TY - JOUR
T1 - De novo GABRA1 mutations in Ohtahara and West syndromes
AU - Kodera, Hirofumi
AU - Ohba, Chihiro
AU - Kato, Mitsuhiro
AU - Maeda, Toshiyuki
AU - Araki, Kaoru
AU - Tajima, Daisuke
AU - Matsuo, Muneaki
AU - Hino-Fukuyo, Naomi
AU - Kohashi, Kosuke
AU - Ishiyama, Akihiko
AU - Takeshita, Saoko
AU - Motoi, Hirotaka
AU - Kitamura, Taro
AU - Kikuchi, Atsuo
AU - Tsurusaki, Yoshinori
AU - Nakashima, Mitsuko
AU - Miyake, Noriko
AU - Sasaki, Masayuki
AU - Kure, Shigeo
AU - Haginoya, Kazuhiro
AU - Saitsu, Hirotomo
AU - Matsumoto, Naomichi
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Objective GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations. Methods In total, 526 and 145 patients with infantile epilepsy were analyzed by whole-exome sequencing and GABRA1-targeted resequencing, respectively. Results We identified five de novo missense GABRA1 mutations in six unrelated patients. A p.R112Q mutation in the long extracellular N-terminus was identified in a patient with infantile epilepsy; p.P260L, p.M263T, and p.M263I in transmembrane spanning domain 1 (TM1) were identified in three unrelated patients with West syndrome and a patient with Ohtahara syndrome, respectively; and p.V287L in TM2 was identified in a patient with unclassified early onset epileptic encephalopathy. Four of these mutations have not been observed previously. Significance Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome.
AB - Objective GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations. Methods In total, 526 and 145 patients with infantile epilepsy were analyzed by whole-exome sequencing and GABRA1-targeted resequencing, respectively. Results We identified five de novo missense GABRA1 mutations in six unrelated patients. A p.R112Q mutation in the long extracellular N-terminus was identified in a patient with infantile epilepsy; p.P260L, p.M263T, and p.M263I in transmembrane spanning domain 1 (TM1) were identified in three unrelated patients with West syndrome and a patient with Ohtahara syndrome, respectively; and p.V287L in TM2 was identified in a patient with unclassified early onset epileptic encephalopathy. Four of these mutations have not been observed previously. Significance Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome.
KW - De novo mutation
KW - Early onset epileptic encephalopathy
KW - GABA receptor
KW - GABRA1
KW - Infantile epilepsy
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U2 - 10.1111/epi.13344
DO - 10.1111/epi.13344
M3 - Article
C2 - 26918889
AN - SCOPUS:84960968522
VL - 57
SP - 566
EP - 573
JO - Epilepsia
JF - Epilepsia
SN - 0013-9580
IS - 4
ER -