Novel West syndrome candidate genes in a Chinese cohort

<jats:title>Summary</jats:title><jats:sec><jats:title>Aims</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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: <jats:italic>ATP2A2</jats:italic>,<jats:italic> CD99L2</jats:italic>,<jats:italic> CLCN6</jats:italic>,<jats:italic> CYFIP1</jats:italic>,<jats:italic> CYFIP2</jats:italic>,<jats:italic> GNB1</jats:italic>,<jats:italic> GPT2</jats:italic>,<jats:italic> HUWE1</jats:italic>,<jats:italic> KMT2D</jats:italic>,<jats:italic> MYO18A</jats:italic>,<jats:italic> NOS3</jats:italic>,<jats:italic> RYR1</jats:italic>,<jats:italic> RYR2</jats:italic>,<jats:italic> RYR3</jats:italic>,<jats:italic> TAF1</jats:italic>,<jats:italic> TECTA</jats:italic>, and <jats:italic>UBA1</jats:italic>. The majority of highlight candidate genes are calcium‐signaling pathway and mental retardation genes.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec>