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 ultra-rare genetic risk factors for different
types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170
epilepsy-affected individuals and 8,436 controls of European ancestry. We focused
on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs),
genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed
that compared to controls, individuals with any type of epilepsy carried an excess
of ultra-rare, 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 three 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. Our study, the largest epilepsy WES study
to date, confirms a convergence in the genetics of severe and less-severe epilepsies
associated with ultra-rare coding variation, and it highlights a ubiquitous role for
GABAergic inhibition in epilepsy etiology.