title: De novo KCNT1 mutations in early-onset epileptic encephalopathy.
abstract: KCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1-targeted next-generation sequencing (207 samples) and/or whole-exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0.56%), and one of 66 unclassified EOEE cases (1.52%). KCNT1 mutations occurred de novo in 10 patients, and one was transmitted from the patient's mother who carried a somatic mosaic mutation. The mutations accumulated in transmembrane segment 5 (2/9, 22.2%) and regulators of K(+) conductance domains (7/9, 77.8%). Five of nine mutations were recurrent. Onset ages ranged from the neonatal period (<1 month) in five patients (5/11, 45.5%) to 1-4 months in six patients (6/11, 54.5%). A generalized attenuation of background activity on electroencephalography was seen in six patients (6/11, 54.5%). Our study demonstrates that the phenotypic spectrum of de novo KCNT1 mutations is largely restricted to EIMFS.
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.|Department of Clinical Neurology and Stroke Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ohba
authors.affiliation: Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.|Department of Pediatrics, Jichi Medical School, Shimotsuke, Tochigi, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.affiliation: Department of Neurology, Gunma Children's Medical Center, Shibukawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiihara
authors.affiliation: Department of Pediatrics, Epilepsy Center, Nishi-Niigata Chuo National Hospital, Niigata, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Tohyama
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Nabatame
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Azuma
authors.affiliation: Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Department of Neonatology, Medical Center for Maternal and Child Health, St. Mary's Hospital, Kurume, Japan.|Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Munetsugu
authors.initials: M
authors.lastname: Hara
authors.affiliation: Department of Pediatrics, Fukuoka University Chikushi Hospital, Fukuoka, Japan.
authors.forename: Reimi
authors.initials: R
authors.lastname: Tsurusawa
authors.affiliation: Department of Pediatrics, Fukuoka University Chikushi Hospital, Fukuoka, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan.
authors.forename: Reina
authors.initials: R
authors.lastname: Ogata
authors.affiliation: Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Neurology, Miyagi Children's Hospital, Sendai, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Togashi
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kodera
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Clinical Neurology and Stroke Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics*; D000081033:Potassium Channels, Sodium-Activated; D013036:Spasms, Infantile / Q000235:genetics*
chemical_list: C585122:KCNT1 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated
keywords: De novo mutation; Early onset epileptic encephalopathies; Epilepsy of infancy with migrating focal seizures; KCNT1