TY - JOUR T1 - <em>GRIN2B</em> encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2016-104509 SP - jmedgenet-2016-104509 AU - Konrad Platzer AU - Hongjie Yuan AU - Hannah Schütz AU - Alexander Winschel AU - Wenjuan Chen AU - Chun Hu AU - Hirofumi Kusumoto AU - Henrike O Heyne AU - Katherine L Helbig AU - Sha Tang AU - Marcia C Willing AU - Brad T Tinkle AU - Darius J Adams AU - Christel Depienne AU - Boris Keren AU - Cyril Mignot AU - Eirik Frengen AU - Petter Strømme AU - Saskia Biskup AU - Dennis Döcker AU - Tim M Strom AU - Heather C Mefford AU - Candace T Myers AU - Alison M Muir AU - Amy LaCroix AU - Lynette Sadleir AU - Ingrid E Scheffer AU - Eva Brilstra AU - Mieke M van Haelst AU - Jasper J van der Smagt AU - Levinus A Bok AU - Rikke S Møller AU - Uffe B Jensen AU - John J Millichap AU - Anne T Berg AU - Ethan M Goldberg AU - Isabelle De Bie AU - Stephanie Fox AU - Philippe Major AU - Julie R Jones AU - Elaine H Zackai AU - Rami Abou Jamra AU - Arndt Rolfs AU - Richard J Leventer AU - John A Lawson AU - Tony Roscioli AU - Floor E Jansen AU - Emmanuelle Ranza AU - Christian M Korff AU - Anna-Elina Lehesjoki AU - Carolina Courage AU - Tarja Linnankivi AU - Douglas R Smith AU - Christine Stanley AU - Mark Mintz AU - Dianalee McKnight AU - Amy Decker AU - Wen-Hann Tan AU - Mark A Tarnopolsky AU - Lauren I Brady AU - Markus Wolff AU - Lutz Dondit AU - Helio F Pedro AU - Sarah E Parisotto AU - Kelly L Jones AU - Anup D Patel AU - David N Franz AU - Rena Vanzo AU - Elysa Marco AU - Judith D Ranells AU - Nataliya Di Donato AU - William B Dobyns AU - Bodo Laube AU - Stephen F Traynelis AU - Johannes R Lemke Y1 - 2017/04/04 UR - http://jmg.bmj.com/content/early/2017/04/03/jmedgenet-2016-104509.abstract N2 - 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. ER -