Clinical concordance evaluation of the causality of sequence variants DOI Creative Commons
Peng Zhou, Na He,

Zhi-Jian Lin

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 18, 2023

Abstract Interpreting sequence variants is a scientific challenge as well realistic task in clinical practice. The pathogenicity of variant depends on not only its damage but also the genetic dependent quantity (GDQ, quantitative function required for normal life) that differs each gene was considered previous protocols. We developed concordance evaluation (CCE) framework to evaluate pathogenicity/causality by comparing and features patient with pathogenic candidate genes, including phenotype specificity, genotype, genotype-phenotype (severity) correlation, inheritance, which are associated GDQ. In 337 patients epilepsy testing, 70 were evaluated pathogenic/likely American College Medical Genetics Genomics guidelines (ACMG). CCE identified all these excluded one variant. an additional 13 possibly-causative, likely-causative, two causative variants, homozygous MFSD8 ceroid lipofuscinosis, “uncertain significance” ACMG. individualized criteria clinical/genetic abnormalities individual potentially practical protocol medicine.

Language: Английский

Variants in EP400, encoding a chromatin remodeler, cause epilepsy with neurodevelopmental disorders DOI
Sheng Luo, Pengyu Wang, Peng Zhou

et al.

The American Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 112(1), P. 87 - 105

Published: Dec. 20, 2024

Language: Английский

Citations

8
MDN1 variants cause susceptibility to epilepsy DOI Creative Commons

Q. G. Wen,

Dongming Zhang, Yan Ding

et al.

Acta Epileptologica, Journal Year: 2025, Volume and Issue: 7(1)

Published: March 3, 2025

Abstract Background The Midasin AAA (ATPase associated with various activities) ATPase 1 ( MDN1 ) gene, a member of the protein family, plays crucial role in ribosome maturation. is expressed human brain throughout life, especially during early development and adulthood. However, variants have not been previously reported patients epilepsy. This study aims to explore association between Methods Trios-based whole-exome sequencing was performed cohort epilepsy susceptibility from China Epilepsy Gene 1.0 Project. excess, damaging effects, molecular subregional implications variants, as well spatio-temporal expression , were analyzed validate gene-disease association. Results Compound heterozygous identified five unrelated febrile seizures or secondary Three presented seizures/epilepsy plus, while two developed damage (five seven years after). These either absent present at low frequencies control group, exhibited statistically significant higher case group compared controls. All missense predicted be by least one silico tool. In each pair compound allele located AAA2-AAA3 domains, other linker domain its vicinity. contrast, most asymptomatic outside suggesting implication variants. Conclusions potentially gene for

Language: Английский

Citations

1
CCDC22 variants caused X-linked focal epilepsy and focal cortical dysplasia DOI
Ye He, Yi-Chen Ye,

Peng-Yu Wang

et al.

Seizure, Journal Year: 2024, Volume and Issue: 123, P. 1 - 8

Published: Oct. 12, 2024

Language: Английский

Citations

7
Heterozygous variants in USP25 cause genetic generalized epilepsy DOI

Cui-Xia Fan,

Xiao‐Rong Liu,

Daoqi Mei

et al.

Brain, Journal Year: 2024, Volume and Issue: 147(10), P. 3442 - 3457

Published: June 14, 2024

Abstract USP25 encodes ubiquitin-specific protease 25, a key member of the deubiquitinating enzyme family that is involved in neural fate determination. Although abnormal expression Down's syndrome was reported previously, specific role human diseases has not been defined. In this study, we performed trio-based whole exome sequencing cohort 319 cases (families) with generalized epilepsy unknown aetiology. Five heterozygous variants, including two de novo and three co-segregated were determined eight individuals affected by seizures and/or febrile from five unrelated families. The frequency variants showed significantly high aggregation compared East Asian population all populations gnomAD database. mean age at onset afebrile 10 months (infancy) 11.8 years (juvenile), respectively. patients achieved seizure freedom, except one had occasional nocturnal last follow-up. Two exhibited intellectual disability. Usp25 expressed ubiquitously mouse brain peaks, on embryonic Days 14–16 postnatal Day 21, brain, likewise, fetus/early childhood stage second peak ∼12–20 old, consistent during infancy juveniles. To investigate functional impact deficiency vivo, established knockout mice, which increased susceptibility wild-type mice pentylenetetrazol-induced test. explore used multiple detections. HEK293 T cells, variant associated severe phenotype (p.Gln889Ter) led to significant reduction mRNA protein expressions but formed stable truncated dimers an increment activities cellular aggregations, indicating gain-of-function effect. p.Gln889Ter p.Leu1045del neuronal excitability higher firing ability p.Gln889Ter. These impairments align severity observed phenotypes, suggesting genotype–phenotype correlation. Hence, moderate association between noted, potentially predisposing gene for epilepsy. Our results null patient-derived indicated would play epileptogenic via loss-of-function or effects. have profoundly different effect Together, our underscore significance epilepsy, thereby highlighting critical brain.

