Publication

GRIN2A-related disorders: genotype and functional consequence predict phenotype

GRIN2A Study Grp, Strehlow, V., Heyne, H. O., Vlaskamp, D. R. M., Marwick, K. F. M., Rudolf, G., De Bellescize, J., Biskup, S., Brilstra, E. H., Brouwer, O. F., Callenbach, P. M. C., Hentschel, J., Hirsch, E., Kind, P. C., Mignot, C., Platzer, K., Rump, P., Skehel, P. A., Wyllie, D. J. A., Hardingham, G. E., van Ravenswaaij-Arts, C. M. A., Lesca, G. & Lemke, J. R., Jan-2019, In : Brain. 142, 1, p. 80-92 13 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

GRIN2A Study Grp, Strehlow, V., Heyne, H. O., Vlaskamp, D. R. M., Marwick, K. F. M., Rudolf, G., ... Lemke, J. R. (2019). GRIN2A-related disorders: genotype and functional consequence predict phenotype. Brain, 142(1), 80-92. https://doi.org/10.1093/brain/awy304

Author

GRIN2A Study Grp ; Strehlow, Vincent ; Heyne, Henrike O. ; Vlaskamp, Danique R. M. ; Marwick, Katie F. M. ; Rudolf, Gabrielle ; De Bellescize, Julitta ; Biskup, Saskia ; Brilstra, Eva H. ; Brouwer, Oebele F. ; Callenbach, Petra M. C. ; Hentschel, Julia ; Hirsch, Edouard ; Kind, Peter C. ; Mignot, Cyril ; Platzer, Konrad ; Rump, Patrick ; Skehel, Paul A. ; Wyllie, David J. A. ; Hardingham, Giles E. ; van Ravenswaaij-Arts, Conny M. A. ; Lesca, Gaetan ; Lemke, Johannes R. / GRIN2A-related disorders : genotype and functional consequence predict phenotype. In: Brain. 2019 ; Vol. 142, No. 1. pp. 80-92.

Harvard

GRIN2A Study Grp, Strehlow, V, Heyne, HO, Vlaskamp, DRM, Marwick, KFM, Rudolf, G, De Bellescize, J, Biskup, S, Brilstra, EH, Brouwer, OF, Callenbach, PMC, Hentschel, J, Hirsch, E, Kind, PC, Mignot, C, Platzer, K, Rump, P, Skehel, PA, Wyllie, DJA, Hardingham, GE, van Ravenswaaij-Arts, CMA, Lesca, G & Lemke, JR 2019, 'GRIN2A-related disorders: genotype and functional consequence predict phenotype', Brain, vol. 142, no. 1, pp. 80-92. https://doi.org/10.1093/brain/awy304

Standard

GRIN2A-related disorders : genotype and functional consequence predict phenotype. / GRIN2A Study Grp; Strehlow, Vincent; Heyne, Henrike O.; Vlaskamp, Danique R. M.; Marwick, Katie F. M.; Rudolf, Gabrielle; De Bellescize, Julitta; Biskup, Saskia; Brilstra, Eva H.; Brouwer, Oebele F.; Callenbach, Petra M. C.; Hentschel, Julia; Hirsch, Edouard; Kind, Peter C.; Mignot, Cyril; Platzer, Konrad; Rump, Patrick; Skehel, Paul A.; Wyllie, David J. A.; Hardingham, Giles E.; van Ravenswaaij-Arts, Conny M. A.; Lesca, Gaetan; Lemke, Johannes R.

In: Brain, Vol. 142, No. 1, 01.2019, p. 80-92.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

GRIN2A Study Grp, Strehlow V, Heyne HO, Vlaskamp DRM, Marwick KFM, Rudolf G et al. GRIN2A-related disorders: genotype and functional consequence predict phenotype. Brain. 2019 Jan;142(1):80-92. https://doi.org/10.1093/brain/awy304


