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GRIN2D variants in three cases of developmental and epileptic encephalopathy
Author(s) -
Tsuchida Naomi,
Hamada Keisuke,
Shiina Masaaki,
Kato Mitsuhiro,
Kobayashi Yu,
Tohyama Jun,
Kimura Kazue,
Hoshino Kyoko,
Ganesan Vigneswari,
Teik Keng W.,
Nakashima Mitsuko,
Mitsuhashi Satomi,
Mizuguchi Takeshi,
Takata Atsushi,
Miyake Noriko,
Saitsu Hirotomo,
Ogata Kazuhiro,
Miyatake Satoko,
Matsumoto Naomichi
Publication year - 2018
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13454
Subject(s) - missense mutation , nmda receptor , epilepsy , exome sequencing , glutamate receptor , neuroscience , encephalopathy , biology , loss function , receptor , genetics , mutation , medicine , phenotype , gene
N ‐methyl‐ d ‐aspartate (NMDA) receptors are glutamate‐activated ion channels that are widely distributed in the central nervous system and essential for brain development and function. Dysfunction of NMDA receptors has been associated with various neurodevelopmental disorders. Recently, a de novo recurrent GRIN2D missense variant was found in two unrelated patients with developmental and epileptic encephalopathy. In this study, we identified by whole exome sequencing novel heterozygous GRIN2D missense variants in three unrelated patients with severe developmental delay and intractable epilepsy. All altered residues were highly conserved across vertebrates and among the four GluN2 subunits. Structural consideration indicated that all three variants are probably to impair GluN2D function, either by affecting intersubunit interaction or altering channel gating activity. We assessed the clinical features of our three cases and compared them to those of the two previously reported GRIN2D variant cases, and found that they all show similar clinical features. This study provides further evidence of GRIN2D variants being causal for epilepsy. Genetic diagnosis for GluN2‐related disorders may be clinically useful when considering drug therapy targeting NMDA receptors.