背景:发育性和癫痫性脑病(DEE)是最严重的一组癫痫,与发育迟缓和智力障碍(ID)并存。DEEs通常发生在没有癫痫家族史的人群中,并且主要表现为单基因,在50%的患者中发现了破坏性的罕见突变。对未发现致病性变异的DEE患者的遗传结构知之甚少。多基因风险评分(PRS)是一种测量一个人的特征或条件的共同遗传负担的方法。这里,我们使用PRS来测试癫痫的遗传负担是否与患有DEE的个体有关,和其他形式的癫痫与ID。
方法:2,759例DEE患者的遗传数据,或具有推测为单基因基础的ID的癫痫,并对447,760名人口匹配的对照进行了分析。我们比较了“所有癫痫”的PRS,\'局灶性癫痫\',病例和对照之间的“遗传广泛性癫痫”(GGE)。我们在针对可识别的罕见有害遗传变异和对照进行分层的病例之间进行了成对比较。
结果:假定的单基因重度癫痫病例对“所有癫痫”的PRS增加(p<0.0001),“局灶性癫痫”(p<0.0001),和\'GGE\'(p=0.0002)相对于控件,这解释了0.08%到3.3%的表型变异。在有或没有确定的主要效应的有害变体的情况下,PRS均增加。两组间PRS差异无统计学意义。
结论:我们提供的证据表明,常见的遗传变异有助于DEEs和其他形式的ID型癫痫的病因,即使有已知的致病变异的主要影响。这些结果提供了对严重癫痫的遗传基础的见解,并保证了我们对复杂的DEE病因的理解的转变。而不是单基因,障碍。
背景:爱尔兰科学基金会,人类基因组研究所;国家心脏,肺,和血液研究所;德国研究基金会。
BACKGROUND: The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person\'s common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID.
METHODS: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for \'all epilepsy\', \'focal epilepsy\', and \'genetic generalised epilepsy\' (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls.
RESULTS: Cases of presumed monogenic severe epilepsy had an increased PRS for \'all epilepsy\' (p<0.0001), \'focal epilepsy\' (p<0.0001), and \'GGE\' (p=0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups.
CONCLUSIONS: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders.
BACKGROUND: Science foundation Ireland, Human Genome Research Institute; National Heart, Lung, and Blood Institute; German Research Foundation.