Genetics of Epileptic Networks: from Focal to Generalized Genetic Epilepsies

Purpose of Review Seizures can arise in neocortical, thalamocortical, limbic or brainstem networks. Here, we review recent genetic mechanisms implicated in focal and genetic generalized epilepsies (GGEs). Recent Findings Pathogenic variation in GAP activity toward RAGs 1 (GATOR1) complex genes (i.e., DEPDC5 , NPRL2 and NPRL3 ) mainly result in focal epilepsies. They are associated with high rates of sudden unexpected death in epilepsy and malformations of cortical development (MCD), where “two-hits” in GATOR1-related pathways are also found in MCDs. Large-scale sequencing studies continue to reveal new genetic risk (germline or somatic) variants, and new genes relevant to epileptic encephalopathies (EEs). Genes previously associated with EEs, including GABA A receptor genes, are now known to play a role in both common focal and GGEs in individuals without intellectual disabilities. These findings suggest that there may be a common pathophysiological mechanism in GGEs and focal epilepsies. Finally, polygenic risk scores, based on common genetic variation, offer promise in helping to differentiate between GGEs and common forms of focal epilepsies. Summary Genetic abnormalities are a significant cause of common sporadic epilepsies, epilepsies associated with inflammatory markers, and focal epilepsies with or without MCD. Future studies using genome sequencing may provide more answers to the remaining unresolved epilepsy cases.