RT Journal Article SR Electronic T1 ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 652 OP 660 DO 10.1136/jmg-2023-109725 VO 61 IS 7 A1 He, Ming-Feng A1 Liu, Li-Hong A1 Luo, Sheng A1 Wang, Juan A1 Guo, Jia-Jun A1 Wang, Peng-Yu A1 Zhai, Qiong-Xiang A1 He, Su-Li A1 Zou, Dong-Fang A1 Liu, Xiao-Rong A1 Li, Bing-Mei A1 Ma, Hai-Yan A1 Qiao, Jing-Da A1 Zhou, Peng A1 He, Na A1 Yi, Yong-Hong A1 Liao, Wei-Ping YR 2024 UL http://jmg.bmj.com/content/61/7/652.abstract 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.