Open AccessNovel West syndrome candidate genes in a Chinese cohort
Author(s) -
Peng Jing,
Wang Ying,
He Fang,
Chen Chen,
Wu LiWen,
Yang LiFen,
Ma YuPing,
Zhang Wen,
Shi ZiQing,
Chen Chao,
Xia Kun,
Guo Hui,
Yin Fei,
Pang Nan
Publication year - 2018
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12860
Subject(s) - candidate gene , genetics , exome sequencing , omim : online mendelian inheritance in man , biology , gene , west syndrome , exome , bioinformatics , epilepsy , phenotype , neuroscience
Summary Aims West syndrome (WS) is a classic form of early infantile epileptic encephalopathy (EIEE) characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on electroencephalography. Genetic defects play a critical role in the pathology of WS, and 54 EIEE genes have been identified till date. This study was designed to uncover new candidate genes for West syndrome. Methods In this study, we recruited 56 Chinese families with WS of unknown etiology. Whole exome sequencing (WES) was performed to identify Mendelian inheritance rare or novel variants. The association between candidate genes and WS was analyzed from many aspects, including recurrent genes in patients, predicted variant effect on genes, human tolerance to deficient genes, gene expression in the nervous system, coexpression with EIEE genes, mutual interaction with known EIEE proteins, genes related to ion channel or fragile X mental retardation protein function, and mouse models with manifestation of seizures. Genes with supporting evidence from those aspects were defined as highlight candidate genes. Results Whole exome sequencing identified 112 candidate variants in 89 genes. Among the candidate genes, 33 were autosomal dominant, 22 were autosomal recessive, and 34 were X‐linked. Complex bioinformatic analysis revealed 17 highlight candidate genes: ATP2A2 , CD99L2 , CLCN6 , CYFIP1 , CYFIP2 , GNB1 , GPT2 , HUWE1 , KMT2D , MYO18A , NOS3 , RYR1 , RYR2 , RYR3 , TAF1 , TECTA , and UBA1 . The majority of highlight candidate genes are calcium‐signaling pathway and mental retardation genes. Conclusions This is the first WES study of Chinese WS patients with unknown etiology. This combination of phenotypic and genomic data will enable further testing to elucidate mechanisms underlying the pathogenesis of WS.