AI Article Synopsis
- The study investigated how polygenic risk factors influence the severity and occurrence of epilepsy within families that have a known genetic cause, particularly focusing on families with genetic epilepsy with febrile seizures plus (GEFS+).
- Researchers analyzed data from 304 individuals, finding that a higher polygenic risk score (PRS) was linked to a greater likelihood of an epilepsy diagnosis and was associated with more severe epilepsy phenotypes.
- The results suggest that the genetic background can modify how rare pathogenic variants express themselves in terms of disease severity, highlighting the role of polygenic risk in understanding familial epilepsy.
Article Abstract
Background: Phenotypic 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.
Methods: We 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.
Findings: 304 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 = 0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of +0.19 higher than relatives with a milder phenotype (p = 0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype-phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (p = 0.0010), the effect was not significant for SCN1B p.Cys121Trp.
Interpretation: We 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.
Funding: National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558038 | PMC |
| http://dx.doi.org/10.1016/j.ebiom.2024.105404 | DOI Listing |
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Article Synopsis
- EP400 is a gene that encodes an essential protein for ATP-dependent chromatin remodeling, and its role in diseases is not well understood, although this study suggests a link to epilepsy and neurodevelopmental disorders (NDDs).
- Researchers conducted whole-exome sequencing on 402 families and found EP400 variants associated with individuals experiencing epilepsy and NDDs, with some variants being inherited and others newly formed.
- The study also demonstrated that EP400 is crucial during brain development, particularly in neurons, and its deficiency can lead to significant neurological issues, making it a potentially key player in these conditions.
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