Identification of novel causative genes of childhood epileptic encephalopathies

作者：Yi‐Wu Shi, Jianguo Zhang, Zi-Long Ye, Na He, Wenbin Li, Hankui Liu, Zhi-Gang Liu, Nan-Xiang Shen, Xiao-Chong Qu, Cui-Xia Fan, Jie Wang, Sheng Luo, Yudan Lv, Li Gao, Jing Chen, Shaoping Huang, Xinguo Lu, Jing Yu, Jie Zhang, Xiuxia Wang, Quwen Gao, Li Jiang, Yanhui Chen, Hui Qi, Jing‐Da Qiao, Lizhi Chen, Yuan-Jin Zeng, Xiaoxue Yang, Hong-Jun Yan, Chengyan Li, Tao Zeng, Fuli Min, Bing Qin, Haiqing Xu, Lin Xu, Bing-Mei Li, Yong‐Hong Yi, Zhihong Zhuo, Qing-Hui Guo, Su‐Li He, Hongwei Zhang, Liping Guan, Wei‐Yi Deng, Xiaofan Ren, Dongfang Zou, Weiyue Gu, Tao Su, Xiao‐Rong Liu, Yibo Qu, Xinping Yang, Wei‐Ping Liao · 发表于：medRxiv · 年份：2023 · DOI：10.1101/2023.07.25.23293037 · 被引用次数：8 · 研究领域：Epilepsy research and treatment、Genetics and Neurodevelopmental Disorders、Genomics and Rare Diseases

Background and Objectives: Epileptic encephalopathy is a devastating epilepsy with etiologies largely elusive, despite recent whole gene/exon sequencing on large cohorts. This study targeted on the genetic causes of childhood epileptic encephalopathy, typically Lennox-Gastaut syndrome (LGS) featured by age-dependent onset and characteristic clinical manifestations. Methods: Trio-based whole-exome sequencing was performed in 241 unrelated cases from 21 epilepsy centers through China Epilepsy Gene 1.0 Project with individualized analyses on each trio by explainable inheritance origin with stratified frequency filtration, on each gene in four aspects that include gene expression in the brain, previously reported phenotypes, pLI/pRec/Z-missense index, and genetic knockout/knockdown phenotypes, followed by multiple/specific statistical analyses depending on the inheritance pattern of variants, including the establishment of controls for analysis of compound heterozygous variants. Results: Three genes presented highly repetitive variants with statistical significances, including SBF1 with de novo, CELSR2 with recessive, and TENM1 with X-linked recessive variants. The frequency of compound heterozygous/homozygous CELSR2 variants in the cases was significantly higher than that in 1942 asymptomatic parent controls. The variants located at functional domains in SBF1 and TENM1, and homozygous/compound heterozygous variants with one of the paired variants located in functional domains in...