Genetics of Epileptic Networks: from Focal to Generalized Genetic Epilepsies
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(2020) 20:46
EPILEPSY (C.W. BAZIL, SECTION EDITOR)
Genetics of Epileptic Networks: from Focal to Generalized Genetic Epilepsies Farah Qaiser 1,2 & Ryan K. C. Yuen 1,2 & Danielle M. Andrade 3,4,5
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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 GABAA 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. Keywords Focal epilepsy . Genetic generalized epilepsy . Polygenic risk score . Somatic variants, malformation of cortical development, burden of genetic variants
Introduction Epilepsies are a clinically heterogeneous group of neurological disorders, which affect over 65 million individuals worldwide [1, This article is part of the Topical Collection on Epilepsy * Danielle M. Andrade [email protected] 1
Department of Molecular Genetics, University of Toronto, Toronto, Canada
2
Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, Canada
3
Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada
4
Epilepsy Genetics Program, Krembil Brain Institute, University Health Network, University of Toronto, Toronto, Canada
5
Division of Neurology, Toronto Western Hospital, Krembil Brain Institute, University of Toronto, 5W-445, 399 Bathurst St, Toronto M5T 2S8, Canada
2]. They are characterized by recurrent spontaneous seizures, where seizure onset may be focal (i.e. originating within networks limited to one hemisphere) or generalized (involving both hemispheres), arising in neocortical, thalamocortical, limbic or brainstem networks [3, 4]. Currently, epilepsies are classified by seizure type (focal, generalized or an unknown onset), epilepsy type (focal, generalized
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