title: WDR45 mutations in three male patients with West syndrome.
abstract: West syndrome is an early-onset epileptic encephalopathy characterized by clustered spasms with hypsarrhythmia seen on electroencephalogram (EEG). West syndrome is genetically heterogeneous, and its genetic causes have not been fully elucidated. WD Repeat Domain 45 (WDR45) resides on Xp11.23, and encodes a member of the WD repeat protein interacting with phosphoinositides (WIPI) family, which is crucial in the macroautophagy pathway. De novo mutations in WDR45 cause beta-propeller protein-associated neurodegeneration characterized by iron accumulation in the basal ganglia. In this study, we performed whole exome sequencing of individuals with West syndrome and identified three WDR45 mutations in three independent males (patients 1, 2 and 3). Two novel mutations occurred de novo (patients 1 and 2) and the remaining mutation detected in a male patient (patient 3) and his affected sister was inherited from the mother, harboring the somatic mutation. The three male patients showed early-onset intractable seizures, profound intellectual disability and developmental delay. Their brain magnetic resonance imaging scans showed cerebral atrophy. We found no evidence of somatic mosaicism in the three male patients. Our findings indicate that hemizygous WDR45 mutations in males lead to severe epileptic encephalopathy.
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: Division of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan.|Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takano
authors.affiliation: Division of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tsuyusaki
authors.affiliation: Department of Pediatrics, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Yoshitomi
authors.affiliation: Department of Pediatrics, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimono
authors.affiliation: Department of Pediatrics, Asahi General Hospital, Asahi, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Aoki
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 Radiology, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Aida
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mizuguchi
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
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: Division of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan.|Department of Pediatrics, Jichi Medical University, Tochigi, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.|Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Hirotomo
authors.identifier: http://orcid.org/0000-0003-0723-0960
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: D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D059472:Exome; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013036:Spasms, Infantile / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C578284:WDR45 protein, human