BibTeX

@article{a79d6404380443818a178d930680eb5e,
title = "GRIN2A-related disorders: genotype and functional consequence predict phenotype",
abstract = "Strehlow et al. describe the largest cohort to date of individuals with GRIN2A-related disorders. The results reveal two phenotypic subgroups associated with different classes of variants affecting distinct domains of the GluN2A protein with different functional consequences. The findings will help predict outcomes in newly diagnosed individuals.Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (mis(TMD+Linker)) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (mis(ATD+LBD)) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10(6)) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where mis(TMD+Linker) predominantly led to NMDAR gain-of-function, while mis(ATD+LBD) exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a(+/) cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and mis(ATD+LBD) of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of mis(TMD+Linker) (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders.",
keywords = "channelopathy, molecular genetics, learning disability, childhood epilepsy, spike-wave EEG, GRIN2A MUTATIONS, NMDA, EPILEPSY, ENCEPHALOPATHY, SUBUNIT, VARIANTS, SPECTRUM, APHASIA, GLUN2A",
author = "{GRIN2A Study Grp} and Vincent Strehlow and Heyne, {Henrike O.} and Vlaskamp, {Danique R. M.} and Marwick, {Katie F. M.} and Gabrielle Rudolf and {De Bellescize}, Julitta and Saskia Biskup and Brilstra, {Eva H.} and Brouwer, {Oebele F.} and Callenbach, {Petra M. C.} and Julia Hentschel and Edouard Hirsch and Kind, {Peter C.} and Cyril Mignot and Konrad Platzer and Patrick Rump and Skehel, {Paul A.} and Wyllie, {David J. A.} and Hardingham, {Giles E.} and {van Ravenswaaij-Arts}, {Conny M. A.} and Gaetan Lesca and Lemke, {Johannes R.} and Alexis Arzimanoglou and Augustijn, {Paul B.} and {Van Bogaert}, Patrick and Helene Bourry and Peter Burfeind and Yoyo Chu and Brian Chung and Diane Doummar and Patrick Edery and Aviva Fattal-Valevski and Melanie Fradin and Marion Gerard and {de Geus}, Christa and Boudewijn Gunning and Danielle Hasaerts and Ingo Helbig and Helbig, {Katherine L.} and Rami Jamra and Lyver, {Melanie Jennesson} and Wassink-Ruiter, {Jolien S. Klein} and Koolen, {David A.} and Damien Lederer and Lunsing, {Roelineke J.} and Mikael Mathot and Helene Maurey and Shay Menascu and Anne Michel and Vos, {Yvonne J.}",
year = "2019",
month = "1",
doi = "10.1093/brain/awy304",
language = "English",
volume = "142",
pages = "80--92",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "1",

}

RIS

TY - JOUR

T1 - GRIN2A-related disorders

T2 - genotype and functional consequence predict phenotype

AU - GRIN2A Study Grp

AU - Strehlow, Vincent

AU - Heyne, Henrike O.

AU - Vlaskamp, Danique R. M.

AU - Marwick, Katie F. M.

AU - Rudolf, Gabrielle

AU - De Bellescize, Julitta

AU - Biskup, Saskia

AU - Brilstra, Eva H.

AU - Brouwer, Oebele F.

AU - Callenbach, Petra M. C.

AU - Hentschel, Julia

AU - Hirsch, Edouard

AU - Kind, Peter C.

AU - Mignot, Cyril

AU - Platzer, Konrad

AU - Rump, Patrick

AU - Skehel, Paul A.

AU - Wyllie, David J. A.

AU - Hardingham, Giles E.

AU - van Ravenswaaij-Arts, Conny M. A.

AU - Lesca, Gaetan

AU - Lemke, Johannes R.

AU - Arzimanoglou, Alexis

AU - Augustijn, Paul B.

AU - Van Bogaert, Patrick

AU - Bourry, Helene

AU - Burfeind, Peter

AU - Chu, Yoyo

AU - Chung, Brian

AU - Doummar, Diane

AU - Edery, Patrick

AU - Fattal-Valevski, Aviva

AU - Fradin, Melanie

AU - Gerard, Marion

AU - de Geus, Christa

AU - Gunning, Boudewijn

AU - Hasaerts, Danielle

AU - Helbig, Ingo

AU - Helbig, Katherine L.

AU - Jamra, Rami

AU - Lyver, Melanie Jennesson

AU - Wassink-Ruiter, Jolien S. Klein

AU - Koolen, David A.

AU - Lederer, Damien

AU - Lunsing, Roelineke J.

AU - Mathot, Mikael

AU - Maurey, Helene

AU - Menascu, Shay

AU - Michel, Anne

AU - Vos, Yvonne J.

PY - 2019/1

Y1 - 2019/1

N2 - Strehlow et al. describe the largest cohort to date of individuals with GRIN2A-related disorders. The results reveal two phenotypic subgroups associated with different classes of variants affecting distinct domains of the GluN2A protein with different functional consequences. The findings will help predict outcomes in newly diagnosed individuals.Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (mis(TMD+Linker)) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (mis(ATD+LBD)) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10(6)) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where mis(TMD+Linker) predominantly led to NMDAR gain-of-function, while mis(ATD+LBD) exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a(+/) cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and mis(ATD+LBD) of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of mis(TMD+Linker) (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders.

AB - Strehlow et al. describe the largest cohort to date of individuals with GRIN2A-related disorders. The results reveal two phenotypic subgroups associated with different classes of variants affecting distinct domains of the GluN2A protein with different functional consequences. The findings will help predict outcomes in newly diagnosed individuals.Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (mis(TMD+Linker)) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (mis(ATD+LBD)) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10(6)) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where mis(TMD+Linker) predominantly led to NMDAR gain-of-function, while mis(ATD+LBD) exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a(+/) cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and mis(ATD+LBD) of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of mis(TMD+Linker) (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders.

KW - channelopathy

KW - molecular genetics

KW - learning disability

KW - childhood epilepsy

KW - spike-wave EEG

KW - GRIN2A MUTATIONS

KW - NMDA

KW - EPILEPSY

KW - ENCEPHALOPATHY

KW - SUBUNIT

KW - VARIANTS

KW - SPECTRUM

KW - APHASIA

KW - GLUN2A

U2 - 10.1093/brain/awy304

DO - 10.1093/brain/awy304

M3 - Article

VL - 142

SP - 80

EP - 92

JO - Brain

JF - Brain

SN - 0006-8950

IS - 1

ER -

ID: 72119887