Common genetic epilepsies, pathogenicity of genes/variants, and genetic dependence

He, Na; Li, Bin; Lin, Zhi-Jian; Zhou, Peng; Su, Tao; Liao, Wei‐Ping

doi:10.1016/j.seizure.2023.05.008

Cited by 12 publications

(6 citation statements)

References 15 publications

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“…Recent studies have indicated that the genetic-dependent (expression) stage (GDS) is associated with the natural course and outcomes of illness. 14, 24, 25, 38 We thus analyzed the temporal expression pattern of ZFHX3 orthologs. In Drosophila , the expression of Zfh2 was high in larvae, decreased in pupae and early adults, and increased in later adults ( Figure 5A ).…”

Section: Resultsmentioning

confidence: 99%

“…Our recent study showed that GDS is associated with the natural course and outcomes of diseases. 14,[35][36][37] In this study, the two patients with early spasms presented favorable outcomes. Studies on the temporal expression stage showed that ZFHX3 orthologs were highly expressed in the embryonic stage and decreased dramatically in childhood, which is potentially one of the explanations for the favorable outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Our recent study showed that GDS is associated with the evolutional course and outcomes of diseases. [14, 24] In this study, two patients with early spasms achieved seizure-free after prompt antiepileptic-drug treatment without ACTH/steroids, which were commonly used for treatment of infantile spasms but potentially with severe side effects. The genetic diagnosis thus implies a significance in precise treatment of the patients with ZFHX3 variants.…”

Section: Discussionmentioning

confidence: 99%

“…A Drosophila model with Zfh2 knockdown was established to investigate the association between ZFHX3 and epilepsy. To explore the underlying mechanism of favorable outcomes, the genetic-dependent stages (GDS) 14, 24, 25 of ZFHX3 orthologs were investigated, in which the expression of flies and mice was determined by RT-qPCR and that of humans was analyzed using data from the Brainspan database. This study suggests that the ZFHX3 gene is potentially a novel causative gene of partial epilepsy of childhood and infantile spasms with/without developmental abnormalities.…”

Section: Introductionmentioning

confidence: 99%

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ZFHX3variants cause childhood partial epilepsy and infantile spasms with favorable outcomes

Luo

Wang

et al. 2023

Preprint

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Background: TheZFHX3gene 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 undefined. This study aims to explore the relationship betweenZFHX3variants and epilepsy. Methods: Whole-exome sequencing was performed in patients with partial epilepsy without acquired causes.Drosophilamodel ofZfh2(ortholog ofZFHX3) knockdown was used to validate the association betweenZFHX3and epilepsy. The expression level ofZFHX3in different developmental stages was analyzed by using the data in humans from the Brainspan database and in flies and mice determined by RT-qPCR. Results: Eight pairs of compound heterozygous variants inZFHX3were identified in eight unrelated cases of childhood epilepsies. All patients presented partial epilepsy, including two with early spasms and one with frequent nonconvulsive status epilepticus. The three cases with severe epilepsies also had neurodevelopmental abnormities. However, all patients became seizure-free, including the patients with spasms. These variants had no or low allele frequencies in controls and presented statistically higher frequency in the case cohort than the controls. The number of recessiveZFHX3variants identified in this cohort was significantly more than the expected number of the East Asian population and that of the control of 1942 asymptomatic parents. Variants were predicted to be damaging by protein modeling and/or in silico prediction tools. Genotype-phenotype correlation analysis revealed that the patients with missense variants in C-terminus or C-terminus-truncated variant exhibited mild phenotype (only partial epilepsy). Knockdown ofZfh2in flies led to increased susceptibility to seizures and abnormal firing of excitability neurons. InDrosophila, the expression ofZfh2is high in larvae, decreased in pupae and early adults, and increased in later adults. In mice,Zfhx3is predominantly expressed in fetuses and decreased dramatically after birth. In humans, the data from the Brainspan database showed thatZFHX3is highly expressed in the embryonic period and decreased after birth with a nadir at approximately 10 years old. The dramatical decreasing ofZFHX3in early life correlated with the natural course of the illness. Conclusion:ZFHX3variants were potentially associated with partial epilepsy of childhood and infant 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 management of the patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ZFHX3variants cause childhood partial epilepsy and infantile spasms with favorable outcomes

Luo

Wang

et al. 2023

Preprint

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“…The variable age of onset and the difference in inheritance model could be understood through the relationship of damage (D) of the variant and GDQ (Q) of the gene (http://www.gdap.org.cn). 27 GDQ is defined as the lowest limit of the required quantity of genetic function to maintain the biophysiological function of the gene. A variant is pathogenic when its damage impaired GDQ, and phenotype severity is correlated with the extent of damaging effect of variants.…”

Section: Discussionmentioning

confidence: 99%

CCDC88C variants are associated with focal epilepsy and genotype–phenotype correlation

Chen,

Wang,

Zou

et al. 2024

Clinical Genetics

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CCDC88C gene, which encodes coiled‐coil domain containing 88C, is essential for cell communication during neural development. Variants in the CCDC88C caused congenital hydrocephalus, some accompanied by seizures. In patients with epilepsy without acquired etiologies, we performed whole‐exome sequencing (trio‐based). Two de novo and two biallelic CCDC88C variants were identified in four cases with focal (partial) epilepsy. These variants did not present or had low frequencies in the gnomAD populations and were predicted to be damaging by multiple computational algorithms. Patients with de novo variants presented with adult‐onset epilepsy, whereas patients with biallelic variants displayed infant‐onset epilepsy. They all responded well to anti‐seizure medications and were seizure‐free. Further analysis showed that de novo variants were located at crucial domains, whereas one paired biallelic variants were located outside the crucial domains, and the other paired variant had a non‐classical splicing and a variant located at crucial domain, suggesting a sub‐molecular effect. CCDC88C variants associated with congenital hydrocephalus were all truncated, whereas epilepsy‐associated variants were mainly missense, the proportion of which was significantly higher than that of congenital hydrocephalus‐associated variants. CCDC88C is potentially associated with focal epilepsy with favorable outcome. The underlying mechanisms of phenotypic variation may correlation between genotype and phenotype.

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ARHGAP4 variants are associated with X-linked early-onset temporal lobe epilepsy

Hu,

Song,

Liu

et al. 2024

World J Pediatr

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Common genetic epilepsies, pathogenicity of genes/variants, and genetic dependence

Cited by 12 publications

References 15 publications

ZFHX3variants cause childhood partial epilepsy and infantile spasms with favorable outcomes

ZFHX3variants cause childhood partial epilepsy and infantile spasms with favorable outcomes

CCDC88C variants are associated with focal epilepsy and genotype–phenotype correlation

ARHGAP4 variants are associated with X-linked early-onset temporal lobe epilepsy

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