GRIN2A-related disorders: genotype and functional consequence predict phenotype.

1. Januar 2019

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.