title: Genomic analysis identifies candidate pathogenic variants in 9 of 18 patients with unexplained West syndrome.
abstract: West syndrome, which is narrowly defined as infantile spasms that occur in clusters and hypsarrhythmia on EEG, is the most common early-onset epileptic encephalopathy (EOEE). Patients with West syndrome may have clear etiologies, including perinatal events, infections, gross chromosomal abnormalities, or cases followed by other EOEEs. However, the genetic etiology of most cases of West syndrome remains unexplained. DNA from 18 patients with unexplained West syndrome was subjected to microarray-based comparative genomic hybridization (array CGH), followed by trio-based whole-exome sequencing in 14 unsolved families. We identified candidate pathogenic variants in 50% of the patients (n = 9/18). The array CGH revealed candidate pathogenic copy number variations in four cases (22%, 4/18), including an Xq28 duplication, a 16p11.2 deletion, a 16p13.1 deletion and a 19p13.2 deletion disrupting CACNA1A. Whole-exome sequencing identified candidate mutations in known epilepsy genes in five cases (36%, 5/14). Three candidate de novo mutations were identified in three cases, with two mutations occurring in two new candidate genes (NR2F1 and CACNA2D1) (21%, 3/14). Hemizygous candidate mutations in ALG13 and BRWD3 were identified in the other two cases (14%, 2/14). Evaluating a panel of 67 known EOEE genes failed to identify significant mutations. Despite the heterogeneity of unexplained West syndrome, the combination of array CGH and whole-exome sequencing is an effective means of evaluating the genetic background in unexplained West syndrome. We provide additional evidence for NR2F1 as a causative gene and for CACNA2D1 and BRWD3 as candidate genes for West syndrome.
authors: Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors: Naomi
authors: N
authors: Hino-Fukuyo
authors: Atsuo
authors: A
authors: Kikuchi
authors: Natsuko
authors: N
authors: Arai-Ichinoi
authors: Tetsuya
authors: T
authors: Niihori
authors: Ryo
authors: R
authors: Sato
authors: Tasuku
authors: T
authors: Suzuki
authors: Hiroki
authors: H
authors: Kudo
authors: Yuko
authors: Y
authors: Sato
authors: Tojo
authors: T
authors: Nakayama
authors: Yosuke
authors: Y
authors: Kakisaka
authors: Yuki
authors: Y
authors: Kubota
authors: Tomoko
authors: T
authors: Kobayashi
authors: Ryo
authors: R
authors: Funayama
authors: Keiko
authors: K
authors: Nakayama
authors: Mitsugu
authors: M
authors: Uematsu
authors: Yoko
authors: Y
authors: Aoki
authors: Kazuhiro
authors: K
authors: Haginoya
authors: Shigeo
authors: S
authors: Kure
mesh_terms: D051838:COUP Transcription Factor I / Q000235:genetics*; D015220:Calcium Channels / Q000235:genetics*; D002877:Chromosomes, Human / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D057898:Hemizygote; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D013036:Spasms, Infantile / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D000092468:Bromodomain Containing Proteins
chemical_list: D051838:COUP Transcription Factor I; D015220:Calcium Channels; D017351:N-Acetylglucosaminyltransferases; D014157:Transcription Factors; C502037:BRWD3 protein, human; D000092468:Bromodomain Containing Proteins; C425903:CACNA2D1 protein, human; C497589:NR2F1 protein, human; C583889:ALG13 protein, human