The Seizure‐Associated Genes Across Species (SAGAS) database offers insights into epilepsy genes, pathways and treatments

Abstract

Objective: Decades of genetic studies on people with many different epilepsies, and on many nonhuman species, using many different technologies, have generated a huge body of literature about the genes associated with seizures/epilepsy.Collating these data can help uncover epilepsy genes, pathways, and treatments that would otherwise be overlooked. We aimed to collate and structure these data into a database, and use the database to identify novel epilepsy genes and pathways, and to prioritize promising treatments. Methods:We collated all the genes associated with all types of seizures/epilepsy in all species, and quantified the supporting evidence for each gene, by manually screening ~10 000 publications, and by extracting data from existing databases.

Hypothermic Protection in Neocortex Is Topographic and Laminar, Seizure Unmitigating, and Partially Rescues Neurons Depleted of RNA Splicing Protein Rbfox3/NeuN in Neonatal Hypoxic-Ischemic Male Piglets

“…In monkey and pig models of neonatal HI, seizures seem to worsen neuropathology [19,20,[32][33][34][35][36]. Discordant outcomes in clinical and experimental settings could have manifold attributes, including seizures not being uniform due to differences in species, genetic background, detection methods, gyrencephaly and network connectivity, metabolic depletion and recovery, and complexity and conservation of RNA splicing proteins [37,38]. Discerning whether seizures in gyrencephalic neonatal animals with HI injury independently add or contribute to brain damage or reflect the underlying severity of encephalopathy is important because the answers can instruct clinical management [39].…”

“…RNA splicing proteins have attracted attention in seizure biology. Rbfox family members splice some candidate genes associated with epilepsy and can be mutated in patients with epilepsy [38,44].…”

The role of rare genetic variants enrichment in epilepsies of presumed genetic etiology

“…This gene can be found expressed mainly in the basal ganglia and cerebral cortex with high specificity among oligodendrocytes precursor cells, and excitatory neurons 28 , 51 . PDZD2 also contributes to the functional expression of Nav1.8 ion channel, which is encoded by SCN10A , a QRV enriched gene in NAFE 52 Another gene with shorter distance to known epilepsy genes, FLNA , has itself been associated with epilepsy and seizure disorders 5 . FLNA is also known to interact with HCN1 channels during neuronal excitability modulation in the mature brain 53 .…”

“…Aside from the established list of epilepsy associated genes from the Epi25 cohort, there are a number of curated lists for epilepsy genes, for instance the SAGAS database, containing candidate genes with possible polygenic and monogenic causal tendencies 5 and Genes4Epilepsy (https://github.com/bahlolab/Genes4Epilepsy). We identified a significant overlap of the QRVs genes from our study with both SAGAS (DEE: pval = 0.001, NAFE: pval Supplemental Figures The distance (y-axis) of the QRV genes (x-axis) to known epilepsy genes was determined by counting the nodes within the protein-protein interaction network.…”

“…With the help of next generation sequencing there was a significant advance in gene discovery. Currently, hundreds of genes are established as monogenic causes for epilepsy 4 , while recent studies have associated a few to polygenic causes 5 . Yet, the biggest leap in diagnostic yield happened mainly for the most severe type of epilepsies, developmental and epileptic encephalopathy (DEE) 6 .…”