Compound-heterozygous GRIN2A null variants associated with severe developmental and epileptic encephalopathy

• Type of Material: Article
• Authors: Vincent Strehlow, University of Leipzig; Claudine Rieubland, University Children's Hospital Inselspital; Sabrina Gallati, University Children's Hospital Inselspital; Sukhan Kim, Emory University; Scott J Myers, Emory University; Vincent Peterson, Emory University; Amy J. Ramsey, University of Toronto; Daniel D. Teuscher, Emory University; Stephen Traynelis, Emory University; Johannes R. Lemke, University of Leipzig
• Language: English
• Date: 2022-08-30
• Publisher: John Wiley and Sons
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
• Final Published Version (URL): https://doi.org/10.1111/epi.17394
• Title of Journal or Parent Work: Epilepsia
• Volume: 63
• Issue: 10
• Start Page: e132
• End Page: e137
• Grant/Funding Information: S.F.T is cofounder of NeurOp Inc and Agrithera Inc, a PI on a research grant from Janssen to Emory, and a member of Advisory Boards for Sage Therapeutics, Eumentis Therapeutics, the GRIN2B Foundation, and the CureGRIN Foundation.; This work was supported by National Institutes of Health National Institute of Neurologic Disorders and Stroke Grants NS111619 (S.F.T.) and NS049666 (S.J.M.). A.J.R. received funding from CureGRIN and CIHR.
• Keywords: recessive; Genetics; Epilepsy
• Research Categories: Biology, Genetics; Biology, Neuroscience

Abstract

We report on an 8-year-old girl with severe developmental and epileptic encephalopathy due to the compound heterozygous null variants p.(Gln661*) and p.(Leu830Profs*2) in GRIN2A resulting in a knockout of the human GluN2A subunit of the N-methyl-D-aspartate receptor. Both parents had less severe GRIN2A-related phenotypes and were heterozygous carriers of the respective null variant. Functional investigations of both variants suggested a loss-of-function effect. This is the first description of an autosomal recessive, bi-allelic type of GRIN2A-related disorder. Still, there are marked parallels to two previously published families with severe epileptic encephalopathy due to homozygous null variants in GRIN1 as well as various knockout animal models. Compared to heterozygous null variants, bi-allelic knockout of either GluN1 or GluN2A is associated with markedly more severe phenotypes in both humans and mice. Furthermore, recent findings enable a potential precision medicine approach targeting GRIN-related disorders due to null variants.