Genetic Dependence and Genetic Diseases

Li, Bin; Bian, Wen-Jun; Zhou, Peng; Wang, Jie; Fan, Cui-Xia; Xu, Hai-Qing; Yu, Lu; He, Na; Shi, Yi-Wu; Su, Tao; Yi, Yong-Hong; Liao, Wei-Ping

doi:10.1101/2023.08.02.551736

Cited by 9 publications

(31 citation statements)

References 33 publications

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“…Our previous study showed that genes differ in expression stage and is potentially correlated with the onset age. 8,28 CCDC88C is expressed in the fetal brain, with an intermission after birth, and increases aging in the adult brain, consistent with the onset age of the patients in this study. In addition, gene expression stage is also potentially associated with evolution of genetic diseases.…”

Section: Clinical Features Of the Cases With Ccdc88c Variantssupporting

confidence: 88%

“…The differences of onset age of seizures are also potentially associated with gene expression stage. Our previous study showed that genes differ in expression stage and is potentially correlated with the onset age 8,28 . CCDC88C is expressed in the fetal brain, with an intermission after birth, and increases aging in the adult brain, consistent with the onset age of the patients in this study.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Clinical Features Of the Cases With Ccdc88c Variantssupporting

confidence: 88%

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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“…Our recent study showed that GDS is associated with the natural course and outcomes of diseases. 14,[34][35][36] 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: 98%

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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“…Among the novel candidate genes, SBF1 presents dominant inheritance (heterozygous de novo variants in three cases), and the remaining majority of candidate genes present recessive inheritance, including XLR. This could be basically understood by the quantitative dependent feature of genes 47,48 . We defined the lowest limit of the required quantity of genetic function of the gene as the genetic dependent quantity (GDQ).…”

Section: Discussionmentioning

confidence: 99%

“…We defined the lowest limit of the required quantity of genetic function of the gene as the genetic dependent quantity (GDQ). If the full scale of GDQ was set at 100% with contributions from two copies of a gene, the genes with GDQ < 50% are much more abundant (https://gdap.org.cn/) 47,48 , since the human genome is diploid and usually a portion of functioning from one copy of a gene is sufficient for biophysiological function. Subsequently, pathogenic recessive (including X-linked recessive) variants are potentially common.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel pathogenic genes of childhood epileptic encephalopathies

Shi¹,

Zhang²,

He³

et al. 2023

Preprint

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Epileptic encephalopathy is a common devastating epilepsy with etiologies remain largely elusive, despite application of whole gene/exon sequencing on large cohorts. This study targeted on childhood epileptic encephalopathy, typically Lennox-Gastaut syndrome that is featured by age-dependent onset and characteristic clinical manifestations. Trio-based whole-exome sequencing with individualized analysis before statistic studies was employed, including individualized analysis on each trio by explainable inheritance origin and stratified frequency filtration and on each gene from four aspects. This study identified three novel candidate genes in 235 patients, includingSBF1withde novovariants in three cases,CELSR2with biallelic recessive variants in eight cases, andTENM1with X-linked recessive variants in six cases. These genes presented significant repetitiveness, including significant higher excess ofde novovariants inSBF1and excess of biallelic variants inCELSR2, and aggregated frequencies of variants inSBF1,CELSR2, andTENM1. The frequency of compound heterozygous/homozygousCELSR2variants in the cases was significantly higher than that in the asymptomatic parent-controls. Further experiments with knock-down/knock-out of these genes showed increased seizure-like behavior and increased firing of excitatory neurons. This study highlights the implication of phenotype sub-classification, individualized analysis in combination with statistic studies, and use of controls for compound heterozygous variants.

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Genetic Dependence and Genetic Diseases

Cited by 9 publications

References 33 publications

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

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

ZFHX3variants cause childhood partial epilepsy and infantile spasms with favorable outcomes

Identification of novel pathogenic genes of childhood epileptic encephalopathies

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