ExACtly zero or once: A clinically helpful guide to assessing genetic variants in mild epilepsies.

Objective: To assist the interpretation of genomic data for common epilepsies, we asked whether variants implicated in mild epilepsies in autosomal dominant families are present in the general population. Methods: We studied 12 genes for the milder epilepsies and identified published variants with strong segregation support (de novo germline mutation or $ 4 affected family members). These variants were checked in the Exome Aggregation Consortium (ExAC), a database of genetic variation in over 60,000 individuals. We subsequently evaluated variants in these epilepsy genes that lacked strong segregation support. To determine whether the findings in epilepsies were representative of other diseases, we also assessed the presence of variants in other dominant neurologic disorders (e.g., CADASIL). Results: Published epilepsy variants with strong segregation support (n = 65) were absent (n = 61) or present once (n = 4) in ExAC. By contrast, of 46 published epilepsy variants without strong segregation support, 8 occurred recurrently (2-186 times). Similarly, none of the 45 diseaseassociated variants from other neurologic disorders with strong segregation support occurred more than once in ExAC. Reanalysis using the larger ExAC V2 plus gnomAD reference cohort showed consistent results. Conclusions: Variants causing autosomal dominant epilepsies are ultra-rare in the general population. Variants observed more than once in ExAC were only found among reports without strong segregation support, suggesting that they may be benign. Clinicians are increasingly faced with the interpretation of genetic variants of unknown significance. These data illustrate that variants present more than once in ExAC are less likely to be pathogenic, reinforcing the valuable clinical role of ExAC.