ZFHX3variants cause childhood partial epilepsy and infantile spasms with favorable outcomes

ABSTRACT 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 behavior 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 nonconvulsive 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 orthologs 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. WHAT IS ALREADY KNOWN ON THIS TOPIC The ZFHX3 protein plays an essential role in neurodevelopment. The relationship between ZFHX3 variants and human diseases remains unknown. WHAT THIS STUDY ADDS Eight pairs of compound heterozygous ZFHX3 variants were identified in eight unrelated patients with partial epilepsy, including two who evolved from early spasms. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY The ZFHX3 gene is a novel pathogenic gene of childhood partial epilepsy and developmental epileptic encephalopathy. The development-dependent expression pattern of ZFHX3 explains the evolutional course of the illness, potentially being helpful in the management of the patients.