Variants in EP400, encoding a chromatin remodeler, cause epilepsy with neurodevelopmental disorders

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

Published: Dec. 20, 2024

Language: Английский

---

De Novo ACTB Variant Associated With Juvenile‐Onset Temporal Lobe Epilepsy With Favorable Outcomes

Human Mutation, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

Genetic factors are estimated to contribute 80% of people with epilepsy. However, only four genes were reported be associated temporal lobe epilepsy (TLE). This study is aimed at investigating the association between ACTB and TLE. Trio‐based exome sequencing was performed in a patient, de novo variant identified. The patient presented TLE featuring by age onset juvenile, seizure‐free status adulthood, complications memory decline irritability, epileptic discharges bilateral lobes, hippocampal sclerosis. pathogenicity identified supposed multiple pieces evidence, including missense tolerance ratio 0%, high conservation affected residue, predicted “damaging” or “conserved” 17 silico tools, classification likely pathogenic American College Medical Genetics Genomics (ACMG) guidelines. Protein modeling indicated alteration protein structure stability caused variant. spatiotemporal expression consistent phenotypic features this patient. suggested that novel candidate causative gene correlation phenotypes spatial–temporal provides perspective for further exploration pathogenesis prognosis disease.

Language: Английский

---

MDN1 variants cause susceptibility to epilepsy

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

---

De novo TANC2 variants caused developmental and epileptic encephalopathy and epilepsy

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

---

De novo KCNK4 variant caused epilepsy with febrile seizures plus, neurodevelopmental abnormalities, and hypertrichosis

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

---

De novo heterozygous missense variants inATP11Aare associated with refractory focal epilepsy

Journal of Medical Genetics, Journal Year: 2025, Volume and Issue: unknown, P. jmg - 110540

Published: April 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.

Language: Английский

---

Designing a Parent-Informed Pediatric Emergency Department Wait Time App: Using Human-Centered Design to Create an Artificial Intelligence Healthcare Tool (Preprint)

Published: Oct. 17, 2024

Waiting has become an unfortunate reality for parents seeking care their child in the emergency department (ED). Long wait times are known to increase morbidity and mortality. Providing patients with information about time increases satisfaction sense of control. There very few patient-facing AI tools currently use EDs, especially that designed caregivers. Our aim was utilize insights from healthcare providers inform design tool provides personalized health during child’s ED visit. The study followed a human-centered methodology. conducted large tertiary care, urban academic children’s hospital. Data were collected by demographic surveys, semi-structured interviews, card sorting, structured observations prototype testing triage nurses. Quantitative data surveys sorting analyzed using descriptive statistics, including means, medians interquartile ranges. Qualitative interviews content analysis creating empathy map. informed tool. implemented improved through iterative rounds improvement. Between May 30, 2023-August 2023, 64 waiting room 5 Parents primarily mothers (59%), college/university graduates (58%) had preferred language English (80%). 100% smart phone 97% used apps on phone. Children median 7 months (IQR 4-12 months) 4 lifetime visits 1->5). qualitative revealed three key themes. Themes development meet needs preferences parents, aiming (1) reduce anxiety uncertainty providing information, (2) provide better understanding process, (3) communicate progress. be informative reassuring companion offering real-time updates, educational content, clear visual representation journey. This employed human-centred approach explore parents' experience pediatric develop improve experience. By prioritizing experiences insights, we have created solution addresses logistical challenges communicating contributes more compassionate efficient environment. implementation this given families control certainty they lacking time. missing gap developing implementing technological innovations clinical space is ensure solutions based need, user-centeredness, acceptability usability.

Language: Английский

---