Project Details
Projekt
Genetic mechanisms of epileptic encephalopathies
Subject Area
Molecular and Cellular Neurology and Neuropathology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 377782854
Epileptic encephalopathies (EEs) are childhood-onset, therapy resistant epilepsies accompanied by developmental delay and various other comorbidities such as ataxia or dystonia. Collectively, the EEs account for up to 20% of all epilepsies starting before the age of 3 years, thus representing a major clinical burden. Inborn errors of metabolism, brain lesions or genetic defects can be identified in these patients. Despite international efforts and large-scale exome studies in the past, only a minority of genetic EEs could be clarified. Reasons were (a) the focus on classical EEs such as Lennox-Gastaut and West syndrome, (b) the emphasis of the analysis on de novo mutations, (c) the limitation on small cohorts in non-classical EEs such as the ongoing trio EE project currently funded by the DFG, which is venturing into further, atypical EE phenotypes. Therefore, within this proposal the analysis of the genetic mechanisms of EE will be extended to a joint analysis of available international exome EE datasets with the following objectives: (i) cohort-wide exome analysis on ca. 1800 patient-parent trios of classical and atypical EEs for various inheritance models (de novo, recessive, x-chromosomal), (ii) analysis of de novo and other rare variants in EE patients in existing exome data (iia) prioritized by results from RNA sequencing from projects Z2 & P5-P7 or with respect to emerging candidate genes and expression quantitative trait loci (eQTLs) from projects P2 & P3, (iib) re-analyzed with respect to epigenetic regulators in collaboration with P2 & P3 and (iic) integrated into a disease model for EE epileptogenesis based on gene networks using genetic and transcriptional data in collaboration with P2, and (iii) functional analysis of detected novel genetic variants. The project will lead to a comprehensive genetic network of genes and susceptibility factors for EE which will lead to a refinement of epileptogenesis models and form the basis for a systematic, precision medicine approach in this disease group
DFG Programme
Research Units
Subproject of
FOR 2715:
Epileptogenesis of genetic epilepsies
