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)1,2. 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.
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We thank all subjects and family members for their participation in this study. Furthermore, we are grateful to all clinicians referring patients and probands for genetic research. We would like to thank all lab technicians for technical assistance with mutation and CNV analysis.
The authors would like to thank the National Heart, Lung and Blood Institute (NHLBI) GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative (WHI) Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).
S.v.S. received institutional support from Christian-Albrechts University Kiel and a scholarship from the German Epilepsy Society for research activities (Otfrid-Foerster-Stipendium). J.R.L. (32EP30_136042/1), P.D.J. (G.A.136.11.N and FWO/ESF-ECRP), T.T. (SF0180035s08), J.M.S. (EUI-EURC-2011-4325) and I.H. (HE5415/3-1) received financial support within the EuroEPINOMICS-RES network, and A.-E.L. (Academy of Finland, grant 141549), P.N. (Nu50/8-1), H.L. (Le1030/11-1), F.Z. (FWF I643-B09) and B.A.N. (Ne416/5-1) received financial support within the EuroEPINOMICS-CoGIE network within the Eurocores framework of the European Science Foundation (ESF). H.L. and S. Biskup received further support from the German Federal Ministry for Education and Research (BMBF; H.L.: NGFNplus/EMINet 01GS08123; H.L. and S. Biskup, IonNeurONet 01GM1105A). M. Schwake received financial support from the German Research Foundation (DFG; SFB877). J.M.S. received support from the Spanish Government (grant SAF2010-18586). D.K.P. and L.A. received support from a European Union Marie Curie International Reintegration Award of the Seventh Framework Programme (PIRG05-GA-2009-248866) and from the Waterloo Foundation, the Ali Paris Fund for Landau-Kleffner Syndrome Research and Education, the Charles Sykes Epilepsy Research Trust and the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health of South London and Maudsley National Health Service (NHS) Foundation Trust.
Supplementary Figures 1–5 and Supplementary Tables 1–5
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Expert Review of Molecular Diagnostics (2019)