Unraveling the Polygenic Architecture of Developmental and Epileptic Encephalopathies

发育性和癫痫性脑病是一种严重的癫痫综合征，其特征是婴幼儿和儿童早期发病，药物难治性癫痫发作，认知和行为障碍甚至下降。虽然DeES只占所有癫痫的一小部分，但它们给患者、照顾者和社会带来了巨大的负担。在过去的十年中，Dees一直处于癫痫领域基因发现的前沿，并导致了许多单基因癫痫综合征的出现。然而，尽管有最先进的测序方法，超过50%的DeE患者仍然没有从基因上得到解决。此外，具有相同疾病基因的个体之间的表型异质性，包括严重程度和药物反应的差异，仍然是一个悬而未决的问题。遗传性全面性癫痫(GGES)是更为常见的癫痫综合征，具有更良性的预后。它们被认为是典型的多基因疾病，这使得它们成为本次分析的一个有趣的参考点。我们认为，多基因危险因素和修饰物可以解释到目前为止“无法解决的”病例的差距，并提高我们在临床异质性方面的地位。在一项对大约200名患者-父母三人组的初步研究中，我们观察到与DIE患者的癫痫风险相关的基因变异比他们未受影响的父母丰富。这种影响在没有携带可能的单基因突变的患者中更加明显，强调了多基因传播在未解决病例中的假定作用。在此，我们建议使用一套基于人群和家庭的已建立的技术，如基于家庭的关联测试(FBAT)、多基因风险评分(PRS)和多基因传递不平衡测试(PTDT)，进一步研究DEES的多基因结构。为了对该项目的预期，我们通过国家和国际合作伙伴关系和协议收集了大约2000名患者-父母-三人组。在没有单核苷酸多态性(SNP)芯片数据的情况下，将进行基因分型。临床和测序数据将使我们能够区分具有和不具有可能的单基因突变的个体，并生成子集来调查与药物反应和疾病严重程度相关的风险因素。我们还将把这种基于家庭的分析方法应用于一组GGE患者，以便对经典的多基因疾病和推测的单基因疾病进行比较。我们的研究将有助于更好地理解Dees GGES的遗传结构。这一结果可能被证明对诊断和预后目的有价值，例如在遗传咨询方面，但最终也可能支持对DIE和GGE患者的个体化治疗。

Developmental and epileptic encephalopathies (DEEs) are severe epileptic syndromes that are defined by an early onset during infancy and early childhood, drug refractory seizures, and cognitive and behavioral impairment or even decline. Although DEEs represent only a small fraction of all epilepsies they impose an immense burden on patients, caregivers, and society. During the last decade, DEEs have been at the forefront of genetic discoveries in the epilepsy field and led to the emergence of many monogenetic epilepsy syndromes. Yet, despite state-of-the-art sequencing methods, more than 50% of DEE patients remain genetically unsolved. Moreover, the phenotypic heterogeneity among individuals with the same disease gene, including differences in severity and drug response, remains an open question. Genetic generalized epilepsies (GGEs) are far more frequent epilepsy syndromes and feature a more benign prognosis. They are deemed classical polygenic disorders, which makes them an interesting point of reference for this analysis.We argue that polygenic risk factors and modifiers could explain the gap of so far “unsolvable” cases and also improve our standing of the clinical heterogeneity. In a preliminary study with approximately 200 patient-parent trios, we observed an enrichment of genetic variants that were associated with epilepsy risk in DEE patients compared with their unaffected parents. This effect was more marked in patients who did not carry a probable monogenic mutation, underlining the putative role of polygenic transmission for unsolved cases.Here, we propose to further investigate the polygenic structure of DEEs, using a set of established population- and family-based techniques, such as family-based association tests (FBAT), polygenic risk scores (PRS), and polygenic transmission disequilibrium tests (pTDT).In anticipation of this project, we have compiled a cohort of about 2000 patient-parent-trios through national and international partnerships and agreements. Where single nucleotide polymorphism (SNP) chip data is not available, genotyping will be performed. Clinical and sequencing data will allow us to discriminate between individuals with and without probable monogenic mutations and generate subsets to investigate risk factors associated with drug response and disease severity. We will apply this family-based analysis approach also to a cohort of individuals with GGE to allow for a comparison between a classical polygenic and a supposedly monogenic disease entity. Our study will help to gain a better understanding of the genetic architecture of DEEs GGEs. The results could prove valuable for diagnostic and prognostic purposes, e.g. in genetic counseling, but could ultimately also support individualized therapy of patients with DEE and GGE.