GRIN2A -related disorders: Genotype and functional consequence predict phenotype

Vincent Strehlow, Henrike O. Heyne, Danique R.M. Vlaskamp, Katie F.M. Marwick, Gabrielle Rudolf, Julitta De Bellescize, Saskia Biskup, Eva H. Brilstra, Oebele F. Brouwer, Petra M.C. Callenbach, Julia Hentschel, Edouard Hirsch, Peter C. Kind, Cyril Mignot, Konrad Platzer, Patrick Rump, Paul A. Skehel, David J.A. Wyllie, Giles E. Hardingham, Conny M.A. Van Ravenswaaij-ArtsGaetan Lesca, Johannes R. Lemke*, Alexis Arzimanoglou, Paul B. Augustijn, Patrick Van Bogaert, Helene Bourry, Peter Burfeind, Yoyo Chu, Brian Chung, Diane Doummar, Patrick Edery, Aviva Fattal-Valevski, Mélanie Fradin, Marion Gerard, Christa De Geus, Boudewijn Gunning, Danielle Hasaerts, Ingo Helbig, Katherine L. Helbig, Rami Jamra, Mélanie Jennesson Lyver, Jolien S.Klein Wassink-Ruiter, David A. Koolen, Damien Lederer, Roelineke J. Lunsing, Mikaël Mathot, Hélène Maurey, Shay Menascu, Anne Michel, Ghayda Mirzaa, Diana Mitter, Hiltrud Muhle, Rikke S. Møller, Caroline Nava, Margaret O'Brien, Evelyn Van Pinxteren-Nagler, Anne Van Riesen, Christelle Rougeot, Damien Sanlaville, Jolanda H. Schieving, Steffen Syrbe, Hermine E. Veenstra-Knol, Nienke Verbeek, Dorothée Ville, Yvonne J. Vos, Pascal Vrielynck, Sabrina Wagner, Sarah Weckhuysen, Marjolein H. Willemsen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)80-92
Number of pages13
Issue number1
StatePublished - 1 Jan 2019


  • channelopathy
  • childhood epilepsy
  • learning disability
  • molecular genetics
  • spike-wave EEG


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