Background We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine.
Methods Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care.
Results Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated.
Conclusions In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.
- epileptic encephalopathy
- pathogenic GRIN2B mutations
- clustering of missense variants
- precision medicine
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Contributors KP, HOY, BIL, SFT, JRL conceived the project. KP, KLH, ST, MCW, BTT, DJA, CD, BK, CM, EF, SB, DD, TMS, HCM, CTM, AMM, AL, LS, IES, EB, LAB, RSM, UBJ, JJM, ATB, EMG, IDB, SF, PM, JRJ, EHZ, RAJ, AR, RJL, JL, TR, FEJ, ER, CMK, MMvH, JJvdS, AEL, CC, TL, DRS, CS, MM, DM, AD, WHT, MAT, BIL, MW, LD, SEP, KLJ, ADP, DNF, RV, EM, JDR, ND, WBD, SFT, JRL recruited and phenotyped patients. HY, HS, AW, WC, CH, HK, BIL, SFT performed in vitro experiments. KP, HY, HS, AW, WC, CH, HK, HOH, ND, WBD, BL, SFT, JRL performed data analysis and statistics. KP, HY, SFT, JRL wrote the manuscript. All authors edited the manuscript.
Funding Funding for the project was provided by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R01HD082373 to HY), by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454 (to HY), and by the National Institute of Neurological Disorders and Stroke (NS036654, R01NS065371 and R24NS092989 to SFT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Additional funding was received from the Australian NHMRC (512123 to TR), NIH NINDS training grant (K12 NS049453 to EMG), Cure Kids NZ to LS and the SNSF Early Postdoc fellowship (P2SKP3_164945 to CC).
Funding for the DECIPHER project was provided by the Wellcome Trust.
Competing interests SFT is a consultant of Janssen Pharmaceuticals, Inc., Pfizer Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, and co-founder of NeurOp Inc.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from and via email from email@example.com.