Common genetic epilepsies, pathogenicity of genes/variants, and genetic dependence

Seizure, Год журнала: 2023, Номер 109, С. 38 - 39

Опубликована: Май 11, 2023

Язык: Английский

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Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation

The American Journal of Human Genetics, Год журнала: 2024, Номер 111(4), С. 761 - 777

Опубликована: Март 18, 2024

Язык: Английский

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Genetic Testing on Epilepsies with Reflex Seizures

Oxford University Press eBooks, Год журнала: 2025, Номер unknown, С. 103 - 126

Опубликована: Март 1, 2025

Abstract Reflex seizures occur in a broad range of epilepsies, including common epilepsies such as idiopathic (or genetic) generalized and more rare epilepsy syndromes progressive myoclonic other monogenic conditions. Idiopathic have polygenic basis, with multiple gene variants contributing to the disorder—but typical clinical presentation, no diagnostic genetic test is indicated. However, several conditions been recognized recent years, intellectual disability reflex seizures, which need be differentiated from epilepsies. Rare include caused by chromosomal abnormalities (e.g., trisomy 21), copy number variants, or single familial adult epilepsy, Dravet syndrome, others photosensitivity, pathogenic varints CACNA1A, CDKL5, CHD2, GNAO1, LGI1, NEXMIF, NOVA2, MECP2, PURA, RORB, SYN1, SYNGAP1). These featuring are at times identified based on their electroclinical characteristics, but confirmed specific testing, ranging karyotyping, microarray analysis, direct Sanger sequencing target gene, next-generation panels genes, trio-based whole exome, genome sequencing. Although choice most appropriate testing it not uncommon for wide-spectrum reveal an underlying abnormality patients even when characteristics do suggest etiology.

Язык: Английский

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Voltage‐gated calcium channels in genetic epilepsies

Journal of Neurochemistry, Год журнала: 2023, Номер unknown

Опубликована: Окт. 11, 2023

Abstract Voltage‐gated calcium channels (VGCC) are abundant in the central nervous system and serve a broad spectrum of functions, either directly cellular excitability or indirectly to regulate Ca 2+ homeostasis. ions act as one main connections excitation–transcription coupling, muscle contraction excitation–exocytosis including synaptic transmission. In recent years, many genes encoding VGCCs α additional auxiliary subunits have been associated with epilepsy. This review sums up current state knowledge on disease mechanisms provides guidance disease‐specific therapies where applicable. image

Язык: Английский

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GLUT1, GGE, and the resilient fallacy of refuted epilepsy genes

Seizure, Год журнала: 2023, Номер 109, С. 97 - 98

Опубликована: Май 25, 2023

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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The landscape of gene loss and missense variation across the mammalian tree informs on gene essentiality

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 19, 2024

ABSTRACT Background The degree of gene and sequence preservation across species provides valuable insights into the relative necessity genes from perspective natural selection. Here, we developed novel interspecies metrics 462 mammalian species, GISMO (Gene identity score orthologs) GISMO-mis (GISMO-missense), to quantify loss traversing millions years evolution. is a measure mammals weighed by evolutionary distance humans, whereas quantifies ratio missense synonymous variants for given gene. Rationale Despite large sample sizes, current human constraint are still not well calibrated short genes. Traversing over 100 million evolution hundreds can identify most essential improve gene-disease association. Beyond genetics, these provide measures further enable genetics research. Results Our analyses showed that both strongly correlated with loss-of-function, missense, copy number dosage derived upwards samples, which highlight power constraint. Importantly, neither nor coding length. Therefore constrained were too small existing capture. We also found scores capture rare variant association signals range phenotypes associated decreased fecundity, such as schizophrenia, autism, neurodevelopmental disorders. Moreover, common heritability disease traits highly enriched in deciles metrics, underscoring biological relevance identifying functionally important have lowest duplication deletion rate UK Biobank, suggesting it may be an metric sensitivity. additionally demonstrate prioritization recessive disorder captures homozygous Conclusions Overall, variation largest fraction heritability, help prioritize genes, conserved tree.

Язык: Английский

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Substantial role of rare inherited variation in individuals with developmental disorders

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 29, 2024

Abstract While the role of de novo and recessively-inherited coding variation in risk for rare developmental disorders (DDs) has been well established, contribution damaging dominantly-inherited from parents is less explored. Here, we investigated variants to DDs by analyzing 13,452 individuals with DDs, 18,613 their family members, 3,943 controls using a combination family-based case/control analyses. In line previous studies other neuropsychiatric traits, found significant burden (allele frequency < 1×10 -5 ) predicted loss-of-function (pLoF) missense variants, vast majority which are inherited apparently unaffected parents. These predominantly burdens strongest DD-associated genes or those intolerant pLoF general population, however estimate that ∼10% excess these DD cases within genes, implying many more loci yet be identified. We similar, but attenuated, when comparing controls, indicating have elevated due overtransmitted affected children. 6-8.5% population attributable population. Finally, apply Bayesian framework combine evidence analyses rare, mostly-inherited prior mutation highlight an additional 25 candidate DD- associated further follow up.

Язык: Английский

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The emerging face of FOXG1 Syndrome: a rare, genetically defined neurodevelopmental disorder coming of age in the genomics era.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Сен. 2, 2024

Background and Objectives FOXG1 Syndrome was first identified in 2005 has been closely associated with Rett Syndrome. However, access to genetic testing an increasing number of patients have that do not fulfill clinical criteria. Utilizing surveys large, severe neurodevelopmental disease (NDD) cohorts, we provide the prevalence estimates independent Methods We performed a systematic review meta-analysis studies conducting extensive on cohorts within last ten years. Fourteen were included, after exclusion outliers biased for patients, providing analysis over 36,000 pediatric total. Results accounted 0.20% [95% CI: 0.15–0.25%] NDD patients. MECP2 CDKL5 0.54% 0.47–0.62%] 0.35% 0.29–0.41%], respectively. This results estimated 0.6–2.2 per 100,000 children or ~ 430–1600 United States. The CDLK5 2.1–7.7 cases female children, 3.2–11.9 children. Conclusions Estimated MECP2-driven comparable based Similarly, CDKL5-driven also earlier study. FOXG1-associated 10 times higher than expected if limited reports data further supports both deficiency represent distinct sizable patient populations as compared MECP2-associated These findings immediate implications improved diagnosis these highlight benefits identifying them.

Язык: Английский

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Oxygen-induced stress reveals context-specific gene regulatory effects in human brain organoids

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 3, 2024

The interaction between genetic variants and environmental stressors is key to understanding the mechanisms underlying neurological diseases. In this study, we used human brain organoids explore how varying oxygen levels expose context-dependent gene regulatory effects. By subjecting a genetically diverse panel of 21 hypoxic hyperoxic conditions, identified thousands changes that are undetectable under baseline with 1,745 trait-associated genes showing effects only in response stress. To capture more nuanced transcriptional patterns, employed topic modeling, which revealed context-specific regulation linked dynamic cellular processes responses, offering deeper modulated brain. These findings underscore importance genotype-environment interactions studies disorders provide new insights into hidden influenced by factors

Язык: Английский

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