GRIN2A mutations cause epilepsy-aphasia spectrum disorders

Journal name:
Nature Genetics
Volume:
45,
Pages:
1073–1076
Year published:
DOI:
doi:10.1038/ng.2727
Received
Accepted
Published online

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.

At a glance

Figures

  1. Phenotypes and segregation of GRIN2A mutations in four families with epilepsy-aphasia syndrome disorders.
    Figure 1: Phenotypes and segregation of GRIN2A mutations in four families with epilepsy-aphasia syndrome disorders.

    ADRESD, autosomal dominant rolandic epilepsy with speech dyspraxia; LKS, Landau-Kleffner syndrome; IEAD, intermediate epilepsy aphasia disorder; ESCWS, epileptic encephalopathy with continuous spike and wave in slow-wave sleep.

  2. The NR2A p.Thr531Met alteration increases the mean time of NMDA receptors in the open state.
    Figure 2: The NR2A p.Thr531Met alteration increases the mean time of NMDA receptors in the open state.

    (a,b) Left, representative steady-state unitary currents through NR1–NR2A WT (wild type) (a) and NR1–NR2A Thr531Met (b) channels, recorded in cell-attached patches from transiently transfected COS-7 wild-type (n = 7) and Thr531Met (n = 5) cells. Holding potential, +100 mV. Channels are activated with 50 μM glycine and 1 mM glutamate. O, open state; C, closed state. Note that single-channel amplitudes were not significantly affected by the mutation (P value = 0.953, Mann-Whitney, two-tailed). Right, histograms showing duration of the open state for the single-channel patches in a,b. Histograms were well fitted with single exponentials.

Accession codes

Referenced accessions

GenBank/EMBL/DDBJ

NCBI Reference Sequence

References

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Author information

  1. These authors contributed equally to this work.

    • Ingrid E Scheffer &
    • Heather C Mefford

Affiliations

  1. Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, USA.

    • Gemma L Carvill,
    • Adiba Khan,
    • Joseph Cook,
    • Eileen Geraghty &
    • Heather C Mefford
  2. Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, Victoria, Australia.

    • Brigid M Regan,
    • Simone C Yendle,
    • Samantha J Turner,
    • Meng-Han Tsai,
    • John A Damiano,
    • Samuel F Berkovic,
    • Michael S Hildebrand &
    • Ingrid E Scheffer
  3. Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

    • Brian J O'Roak &
    • Jay Shendure
  4. Mediterranean Institute of Neurobiology (INMED), Marseille, France.

    • Natalia Lozovaya,
    • Nadine Bruneau,
    • Nail Burnashev &
    • Pierre Szepetowski
  5. Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche Scientifique (UMRS) 901, Marseille, France.

    • Natalia Lozovaya,
    • Nadine Bruneau,
    • Nail Burnashev &
    • Pierre Szepetowski
  6. Aix-Marseille University, Marseille, France.

    • Natalia Lozovaya,
    • Nadine Bruneau,
    • Nail Burnashev &
    • Pierre Szepetowski
  7. INSERM UMRS 663, Paris Descartes University, Paris, France.

    • Natalia Lozovaya
  8. French EPILAND Network on Epilepsy, Language and Development, Marseille, France.

    • Nadine Bruneau,
    • Nail Burnashev &
    • Pierre Szepetowski
  9. Department of Pediatrics, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.

    • Lynette G Sadleir
  10. Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.

    • Samantha J Turner &
    • Ingrid E Scheffer
  11. T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

    • Richard Webster &
    • Robert Ouvrier
  12. Florey Institute, Melbourne, Victoria, Australia.

    • Ingrid E Scheffer

Contributions

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.

Competing financial interests

The authors declare no competing financial interests.

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