RT Journal Article SR Electronic T1 GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2016-104509 DO 10.1136/jmedgenet-2016-104509 A1 Konrad Platzer A1 Hongjie Yuan A1 Hannah Schütz A1 Alexander Winschel A1 Wenjuan Chen A1 Chun Hu A1 Hirofumi Kusumoto A1 Henrike O Heyne A1 Katherine L Helbig A1 Sha Tang A1 Marcia C Willing A1 Brad T Tinkle A1 Darius J Adams A1 Christel Depienne A1 Boris Keren A1 Cyril Mignot A1 Eirik Frengen A1 Petter Strømme A1 Saskia Biskup A1 Dennis Döcker A1 Tim M Strom A1 Heather C Mefford A1 Candace T Myers A1 Alison M Muir A1 Amy LaCroix A1 Lynette Sadleir A1 Ingrid E Scheffer A1 Eva Brilstra A1 Mieke M van Haelst A1 Jasper J van der Smagt A1 Levinus A Bok A1 Rikke S Møller A1 Uffe B Jensen A1 John J Millichap A1 Anne T Berg A1 Ethan M Goldberg A1 Isabelle De Bie A1 Stephanie Fox A1 Philippe Major A1 Julie R Jones A1 Elaine H Zackai A1 Rami Abou Jamra A1 Arndt Rolfs A1 Richard J Leventer A1 John A Lawson A1 Tony Roscioli A1 Floor E Jansen A1 Emmanuelle Ranza A1 Christian M Korff A1 Anna-Elina Lehesjoki A1 Carolina Courage A1 Tarja Linnankivi A1 Douglas R Smith A1 Christine Stanley A1 Mark Mintz A1 Dianalee McKnight A1 Amy Decker A1 Wen-Hann Tan A1 Mark A Tarnopolsky A1 Lauren I Brady A1 Markus Wolff A1 Lutz Dondit A1 Helio F Pedro A1 Sarah E Parisotto A1 Kelly L Jones A1 Anup D Patel A1 David N Franz A1 Rena Vanzo A1 Elysa Marco A1 Judith D Ranells A1 Nataliya Di Donato A1 William B Dobyns A1 Bodo Laube A1 Stephen F Traynelis A1 Johannes R Lemke YR 2017 UL http://jmg.bmj.com/content/early/2017/04/03/jmedgenet-2016-104509.abstract AB 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.