SZT2 variants associated with partial epilepsy or epileptic encephalopathy and the genotype-phenotype correlation

Luo, Sheng; Ye, Xingguang; Jin, Liang; Li, Huan; Guan, Bao-Zhu; Gao, Liang‐Di; Liang, Xiaoyu; Wang, P J; Xiao, Lu; Yan, Hong-Jun; Li, Bing-Mei; Chen, Yongjun; Liu, Zhigang

doi:10.3389/fnmol.2023.1162408

Cited by 6 publications

(6 citation statements)

References 25 publications

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“…[47] The Hippo/YAP pathway plays vital roles in multiple stages of neuronal development;[48] while genes in the mTOR pathway, such as TSC1 , TSC2 , DEPDC5 , and SZT2 , have been identified as common genes involved in epilepsy/neurodevelopmental diseases. [6, 49, 50] Dysfunction of ZFHX3 could disrupt the signal transduction of the Hippo/YAP and mTOR pathways and might be involved in neurodevelopmental diseases/epilepsy, which warrant further studies.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

“…54 Several genes of mTOR pathway have been identified as the common genes of epilepsy/neurodevelopmental diseases, such as TSC1, TSC2, DEPDC5, and SZT2 . 6, 54, 55 The malfunctions of ZFHX3 may disrupt the signal transduction of Hippo/YAP and mTOR pathway to be involved in neurodevelopmental diseases/epilepsy, which warrants further studies.…”

Section: Discussionmentioning

confidence: 99%

ZFHX3variants cause childhood partial epilepsy and infantile spasms with favorable outcomes

Luo

Wang

et al. 2023

Preprint

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“…Using the Qiagen Flexi Gene DNA kit (Qiagen, Hilden, Germany), genomic DNAs were extracted. Whole‐exome‐sequencing (WES) was performed using a NextSeq500 sequencing instrument (Illumina, San Diego, CA) as previously described 6–8 . Sequencing data were generated by massively parallel sequencing, where the average depth of captured regions on the microarray was >125× and >98% coverage to obtain high‐quality read segments that were mapped to the Genome Reference Consortium Human genome build 37 by Burrows‐Wheeler alignment.…”

Section: Methodsmentioning

confidence: 99%

“…Then, candidate pathogenic variants, including nonsense, frameshift, initiation codon, canonical splice sites, and missense variants predicted to be damaging by computational algorithms, were retained. The variants in each family were classified based on the following five models: (a) epilepsy‐associated gene model; (b) de novo dominant model; (c) autosomal recessive inheritance model (d) X‐linked model; and (e) co‐segregation analysis model 7–9 . To find novel genes associated genes with epilepsy, the previously known genes were put aside 9 .…”

Section: Methodsmentioning

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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“…To evaluate the relationship between genotype and phenotype, we conducted a comprehensive review of all previously reported GABRA1 mutations and associated clinical information via the PubMed database 9 and the Human Gene Mutation Database (HGMD) 10 until August 2023, likely our previously studies ( Yan et al, 2022 ; Luo et al, 2023 ). Variants with undefined origination or unexplained origination for the occurrence of genetic diseases were excluded.…”

Section: Methodsmentioning

confidence: 99%

De novo GABRA1 variants in childhood epilepsies and the molecular subregional effects

Liu,

Luo,

Zhang

et al. 2024

Front. Mol. Neurosci.

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BackgroundThe GABRA1 gene, encoding the GABRAR subunit α1, plays vital roles in inhibitory neurons. Previously, the GABRA1 gene has been identified to be associated with developmental and epileptic encephalopathy (DEE) and idiopathic generalized epilepsy (IGE). This study aims to explore the phenotypic spectrum of GABRA1 and molecular subregional effect analysis.MethodsTrios-based whole-exome sequencing was performed in patients with epilepsy. Previously reported GABRA1 mutations were systematically reviewed to analyze the molecular subregional effects.ResultsDe novo GABRA1 mutations were identified in six unrelated patients with heterogeneous epilepsy, including three missense mutations (p.His83Asn, p.Val207Phe, and p.Arg214Cys) and one frameshift mutation (p.Thr453Hisfs*47). The two missense mutations, p.His83Asn and p.Val207Phe, were predicted to decrease the protein stability but no hydrogen bond alteration, with which the two patients also presented with mild genetic epilepsy with febrile seizures plus and achieved seizure-free status by monotherapy. The missense variant p.Arg214Cys was predicted to decrease protein stability and destroy hydrogen bonds with surrounding residues, which was recurrently identified in three cases with severe DEE. The frameshift variant p.Thr453Hisfs*47 was located in the last fifth residue of the C-terminus and caused an extension of 47 amino acids, with which the patients presented with moderated epilepsy with generalized tonic-clonic seizures alone (GTCA) but achieved seizure-free status by four drugs. The four variants were not presented in gnomAD and were evaluated as “pathogenic/likely pathogenic” according to ACMG criteria. Analysis of all reported cases indicated that patients with mutations in the N-terminal extracellular region presented a significantly higher percentage of FS and DEE, and the patients with variants in the transmembrane region presented earlier seizure onset ages.SignificanceThis study suggested that GABRA1 variants were potentially associated with a spectrum of epilepsies, including EFS+, DEE, and GTCA. Phenotypic severity may be associated with the damaging effect of variants. The molecular subregional effects help in understanding the underlying mechanism of phenotypic variation.

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SZT2 variants associated with partial epilepsy or epileptic encephalopathy and the genotype-phenotype correlation

Cited by 6 publications

References 25 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

De novo GABRA1 variants in childhood epilepsies and the molecular subregional effects

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