Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.
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.
Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland.
Johannes R
JR
Lemke
Dennis
D
Lal
Eva M
EM
Reinthaler
Isabelle
I
Steiner
Michael
M
Nothnagel
Michael
M
Alber
Kirsten
K
Geider
Bodo
B
Laube
Michael
M
Schwake
Katrin
K
Finsterwalder
Andre
A
Franke
Markus
M
Schilhabel
Johanna A
JA
Jähn
Hiltrud
H
Muhle
Rainer
R
Boor
Wim
W
Van Paesschen
Roberto
R
Caraballo
Natalio
N
Fejerman
Sarah
S
Weckhuysen
Peter
P
De Jonghe
Jan
J
Larsen
Rikke S
RS
Møller
Helle
H
Hjalgrim
Laura
L
Addis
Shan
S
Tang
Elaine
E
Hughes
Deb K
DK
Pal
Kadi
K
Veri
Ulvi
U
Vaher
Tiina
T
Talvik
Petia
P
Dimova
Rosa
R
Guerrero López
José M
JM
Serratosa
Tarja
T
Linnankivi
Anna-Elina
AE
Lehesjoki
Susanne
S
Ruf
Markus
M
Wolff
Sarah
S
Buerki
Gabriele
G
Wohlrab
Judith
J
Kroell
Alexandre N
AN
Datta
Barbara
B
Fiedler
Gerhard
G
Kurlemann
Gerhard
G
Kluger
Andreas
A
Hahn
D Edda
DE
Haberlandt
Christina
C
Kutzer
Jürgen
J
Sperner
Felicitas
F
Becker
Yvonne G
YG
Weber
Martha
M
Feucht
Hannelore
H
Steinböck
Birgit
B
Neophythou
Gabriel M
GM
Ronen
Ursula
U
Gruber-Sedlmayr
Julia
J
Geldner
Robert J
RJ
Harvey
Per
P
Hoffmann
Stefan
S
Herms
Janine
J
Altmüller
Mohammad R
MR
Toliat
Holger
H
Thiele
Peter
P
Nürnberg
Christian
C
Wilhelm
Ulrich
U
Stephani
Ingo
I
Helbig
Holger
H
Lerche
Fritz
F
Zimprich
Bernd A
BA
Neubauer
Saskia
S
Biskup
Sarah
S
von Spiczak
D019943:Amino Acid Substitution; D004828:Epilepsies, Partial / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D011487:Protein Conformation; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D016194:Receptors, N-Methyl-D-Aspartate