ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes

Journal of Medical Genetics, Год журнала: 2024, Номер 61(7), С. 652 - 660

Опубликована: Март 20, 2024

Background The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and death. This study aims to explore the relationship between variants epilepsy. Methods Whole-exome sequencing was performed a cohort of 378 patients with partial (focal) A Drosophila Zfh2 knockdown model used validate association Results Compound heterozygous were identified eight unrelated cases. burden significantly higher case cohort, shown by multiple/specific statistical analyses. In flies, incidence duration seizure-like behaviour greater than those controls. flies exhibited more firing excitatory neurons. All presented seizures. five C-terminus/N-terminus mild other three included one who experienced frequent non-convulsive status epilepticus two had early spasms. These also neurodevelopmental abnormalities diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. analyses temporal expression (genetic dependent stages) indicated that orthologous highly expressed stage decreased dramatically birth. Conclusion is novel causative childhood epilepsy DEE. infantile spasms adrenocorticotropic-hormone/steroids implies significance genetic diagnosis precise treatment. provided an insight into underlying mechanism evolutional course illness.

Язык: Английский

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Genetic Dependence and Genetic Diseases

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 5, 2023

Abstract The human life depends on the function of proteins that are encoded by about twenty-thousand genes. gene-disease associations in majority genes unknown and mechanisms underlying pathogenicity genes/variants common diseases remain unclear. We studied how genes, i.e., genetic-dependence, which was classified as genetic-dependent nature (GDN, vital consequence abolishing a gene), quantity (GDQ, quantitative genetic required for normal life), stage (GDS, temporal expression pattern). Each gene differs features, determines association extensively. GDN is associated with pathogenic potential/feature strength pathogenicity. GDQ-damage relation variants subsequently genotype, phenotype spectrum, inheritance variants. GDS mainly onset age/evolution/outcome disorders (disease/susceptibility). varied feature genome explains mild phenotype/susceptibility. genetic-dependence discloses gene/variants diseases. One sentence summary Genetic dependent clinical features

Язык: Английский

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RYR3 Variants Are Potentially Associated With Idiopathic (Non‐Lesional) Partial Epilepsy/Susceptibility of Seizures, Toward Understanding the Gene‐Disease Association by Genetic Dependent Nature

American Journal of Medical Genetics Part B Neuropsychiatric Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

The RYR3 gene encodes a brain-type ryanodine receptor that functions to release calcium from intracellular storage and plays an essential role in signaling. associations between variants brain disorders remain unknown. We performed whole-exome sequencing patients with idiopathic (non-lesional) partial epilepsy of unknown etiology. One de novo missense six biallelic were identified seven unrelated cases. These had no or extremely low allele frequencies the general population predicted alter hydrogen bonds/decrease protein stability. Patients presented seizures secondarily generalized tonic-clonic seizures. All seizure-free with/without anti-seizure treatment. Four showed antecedent febrile seizures, typical susceptibility disorder is related precipitating factor fever. genetic dependence nature (GDN) RYR3, which defined as distinct impact absence on normal life, "obligatory" (causing disease phenotypes). Complete abolishing results abnormal phenotypes instead lethality, whereas partial/mild impairment (usually more common) associated mild increased disease, consistent our findings. therefore potentially candidate for epilepsy.

Язык: Английский

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De novo heterozygous missense variants inATP11Aare associated with refractory focal epilepsy

Journal of Medical Genetics, Год журнала: 2025, Номер unknown, С. jmg - 110540

Опубликована: Апрель 4, 2025

Background ATP11A encodes an integral-membrane type IV P-type-adenosine triphosphatase that plays important role in neural development by maintaining membrane lipid asymmetry. de novo heterozygous missense variants have been reported to be associated with hypomyelinating leukodystrophy; however, the neurological symptoms of patients are often varying. In this study, we aimed explore relationship between and epilepsy. Methods Trio-based whole-exome sequencing was performed on focal Multiple bioinformatics analyses were used predict pathogenicity variants. Previously literature collected analyse relation phenotypes. Results Two identified two unrelated refractory epilepsy predicted pathogenic using multiple analyses. Then, six collected. Half (3/6) located on/near transmembrane regions (TMs) had more severe symptoms, while other half non-TM mild single indicating a correlation variant location phenotype. All showed progressively worsening conditions, potentially due gradually increased expression human brain over time. Conclusion This study suggested Missense variant-associated phenotypes range from epileptic seizures symptoms. It should noted potential.

