ArticleNeurology. Genetics2017
ExACtly zero or once: A clinically helpful guide to assessing genetic variants in mild epilepsies.
Article in Neurology. Genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Penetrance of pathogenic epilepsy variants is low and shaped by common genetic background.Epilepsia · 2026Article
- Analyzing 6211 unique variants in the upgraded interactive FVIII web database reveals novel insights into hemophilia A.Blood vessels, thrombosis & hemostasis · 2025Article
- Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland.The New England journal of medicine · 2023Article
- A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure.American journal of human genetics · 2022Article
- The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
- When LUCA met gnomAD: genetic constraints on universal genes in humans.Intractable & rare diseases research · 2022Article
- Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.Brain : a journal of neurology · 2022Article
- Association of ultra-rare coding variants with genetic generalized epilepsy: A case-control whole exome sequencing study.Epilepsia · 2022Article
- No preferential mode of inheritance for highly constrained genes.Intractable & rare diseases research · 2022Article
- Novel Mutations Detection with Next-Generation Sequencing and Its Association with Clinical Outcome in Unilateral Primary Aldosteronism.Biomedicines · 2021Article
- Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals.American journal of human genetics · 2021Article
- Genetic Landscape of Common Epilepsies: Advancing towards Precision in Treatment.International journal of molecular sciences · 2020Review
- Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review.Frontiers in pharmacology · 2020Review
- Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy.Nature communications · 2019Article
- Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies.Annals of clinical and translational neurology · 2019Article
- De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy.Brain : a journal of neurology · 2018Article
- Identification of Misclassified ClinVar Variants via Disease Population Prevalence.American journal of human genetics · 2018Article
- Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy.Journal of immunology (Baltimore, Md. : 1950) · 2018Article
- γ2 GABAFrontiers in cellular neuroscience · 2018Review
- Molecular Genetic Characterization of Patients With Focal Epilepsy Using a Customized Targeted Resequencing Gene Panel.Frontiers in neurology · 2018Article
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveTo assist the interpretation of genomic data for common epilepsies, we asked whether variants implicated in mild epilepsies in autosomal dominant families are present in the general population.
methodsWe studied 12 genes for the milder epilepsies and identified published variants with strong segregation support (de novo germline mutation or ≥4 affected family members). These variants were checked in the Exome Aggregation Consortium (ExAC), a database of genetic variation in over 60,000 individuals. We subsequently evaluated variants in these epilepsy genes that lacked strong segregation support. To determine whether the findings in epilepsies were representative of other diseases, we also assessed the presence of variants in other dominant neurologic disorders (e.g., CADASIL).
resultsPublished epilepsy variants with strong segregation support (n = 65) were absent (n = 61) or present once (n = 4) in ExAC. By contrast, of 46 published epilepsy variants without strong segregation support, 8 occurred recurrently (2-186 times). Similarly, none of the 45 disease-associated variants from other neurologic disorders with strong segregation support occurred more than once in ExAC. Reanalysis using the larger ExAC V2 plus gnomAD reference cohort showed consistent results.
conclusionsVariants causing autosomal dominant epilepsies are ultra-rare in the general population. Variants observed more than once in ExAC were only found among reports without strong segregation support, suggesting that they may be benign. Clinicians are increasingly faced with the interpretation of genetic variants of unknown significance. These data illustrate that variants present more than once in ExAC are less likely to be pathogenic, reinforcing the valuable clinical role of ExAC.
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