Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia; Epilepsy Research Centre, Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, VIC, Australia.
Epilepsy Research Centre, Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, VIC, Australia; Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health, Heidelberg, VIC, Australia; Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC, Australia.
EBioMedicine. 2024 Nov;109:105404. doi: 10.1016/j.ebiom.2024.105404. Epub 2024 Oct 30.
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.
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.
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.
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.
National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.
即使亲属具有相同的单基因病因，也经常观察到癫痫家系内存在表型变异性。我们旨在研究癫痫的常见多基因风险是否可以解释家族性癫痫中罕见致病性变异的外显率和表型表达。
我们研究了 58 个具有遗传易感性的热性惊厥附加综合征（GEFS+）的临床异质性家族。亲属被编码为无癫痫或癫痫发作，根据表型严重程度进行分级：无癫痫发作、热性惊厥（FS）、热性惊厥附加（FS+）、全面性/局灶性癫痫发作或发育性和癫痫性脑病（DEE）。测试癫痫多基因风险评分（PRSs）与癫痫表型的相关性。在家族内，比较表型严重程度一致与不一致的个体之间的平均 PRS 差异。使用混合效应回归模型进行统计分析。
研究了 304 名个体，他们携带已知或推测的具有大效应的罕见变异。在家族内，更高的癫痫多基因风险与癫痫诊断相关（OR=1.39，95%CI 1.08，1.80，p=0.040）。表型更严重的亲属的平均 PRS 差异比表型较轻的亲属高 0.19（p=0.010）。这种差异随着亲属之间表型差异的增加而增加。由于该队列包括两个具有>30 名亲属的罕见变异，因此还可以分析特定变异的基因型-表型相关性。虽然 GABRG2 p.Arg82Gln 致病性变异的癫痫 PRS 效应很强（p=0.0010），但 SCN1B p.Cys121Trp 变异的效应不显著。
我们为遗传背景修饰与“单基因”癫痫相关的罕见变异的外显率和表型表达提供了支持。在 GEFS+家族中，具有更高癫痫 PRS 的亲属更有可能表现出外显率（癫痫诊断）和更严重的表型。特定变异的分析表明，一些罕见变异可能更容易受到 PRS 修饰的影响，这对患者的遗传咨询和疾病预后具有重要意义。
澳大利亚国家卫生和医学研究委员会，澳大利亚医学研究未来基金。
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