Isolated absence epilepsy associated with a de novo FBXW7 missense variant in the F-box domain

The FBXW7 gene encodes a substrate-recognition component of the Skp1-Cul1-F-box (SCF) E3 ubiquitin ligase complex, which targets key regulatory proteins for proteasomal degradation. Recently, loss-of-function FBXW7 variants have been associated with a novel neurodevelopmental disorder characterized by heterogeneous clinical features. Most reported pathogenic variants cluster within the WD40 domains, while variants in other regions, such as the F-box domain, remain poorly characterized. In this study, we performed trio-exome sequencing on a 3-year-old girl with Early-Onset Childhood Absence Epilepsy. We analyzed the identified FBXW7 variant using multiple in silico tools for pathogenicity prediction and structural modeling. Clinical phenotype was compared with previously reported cases. We identified a novel de novo missense variant in FBXW7, c.926G>C; p.(Arg309Pro), affecting a highly conserved residue in the F-box domain. Notably, unlike prior cases predominantly associated with WD40 domain variants and severe phenotypes, our patient exhibited a much milder clinical presentation consisting of isolated, drug-responsive absence seizures without intellectual disability. Structural modeling predicted significant impairment in protein-protein binding affinity, particularly with the SCF complex component SKP1, supporting a potentially disruptive effect of the p.(Arg309Pro) substitution on complex assembly. Overall, our findings expand the genotypic and phenotypic spectrum of FBXW7-related disorders. Variants in the F-box domain may result in milder neurological phenotypes compared to those in the WD40 domains, suggesting domain-specific effects and potentially distinct pathogenic mechanisms. PLAIN LANGUAGE SUMMARY: The FBXW7 gene helps regulate the stability of many proteins essential for brain development and function. Changes in this gene have recently been linked to neurodevelopmental disorders with epilepsy. We identified a new FBXW7 variant in a 3-year-old girl with early-onset absence epilepsy. Computer-based modeling suggests that this change weakens the protein's normal interactions. Our findings broaden the spectrum of FBXW7-related disorders and indicate that variants in different gene regions may result in variable clinical severity.