmayr, Ursula

AU - Geldner, Julia

AU - Harvey, Robert J

AU - Hoffmann, Per

AU - Herms, Stefan

AU - Altmüller, Janine

AU - Toliat, Mohammad R

AU - Thiele, Holger

AU - Nürnberg, Peter

AU - Wilhelm, Christian

AU - Stephani, Ulrich

AU - Helbig, Ingo

AU - Lerche, Holger

AU - Zimprich, Fritz

AU - Neubauer, Bernd A

AU - Biskup, Saskia

AU - von Spiczak, Sarah

PY - 2013/9

Y1 - 2013/9

N2 - Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.

AB - Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.

KW - Amino Acid Substitution

KW - Epilepsies, Partial

KW - Female

KW - Humans

KW - Male

KW - Models, Molecular

KW - Mutation

KW - Mutation, Missense

KW - Pedigree

KW - Protein Conformation

KW - Receptors, N-Methyl-D-Aspartate

U2 - 10.1038/ng.2728

DO - 10.1038/ng.2728

M3 - Journal article

C2 - 23933819

SN - 1061-4036

VL - 45

SP - 1067

EP - 1072

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

Abstract

Keywords

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