Penetrance of pathogenic epilepsy variants is low and shaped by common genetic background

The identification of pathogenic variants in developmental epileptic encephalopathy (DEE) genes can be vital for counseling and individualized treatment. Penetrance is usually considered to be high or full, although this has never been studied in population cohorts. Recent evidence shows that common polygenic risk factors (polygenic risk score [PRS]) are increased in DEE cases, suggesting they might modify risk.

We calculated the penetrance of autosomal dominant epilepsy variants that have previously been classified as (likely) pathogenic in ClinVar, in two large cohorts (n = 42 863 and n = 386 306) using whole genome sequencing data. Next, we calculated PRS to assess whether common variants could modify epilepsy risk among people carrying pathogenic variants.

Most people carrying pathogenic DEE variants did not have epilepsy. Penetrance estimates suggested that the probability of epilepsy in pathogenic variant carriers ranges between 4.1% and 9.8%. Among people carrying epilepsy variants, PRS was predictive of an epilepsy diagnosis. A high PRS was associated with increased risk of severe epilepsy, whereas a low PRS seems protective in people carrying a pathogenic variant.

Our results suggest that average variant penetrance is lower than expected and modified by PRS. A high PRS combined with a pathogenic variant may be necessary to develop a severe epilepsy phenotype like DEE. Reconsidering penetrance assumptions could improve variant classification and diagnostic yield. Our findings may enhance genetic counseling by refining risk estimates and could extend to other diseases.