GRIN2A mutations cause epilepsy-aphasia spectrum disorders.
Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes. We identified four probands with GRIN2A variants that segregated with the disorder in their families. Notably, all four families presented with EAS, accounting for 9% of epilepsy-aphasia cases. We did not detect pathogenic variants in GRIN2A in other epileptic encephalopathies (n = 475) nor in probands with benign childhood epilepsy with centrotemporal spikes (n = 81). We report the first monogenic cause, to our knowledge, for EAS. GRIN2A mutations are restricted to this group of cases, which has important ramifications for diagnostic testing and treatment and provides new insights into the pathogenesis of this debilitating group of conditions.
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, USA.
Gemma L
GL
Carvill
Brigid M
BM
Regan
Simone C
SC
Yendle
Brian J
BJ
O'Roak
Natalia
N
Lozovaya
Nadine
N
Bruneau
Nail
N
Burnashev
Adiba
A
Khan
Joseph
J
Cook
Eileen
E
Geraghty
Lynette G
LG
Sadleir
Samantha J
SJ
Turner
Meng-Han
MH
Tsai
Richard
R
Webster
Robert
R
Ouvrier
John A
JA
Damiano
Samuel F
SF
Berkovic
Jay
J
Shendure
Michael S
MS
Hildebrand
Pierre
P
Szepetowski
Ingrid E
IE
Scheffer
Heather C
HC
Mefford
D004569:Electroencephalography; D005260:Female; D006801:Humans; D018887:Landau-Kleffner Syndrome / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*
D016194:Receptors, N-Methyl-D-Aspartate