title: De novo GABRA1 mutations in Ohtahara and West syndromes.
abstract: 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.
  
  
  CONCLUSIONS
  Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kodera
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ohba
authors.affiliation: Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan.|Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Araki
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tajima
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Muneaki
authors.initials: M
authors.lastname: Matsuo
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Hino-Fukuyo
authors.affiliation: Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kohashi
authors.affiliation: Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ishiyama
authors.affiliation: Department of Pediatrics, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Saoko
authors.initials: S
authors.lastname: Takeshita
authors.affiliation: Department of Pediatrics, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Motoi
authors.affiliation: Division of Pediatrics, Sendai City Hospital, Sendai, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Kitamura
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kikuchi
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.|Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haginoya
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D011963:Receptors, GABA-A / Q000235:genetics*; D013036:Spasms, Infantile / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology
chemical_list: C546240:GABRA1 protein, human; D011963:Receptors, GABA-A
keywords: De novo mutation; Early onset epileptic encephalopathy; GABAA receptor; GABRA1; Infantile epilepsy