Язык: Английский

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SLC2A1 variants cause late-onset epilepsy and the genetic-dependent stage feature

Acta Epileptologica, Год журнала: 2024, Номер 6(1)

Опубликована: Ноя. 7, 2024

Abstract Background The SLC2A1 gene plays a vital role in brain energy metabolism. variants have been reported to be associated with early-onset refractory seizures. This study aims explore the association between and late-onset epilepsy. Methods Trios-based whole-exome sequencing was performed on patients epilepsy without acquired etiologies. pathogenicity of assessed according American College Medical Genetics Genomics (ACMG) guidelines. Results A total 14 heterozygous were identified 16 unrelated families. evaluated as “pathogenic” or “likely pathogenic” ACMG Ten cases (62.5%) presented infantile onset seizures developmental delay/intellectual disability diagnosed epileptic encephalopathy (DEE). other six (37.5%) exhibited normal development. They idiopathic partial ( n = 2) generalized 4). Further analysis showed that DEE-associated tended cluster transmembrane region, whereas mild epilepsy-associated locate regions outside suggesting potential molecular sub-regional effect. 15 had delayed diagnosis, longest delay being 22 years. expression stage, which is expressed at relatively high level throughout whole life span, from embryonic adult stages two peaks approximately four years, generally consistent seizure age. In addition, age potentially severe damage, correlation disease damaging effects variants. Conclusions are epilepsy, genetic-dependent stage feature . Early genetic diagnosis important for treatment

Язык: Английский

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CSMD1 is a causative gene of developmental and epileptic encephalopathy and generalized epilepsies

Genes & Diseases, Год журнала: 2024, Номер unknown, С. 101473 - 101473

Опубликована: Ноя. 1, 2024

Язык: Английский

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

World Journal of Pediatrics, Год журнала: 2024, Номер 20(8), С. 859 - 867

Опубликована: Июль 26, 2024

Язык: Английский

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Identification of novel pathogenic genes of childhood epileptic encephalopathies

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июль 27, 2023

Abstract Background Epileptic encephalopathy is a devastating epilepsy with etiologies largely elusive, despite whole-gene/exon sequencing of large cohorts. This study targeted the genetic causes childhood epileptic encephalopathy, typically Lennox-Gastaut syndrome (LGS) featured by age-dependent onset and characteristic clinical manifestations. Methods Trio-based whole-exome was performed in 235 LGS cases individualized analyses on each trio explainable inheritance origin stratified frequency filtration gene four aspects, specified statistical including that compound heterozygous variants controls 1942 asymptomatic parents. Animal models were used to validate roles novel candidate genes. Results We identified three causative genes, SBF1 de novo , CELSR2 recessive, TENM1 X-linked recessive variants. Significantly higher excesses biallelic variants, aggregated variant frequencies detected. Phenotype severity/outcome correlated genotype these In Drosophila knockdown genes showed increased seizure-like behavior firing excitatory neurons. Sbf1 knockout zebrafish behavior, premature death, Celsr2 mice spontaneous seizures epileptiform discharges. Additional 42 as pathogenic evidence aspects/statistics. Conclusions suggests are highlights implications phenotype subclassification protocol identifying human diseases.

Язык: Английский

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IFIH1 variants are associated with generalised epilepsy preceded by febrile seizures

Journal of Medical Genetics, Год журнала: 2024, Номер 61(9), С. 895 - 903

Опубликована: Июль 4, 2024

variants have been reported to be associated with immune-related disorders with/without seizures. It is unknown whether

Язык: Английский

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ZFHX3variants cause childhood partial epilepsy and infantile spasms with favorable outcomes

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июль 18, 2023

ABSTRACT Background The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation, and death. This study aims to explore the relationship between variants epilepsy. Methods Whole-exome sequencing was performed a cohort of 378 patients with partial (focal) A Drosophila Zfh2 knockdown model used validate association Results Compound heterozygous were identified eight unrelated cases. burden significantly higher case cohort, shown by multiple/specific statistical analyses. In flies, incidence duration seizure-like behavior greater than those controls. flies exhibited more firing excitatory neurons. All presented seizures. five C-terminus/N-terminus mild other three included one who experienced frequent nonconvulsive status epilepticus two had early spasms. These also neurodevelopmental abnormalities diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. analyses temporal expression (genetic dependent stages) indicated that orthologs highly expressed stage decreased dramatically birth. Conclusion is novel causative childhood epilepsy DEE. infantile spasms adrenocorticotropic-hormone/steroids implies significance genetic diagnosis precise treatment. provided an insight into underlying mechanism evolutional course illness. WHAT IS ALREADY KNOWN ON THIS TOPIC protein essential role neurodevelopment. human diseases remains unknown. STUDY ADDS Eight pairs compound epilepsy, including evolved from HOW MIGHT AFFECT RESEARCH, PRACTICE OR POLICY pathogenic encephalopathy. development-dependent pattern explains illness, potentially being helpful management patients.

Язык: Английский

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