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 JongheJan 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

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

359 Citations (Scopus)

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
Pages (from-to)	1067-1072
Number of pages	6
Journal	Nature Genetics
Volume	45
Issue number	9
DOIs	https://doi.org/10.1038/ng.2728
Publication status	Published - Sept 2013

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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{ccaf9bed82e446e79da857df6886b2c1,

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 × 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.",

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",

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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.

U2 - 10.1038/ng.2728

DO - 10.1038/ng.2728

M3 - 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

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