Language: Английский

Citations

6
Association of FAT1 with focal epilepsy and correlation between seizure relapse and gene expression stage DOI Creative Commons
Dongfang Zou, Xiaoyan Li,

Xinguo Lu

et al.

Seizure, Journal Year: 2023, Volume and Issue: 116, P. 37 - 44

Published: March 11, 2023

Language: Английский

Citations

14
Common genetic epilepsies, pathogenicity of genes/variants, and genetic dependence DOI Creative Commons
Na He, Bin Li,

Zhi-Jian Lin

et al.

Seizure, Journal Year: 2023, Volume and Issue: 109, P. 38 - 39

Published: May 11, 2023

Language: Английский

Citations

13
RYR3 Variants Are Potentially Associated With Idiopathic (Non‐Lesional) Partial Epilepsy/Susceptibility of Seizures, Toward Understanding the Gene‐Disease Association by Genetic Dependent Nature DOI Open Access

Yang Tian,

Yunqi Hou,

Qiong‐Xiang Zhai

et al.

American Journal of Medical Genetics Part B Neuropsychiatric Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 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.

Language: Английский

Citations

0
De novo TANC2 variants caused developmental and epileptic encephalopathy and epilepsy DOI Open Access
Sheng Luo, Wenjun Zhang,

Mi Jiang

et al.

Epilepsia, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Abstract Objective The TANC2 gene encodes a scaffolding synaptic protein with essential roles in transmission. This study aims to explore the association between and epilepsy mechanism underlying phenotypic variation. Methods Trio‐based exome sequencing was performed patients from China Epilepsy 1.0 cohort. validated Drosophila model. role of development investigated by single‐cell RNA cerebral organoids spatiotemporal expression across brain regions. Results De novo variants were identified six unrelated cases, including four null two missense variants. classified as “pathogenic”/“likely pathogenic,” according American College Medical Genetics Genomics guidelines. Patients exhibited severe phenotypes, three neurodevelopmental disorders (NDDs) one developmental epileptic encephalopathy (DEE). In contrast, presented only epilepsy. Genotype–phenotype correlation analysis revealed that associated NDD mostly variants, whereas or NDD‐associated more damage effects, compared epilepsy‐associated Functional studies suggested knockdown led increased susceptibility seizure‐like behavior. expresses highly brain, peaks early fetal, infancy, adulthood, coinciding onset ages patients. Specifically, highest fetal stage, indicating its vital development. Single‐cell an extensive neurons 1‐month‐old organoids, suggesting neurodevelopment. Significance causative DEE. spectrums potentially ranged lethality, DEE, NDD, mild epilepsy, depending on damaging effects caused

Language: Английский

Citations

0
De novo KCNK4 variant caused epilepsy with febrile seizures plus, neurodevelopmental abnormalities, and hypertrichosis DOI Creative Commons

Hong-Jun Yan,

Wenhui Liu, Min Xu

et al.

Frontiers in Genetics, Journal Year: 2025, Volume and Issue: 16

Published: March 31, 2025

Background Epilepsy with febrile seizures plus (EFS+) is a syndrome strong genetic component. Previously, variants in several genes encoding ion channels have been associated EFS+. However, the etiology majority of patients remains undetermined. Methods Trio-based whole-exome sequencing was performed on patient Previously reported KCNK4 were systemically reviewed to analyze phenotypic spectrum and core phenotypes. Results A novel de novo variant (c.415G>A/p.Gly139Arg) identified EFS+, neurodevelopmental abnormalities, hypertrichosis. The absent normal populations, indicated alter hydrogen bonds surrounding residues by various protein modeling, predicted be damaging for function twenty algorithms, located high conservation across species, classified as pathogenic ACMG guidelines. Protein modeling analyses suggested possible gain-of-function effect. Analysis other eight cases outlined spectrums , ranging from mild benign epilepsy, EFS+ syndromic disorders revealed abnormalities epilepsy its Integrated analysis that minor allele frequency silico meta-predictors effectively distinguish variants. Conclusion This study gene candidate causative which would helpful diagnosis clinical management patients.

Language: Английский

Citations

0
CSMD1 is a causative gene of developmental and epileptic encephalopathy and generalized epilepsies DOI Creative Commons
Wenjun Zhang, Sheng Luo,

Mi Jiang

et al.

Genes & Diseases, Journal Year: 2024, Volume and Issue: unknown, P. 101473 - 101473

Published: Nov. 1, 2024

Language: Английский

Citations

3