Abstract
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.
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Acknowledgements
We thank the subjects and their families for participating in our research. H.C.M. is supported by a grant from the US National Institutes of Health (NIH; NINDS 1R01NS069605) and is a recipient of a Burroughs Wellcome Fund Career Award for Medical Scientists. This work was supported by the National Health and Medical Research Council of Australia (Program Grant 628952 to S.F.B. and I.E.S., Practitioner Fellowship 1006110 to I.E.S. and CJ Martin Fellowship (546493) to M.S.H.) and by a Health Research Council of New Zealand project grant to L.G.S. P.S. is supported by ANR (Agence Nationale de la Recherche) grant EPILAND with EuroBiomed label, and P.S., N. Burnashev and N. Bruneau are supported by INSERM.
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G.L.C., H.C.M. and I.E.S. designed the study and wrote the manuscript. H.C.M. and I.E.S. supervised the study. G.L.C. constructed libraries, developed the variant calling pipeline (assisted by J.C.), analyzed sequence data, conducted RNA transcript analysis (assisted by E.G.) and performed haplotyping. J.C. and G.L.C. performed aCGH. A.K. performed mutation segregation analysis. B.J.O. and J.S. developed the MIP methodology and analysis pipeline. B.M.R., S.C.Y., L.G.S., S.J.T., M.-H.T. and R.W. performed phenotypic analysis. R.O., J.A.D. and M.S.H. conducted mutation screening in the BECTS cohort. B.M.R., S.F.B. and I.E.S. critically reviewed the manuscript. N.L., N. Bruneau, N. Burnashev and P.S. generated mutant transcripts and performed single-channel recordings and analysis.
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Carvill, G., Regan, B., Yendle, S. et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet 45, 1073–1076 (2013). https://doi.org/10.1038/ng.2727
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DOI: https://doi.org/10.1038/ng.2727
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