Broadening the phenotype associated with pathogenic variants in the FGF12 gene: From developmental and epileptic encephalopathy to drug-responsive epilepsy with favorable cognitive outcome.

The fibroblast growth factor 12 (FGF12) gene encodes a protein interacting with voltage-gated sodium channels. Two variants, p.(Arg52His) and p.(Gly50Ser), have repeatedly been associated with developmental and epileptic encephalopathy-47 (DEE47; Mendelian Inheritance in Man #617166) with poor outcome. We aim to refine the electroclinical phenotype and outcomes of 10 unpublished patients (2-38 years old) with these recurrent pathogenic variants in the FGF12 gene without DEE (p.[Arg52His], n = 4; p.[Gly50Ser], n = 6). The patients with p.(Gly50Ser) showed later and more explosive epilepsy onset, whereas p.(Arg52His) cases had gradual onset. All developed epilepsy before 5 months, with 70% achieving seizure remission by 6 months with antiseizure medication (ASM), leading to good neurodevelopmental outcomes (median follow-up = 6.8 years). In contrast, the patients with mild intellectual disability had persistent epilepsy despite ASM. Additionally, patients with favorable neurodevelopmental outcomes and FGF12 pathogenic variants showed no signs of cerebellar atrophy. Moreover, we did not find a clear correlation between treatment with sodium channel blockers, its timing, and neurodevelopmental outcome. Here, we expand the phenotypic spectrum of FGF12 pathogenic variants and underscore cases with favorable neurodevelopmental outcomes.