Epilepsy Genetics: What Once Was Rare, Is Now Common

Ultrarare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17 606 Individuals Epi25 Collaborative. Am J Hum Genet. 2019;105(2):267-282. doi: 10.1016/j.ajhg.2019.05.020. Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultrarare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9170 epilepsy-affected individuals and 8436 controls of European ancestry. We focused on 3 phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and nonacquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultrarare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA_A receptor genes were enriched for missense variants across all 3 classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE, respectively. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultrarare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.