ArticleEBioMedicine2024
Investigating the effect of polygenic background on epilepsy phenotype in 'monogenic' families.
Article in EBioMedicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Genetic Diagnosis in Epilepsy: Implications for Clinical Management.Current neurology and neuroscience reports · 2026Review
- The genetic architecture of epilepsy across molecular mechanisms and clinical heterogeneity.Epilepsia open · 2026Review
- A novel FLNA missense variant in a mother-daughter pair with epilepsy: case series evidence of variable multisystem expressivity.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Article
- Polygenic scores as modifiers in Mendelian diseases.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2026Article
- Polygenic background contributes to GCK-MODY clinical presentation and glycaemic variability.Diabetologia · 2026Article
- Polygenic risk scores in neurological disorders: restless legs syndrome as a translational model.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2026Article
- Genome sequencing boosts diagnostic yield for the developmental and epileptic encephalopathies.medRxiv : the preprint server for health sciences · 2026Article
- Leukocytes Transcriptome Analysis of Genes Associated with Epilepsy Duration and Age of Onset.Molecular neurobiology · 2026Article
- Testing the performance of polygenic scores for multiple traits to explain cerebral palsy in two independent cohorts.EBioMedicine · 2026Article
- Heterogeneity of monogenic epilepsy in loci, phenotypes, and treatment approaches.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Review
- AProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Penetrance of pathogenic epilepsy variants is low and shaped by common genetic background.Epilepsia · 2026Article
- Increased excitability of layer 5 neocortical pyramidal neurons and its contribution to seizure activity in Gabrg2 gene-deficient mice.iScience · 2026Article
- Epilepsy concordance in monozygotic twins: the role of common genetic variants.Brain : a journal of neurology · 2026Article
- The genotypic spectrum of complex febrile seizures: insights from high-risk population genetic screening in a pediatric cohort.Frontiers in neuroscience · 2026Article
- Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.Frontiers in genetics · 2026Review
- Genomics and epilepsy: Opportunities to improve understanding and management.Developmental medicine and child neurology · 2026Review
- Human Cortical Organoids with a Novel SCN2A Variant Exhibit Hyperexcitability and Differential Responses to Anti-Seizure Compounds.Neuroscience bulletin · 2025Article
- Phenotypic heterogeneity in familial epilepsies is influenced by polygenic risk for generalized and focal epilepsies.Epilepsia · 2025Article
- Precision therapies for genetic epilepsies in 2025: Promises and pitfalls.Epilepsia open · 2025Article
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7 authors.
Funding
Abstract
backgroundPhenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies.
methodsWe studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models.
findings304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR = 1.39, 95% CI 1.08, 1.80, p
interpretationWe provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with 'monogenic' epilepsies. In GEFS+ families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients.
fundingNational Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.
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