GRIN2A mutations cause epilepsy-aphasia spectrum disorders

Gemma L. Carvill; Brigid M. Regan; Simone C. Yendle; Brian J. O'Roak; Natalia Lozovaya; Nadine Bruneau; Nail Burnashev; Adiba Khan; Joseph Cook; Eileen Geraghty; Lynette G. Sadleir; Samantha J. Turner; Meng Han Tsai; Richard Webster; Robert Ouvrier; John A. Damiano; Samuel F. Berkovic; Jay Shendure; Michael S. Hildebrand; Pierre Szepetowski; Ingrid E. Scheffer; Heather C. Mefford

doi:10.1038/ng.2727

GRIN2A mutations cause epilepsy-aphasia spectrum disorders

Gemma L. Carvill, Brigid M. Regan, Simone C. Yendle, Brian J. O'Roak, Natalia Lozovaya, Nadine Bruneau, Nail Burnashev, Adiba Khan, Joseph Cook, Eileen Geraghty, Lynette G. Sadleir, Samantha J. Turner, Meng Han Tsai, Richard Webster, Robert Ouvrier, John A. Damiano, Samuel F. Berkovic, Jay Shendure, Michael S. Hildebrand, Pierre SzepetowskiIngrid E. Scheffer, Heather C. Mefford^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	1073-1076
Number of pages	4
Journal	Nature Genetics
Volume	45
Issue number	9
DOIs	https://doi.org/10.1038/ng.2727
State	Published - Sep 2013

ASJC Scopus subject areas

Genetics

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Carvill, G. L., Regan, B. M., Yendle, S. C., O'Roak, B. J., Lozovaya, N., Bruneau, N., Burnashev, N., Khan, A., Cook, J., Geraghty, E., Sadleir, L. G., Turner, S. J., Tsai, M. H., Webster, R., Ouvrier, R., Damiano, J. A., Berkovic, S. F., Shendure, J., Hildebrand, M. S., ... Mefford, H. C. (2013). GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nature Genetics, 45(9), 1073-1076. https://doi.org/10.1038/ng.2727

@article{14d00aa71e244381abbfaa7cd7cc7d4d,

title = "GRIN2A mutations cause epilepsy-aphasia spectrum disorders",

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.",

author = "Carvill, {Gemma L.} and Regan, {Brigid M.} and Yendle, {Simone C.} and O'Roak, {Brian J.} and Natalia Lozovaya and Nadine Bruneau and Nail Burnashev and Adiba Khan and Joseph Cook and Eileen Geraghty and Sadleir, {Lynette G.} and Turner, {Samantha J.} and Tsai, {Meng Han} and Richard Webster and Robert Ouvrier and Damiano, {John A.} and Berkovic, {Samuel F.} and Jay Shendure and Hildebrand, {Michael S.} and Pierre Szepetowski and Scheffer, {Ingrid E.} and Mefford, {Heather C.}",

note = "Funding Information: 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.",

year = "2013",

month = sep,

doi = "10.1038/ng.2727",

language = "English (US)",

volume = "45",

pages = "1073--1076",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

}

Carvill, GL, Regan, BM, Yendle, SC, O'Roak, BJ, Lozovaya, N, Bruneau, N, Burnashev, N, Khan, A, Cook, J, Geraghty, E, Sadleir, LG, Turner, SJ, Tsai, MH, Webster, R, Ouvrier, R, Damiano, JA, Berkovic, SF, Shendure, J, Hildebrand, MS, Szepetowski, P, Scheffer, IE & Mefford, HC 2013, 'GRIN2A mutations cause epilepsy-aphasia spectrum disorders', Nature Genetics, vol. 45, no. 9, pp. 1073-1076. https://doi.org/10.1038/ng.2727

TY - JOUR

T1 - GRIN2A mutations cause epilepsy-aphasia spectrum disorders

AU - Carvill, Gemma L.

AU - Regan, Brigid M.

AU - Yendle, Simone C.

AU - O'Roak, Brian J.

AU - Lozovaya, Natalia

AU - Bruneau, Nadine

AU - Burnashev, Nail

AU - Khan, Adiba

AU - Cook, Joseph

AU - Geraghty, Eileen

AU - Sadleir, Lynette G.

AU - Turner, Samantha J.

AU - Tsai, Meng Han

AU - Webster, Richard

AU - Ouvrier, Robert

AU - Damiano, John A.

AU - Berkovic, Samuel F.

AU - Shendure, Jay

AU - Hildebrand, Michael S.

AU - Szepetowski, Pierre

AU - Scheffer, Ingrid E.

AU - Mefford, Heather C.

N1 - Funding Information: 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.

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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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U2 - 10.1038/ng.2727

DO - 10.1038/ng.2727

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VL - 45

SP - 1073

EP - 1076

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

GRIN2A mutations cause epilepsy-aphasia spectrum disorders

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