F‐box and WD repeat domain‐containing 7 ( FBXW7 ) encodes the substrate‐recognition subunit of the SCF (SKP1‐CUL1‐F‐box) E3 ubiquitin ligase complex, where it regulates proteasome‐mediated degradation of key cell cycle and developmental proteins. The aim of this review is to provide a comprehensive overview of the currently available evidence on the clinical and molecular features of FBXW7 ‐related neurodevelopmental disorder (NDD). While somatic mutations in FBXW7 are well‐established drivers of human tumors, germline variants have only recently been linked to a distinctive neurological disorder. Reported germline variants include missense, frameshift, splice‐site, and larger structural variants, with the majority clustering in the WD40 domain and disrupting substrate recognition. Functional studies confirm impaired degradation of critical regulators such as cyclin E, MYC, and NOTCH1. Clinically, affected individuals present with early developmental delay, hypotonia, and impaired language acquisition, frequently accompanied by structural brain anomalies, craniofacial dysmorphisms, and variable growth abnormalities. Additional manifestations include congenital anomalies and broad gastrointestinal involvement. Wilms tumor (WT) has been reported in a few individuals carrying germline or constitutional mosaic FBXW7 variants, with evidence of a second somatic hit documented in tumor tissue, supporting a rare but biologically plausible role of this gene in determining WT predisposition.
Savasta et al. (Thu,) studied this question.