ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes

作者：Ming‐Feng He, Lihong Liu, Sheng Luo, Juan Wang, Jiajun Guo, Peng‐Yu Wang, Qiong‐Xiang Zhai, Su‐Li He, Dongfang Zou, Xiao‐Rong Liu, Bing-Mei Li, Haiyan Ma, Jing‐Da Qiao, Peng Zhou, Na He, Yong‐Hong Yi, Wei‐Ping Liao · 发表于：Journal of Medical Genetics · 年份：2024 · DOI：10.1136/jmg-2023-109725 · 被引用次数：28 · 研究领域：Genetics and Neurodevelopmental Disorders、Genomics and Rare Diseases、Epilepsy research and treatment

Background The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. Methods Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. Results Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically ...