Strehlow V1, Heyne HO1,2,3, Vlaskamp DRM4,5, Marwick KFM6, Rudolf G7,8,9,10, de Bellescize J11, Biskup S12, Brilstra EH13, Brouwer OF4, Callenbach PMC4, Hentschel J1, Hirsch E8,9,10,14, Kind PC6,15,16, Mignot C17,18,19, Platzer K1, Rump P5, Skehel PA6, Wyllie DJA6,15,16, GRIN2A study group, Hardingham GE6,15,20, van Ravenswaaij-Arts CMA5, Lesca G21,22,23, Lemke JR1.
Collaborators: Arzimanoglou A, Augustijn PB, Bogaert PV, Bourry H, Burfeind P, Chu Y, Chung B, Doummar D, Edery P, Fattal-Valevski A, Fradin M, Gerard M, Geus C, Gunning B, Hasaerts D, Helbig I, Helbig KL, Jamra R, Jennesson Lyver M, Klein Wassink-Ruiter JS, Koolen DA, Lederer D, Lunsing RJ, Mathot M, Maurey H, Menascu S, Michel A, Mirzaa G, Mitter D, Muhle H, Møller RS, Nava C, O’Brien M, Pinxteren-Nagler EV, Riesen AV, Rougeot C, Sanlaville D, Schieving JH, Syrbe S, Veenstra-Knol HE, Verbeek N, Ville D, Vos YJ, Vrielynck P, Wagner S, Weckhuysen S, Willemsen MH.
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 (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+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 misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+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 misATD+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 misTMD+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.
- Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, MA, USA.
- Program for Medical and Population Genetics/Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- University of Groningen, University Medical Centre Groningen, Department of Neurology, Groningen, The Netherlands.
- University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, The Netherlands.
- Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, UK.
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France, Centre National de la Recherche Scientifique, U7104, Illirch France.
- Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France.
- Université de Strasbourg, Illkirch, France.
- Department of Neurology, Strasbourg University Hospital, Strasbourg, France
- Department of Pediatric and Clinical Epileptology, Sleep Disorders and Functional Neurology, University Hospitals of Lyon, Lyon, France.
- CeGaT GmbH and Praxis für Humangenetik, Tübingen, Germany.
- University Medical Center Utrecht, Department of Genetics, Utrecht, The Netherlands.
- Medical and Surgical Epilepsy Unit, Hautepierre Hospital, University of Strasbourg, Strasbourg, France.
- Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, UK.
- Centre for Brain Development and Repair, inStem, Bangalore, India.
- Assistance Publique-Hôpitaux de Paris, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
- Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France.
- GRC Sorbonne Université “Déficience Intellectuelle et Autisme”, Paris, France.
- UK Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School, 47 Little France Crescent, Edinburgh, UK.
- Department of Genetics, Lyon University Hospitals, Lyon, France.
- Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.
- Claude Bernard Lyon I University, Lyon, France.