Whole exome sequencing and co-expression analysis identify an SCN1A variant that modifies pathogenicity in a family with genetic epilepsy and febrile seizures plus.

These results support the hypothesis that L375S counteracts the loss-of-function effect of K1372E such that individuals carrying both alleles in trans do not present epilepsy-related symptoms. We demonstrate that monogenic epilepsies with wide expressivity can be modified by additional variants in the disease gene, providing a novel framework for the gene-phenotype relationship in genetic epilepsies.