PT - JOURNAL ARTICLE AU - He, Ming-Feng AU - Liu, Li-Hong AU - Luo, Sheng AU - Wang, Juan AU - Guo, Jia-Jun AU - Wang, Peng-Yu AU - Zhai, Qiong-Xiang AU - He, Su-Li AU - Zou, Dong-Fang AU - Liu, Xiao-Rong AU - Li, Bing-Mei AU - Ma, Hai-Yan AU - Qiao, Jing-Da AU - Zhou, Peng AU - He, Na AU - Yi, Yong-Hong AU - Liao, Wei-Ping TI - <em>ZFHX3</em> variants cause childhood partial epilepsy and infantile spasms with favourable outcomes AID - 10.1136/jmg-2023-109725 DP - 2024 Jul 01 TA - Journal of Medical Genetics PG - 652--660 VI - 61 IP - 7 4099 - http://jmg.bmj.com/content/61/7/652.short 4100 - http://jmg.bmj.com/content/61/7/652.full SO - J Med Genet2024 Jul 01; 61 AB - 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 after birth.Conclusion ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.Data are available upon reasonable request. Data may be obtained from a third party and are not publicly available.Raw data were generated at the Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.