Unraveling the Polygenic Architecture of Developmental and Epileptic Encephalopathies

• Applicant: Dr. Stefan Wolking
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 456794357

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.

• DFG Programme: Research Grants