<scp>Genes4Epilepsy</scp>: An epilepsy gene resource

Oliver, Karen; Scheffer, Ingrid E.; Bennett, Mark F; Grinton, Bronwyn E.; Bahlo, Melanie; Berkovic, Samuel F.

doi:10.1111/epi.17547

Cited by 44 publications

(35 citation statements)

References 26 publications

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“…The developmental and epileptic encephalopathies (DEEs) are a group of severe early onset disorders usually characterized by multiple seizure types, abundant epileptiform activity, and developmental slowing, plateau, or regression 1,2 . The DEEs are clinically and genetically heterogeneous, with the number of genes implicated now into the hundreds 3–5 . Although de novo pathogenic variants in autosomal dominant DEE genes are most commonly implicated, 6 WWOX has emerged as an important, albeit rare, autosomal recessive cause.…”

Section: Introductionmentioning

confidence: 99%

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk

et al. 2023

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Objective WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (WWOX‐DEE), also known as WOREE (WWOX‐related epileptic encephalopathy). We analyzed the epileptology and imaging features of WWOX‐DEE, and investigated genotype–phenotype correlations, particularly with regard to survival. Methods We studied 13 patients from 12 families with WWOX‐DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense, allowing individuals to be classified into one of three genotype classes: (1) null/null, (2) null/missense, (3) missense/missense. Differences in survival outcome were estimated using the Kaplan–Meier method. Results All patients experienced multiple seizure types (median onset = 5 weeks, range = 1 day–10 months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic (n = 5), myoclonic (n = 2), epileptic spasms (n = 2), focal (n = 1), and migrating focal (n = 1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo‐occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p‐value = .0085, log‐rank test). Significance Biallelic WWOX pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.

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Section: Introductionmentioning

confidence: 99%

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk

et al. 2023

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“…The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies, defined by frequent epileptiform activity associated with developmental slowing or regression 1 . While each genetic etiology is rare, with more than 825 genes implicated 2 , the cumulative incidence of DEEs overall is 1 in 590 children 3 . Currently, de novo, X-linked, or recessively inherited pathogenic germline variants are found in ∼50% of individuals with DEEs who undergo genetic testing 4 .…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature

LaFlamme,

Rastin,

Sengupta

et al. 2023

Preprint

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Sequence-based genetic testing currently identifies causative genetic variants in ∼50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. Rare epigenetic variations (“epivariants”) can drive disease by modulating gene expression at single loci, whereas genome-wide DNA methylation changes can result in distinct “episignature” biomarkers for monogenic disorders in a growing number of rare diseases. Here, we interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 516 individuals with genetically unsolved DEEs who had previously undergone extensive genetic testing. We identified rare differentially methylated regions (DMRs) and explanatory episignatures to discover causative and candidate genetic etiologies in 10 individuals. We then used long-read sequencing to identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and two copy number variants. We also identify pathogenic sequence variants associated with episignatures; some had been missed by previous exome sequencing. Although most DEE genes lack known episignatures, the increase in diagnostic yield for DNA methylation analysis in DEEs is comparable to the added yield of genome sequencing. Finally, we refine an episignature forCHD2using an 850K methylation array which was further refined at higher CpG resolution using bisulfite sequencing to investigate potential insights intoCHD2pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate genetic causes as ∼2% (10/516) for unsolved DEE cases.

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“…1 With advances in next-generation sequencing, the genetic basis is determined in almost 40%-50% of DEEs with more than 800 DEE genes identified. [2][3][4] These genes implicate a wide range of neurobiological processes. 5,6 As larger cohorts of patients with a specific genetic DEE are identified, a phenotypic spectrum typically emerges.…”

Section: Introductionmentioning

confidence: 99%

“…1 With advances in next-generation sequencing, the genetic basis is determined in almost 40%–50% of DEEs with more than 800 DEE genes identified. 2-4 These genes implicate a wide range of neurobiological processes. 5,6…”

Section: Introductionmentioning

confidence: 99%

Movement Disorders in Patients With Genetic Developmental and Epileptic Encephalopathies

van der Veen,

Tse,

Ferretti

et al. 2023

Neurology

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Background and Objectives: Movement disorders are underrecognized in the developmental and epileptic encephalopathies (DEEs). There are now over 800 genes implicated in causing the DEEs; relatively few of these rare genetic diseases are known to be associated with movement disorders. We identified patients with genetic DEEs who had movement disorders, classified the nature of their movement disorders and asked whether specific patterns correlated with the underlying mechanism. Methods: We classified the type of movement disorders associated with specific genetic DEEs in a large international cohort of patients and analysed whether specific patterns of movement disorders reflected the underlying biological dysfunction. Results: Our cohort comprised 77 patients with a genetic DEE with a median age of 9 (range 1-38) years. Stereotypies (37/77, 48%) and dystonia (34/77, 44%) were the most frequent movement disorders, followed by chorea (18/77, 23%), myoclonus (14/77, 18%), ataxia (9/77, 12%), tremor (7/77, 9%) and hypokinesia (6/77, 8%). In 47% of patients, a combination of movement disorders was seen. The movement disorders were first observed at a median age of 18 months (range day 2 - 35 years). Dystonia was more likely to be observed in non-ambulatory patients, while ataxia was less likely. In 46% of patients, therapy was initiated with medication (34/77, 44%), DBS (1/77, 1%), or intrathecal baclofen (1/77, 1%). We found that patients with channelopathies or synaptic vesicle trafficking defects were more likely to have dystonia; whereas, stereotypies were most frequent in individuals with transcriptional defects. Discussion: Movement disorders are often underrecognized in patients with genetic DEEs but recognition is critical for the management of these complex neurological diseases. Distinguishing movement disorders from epileptic seizures is important in tailoring patient treatment. Understanding which movement disorders occur with different biological mechsnisms will inform early diagnosis and management.

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Genes4Epilepsy: An epilepsy gene resource

Cited by 44 publications

References 26 publications

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk

Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature

Movement Disorders in Patients With Genetic Developmental and Epileptic Encephalopathies

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