ZFHX3variants cause partial epilepsy of childhood and spasms with favorable outcomes

Abstract

AbstractBackground and ObjectivesTheZFHX3gene is highly expressed in the developing brain and plays vital roles in embryonic development, cell proliferation, neuronal differentiation, and neuronal death. The association between theZFHX3gene and human disease was not defined.MethodsWhole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy of childhood. ADrosophila Zfh2knockdown model was used to validate the association betweenZFHX3and epilepsy. The expression profile of theZFHX3ortholog was assessed by RT-qPCR and the data from the Brainspan database.ResultsEight pairs of compound heterozygous variants inZFHX3were identified in eight unrelated cases with partial epilepsies. The identifiedZFXH3variants had low or no frequencies in the populations of gnomAD. TheZFHX3gene presented significantly higher excesses of variants in the case cohort, including a higher excess of biallelic variants than the expected number of East Asian populations, higher aggregated frequencies than that in gnomAD, and a higher frequency of compound heterozygous variants than that in the asymptomatic parent controls. InZfh2knockdown flies, the incidence and duration of seizure-like behavior were significantly higher than those of the controls. TheZfh2knockdown flies exhibited more firing in excitatory neurons than the wild-type line in electrophysiological recordings. All patients withZFHX3compound heterozygous variants presented focal seizures and focal discharges on EEGs. One patient experienced frequent nonconvulsive status epilepticus, and two patients evolved from early spasms; the three cases also had neurodevelopmental abnormalities. However, all patients achieved seizure-free. InDrosophila, the expression ofZfh2is high in larvae and decreased in pupae and early adults. In mice,Zfhx3is predominantly expressed in fetuses and decreases dramatically after birth. In humans, the data from the Brainspan database showed thatZFHX3is highly expressed in the embryonic period and decreased after birth.ConclusionThis study suggested thatZFHX3is potentially a novel causative gene of partial epilepsy of childhood and infantile spasms. The correlation between the outcome and gene expression stage provided insight into the underlying mechanism of the natural course of illness, potentially being helpful in the management of the patients.