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FBXW7-Related Neurodevelopmental Disorder: Clinical Spectrum, Molecular Mechanisms, and Tumor Predisposition

S Savasta1,2, F F Comisi1, E Fiumicelli3

  • 1Pediatric Clinic and Rare Diseases, Microcitemico Hospital "A. Cao", University of Cagliari, Cagliari, Italy, unica.it.

Human Mutation
|May 11, 2026
PubMed

Insights

Germline variants in the FBXW7 gene cause a neurodevelopmental disorder (NDD) characterized by developmental delay and brain anomalies. These FBXW7 variants disrupt protein degradation, impacting cell cycle and development, and may rarely predispose to Wilms tumor.

Area of Science:

  • Genetics and Molecular Biology
  • Neurodevelopmental Disorders
  • Oncology

Background:

  • F-box and WD repeat domain-containing 7 (FBXW7) is crucial for the SCF E3 ubiquitin ligase complex, regulating degradation of key proteins.
  • Somatic FBXW7 mutations are linked to cancer, but germline variants' role in neurological disorders is a recent discovery.
  • FBXW7 encodes the substrate-recognition subunit, vital for targeting proteins for proteasomal degradation.

Purpose of the Study:

  • To comprehensively review the clinical and molecular features of FBXW7-related neurodevelopmental disorder (NDD).
  • To consolidate evidence on germline FBXW7 variants and their impact on neurological development.
  • To explore the potential link between germline FBXW7 variants and Wilms tumor predisposition.

Main Methods:

  • Literature review of studies reporting germline FBXW7 variants and associated clinical phenotypes.
  • Analysis of functional studies investigating the impact of FBXW7 variants on substrate degradation (e.g., cyclin E, MYC, NOTCH1).
  • Examination of case reports detailing neurodevelopmental, craniofacial, growth, and oncological outcomes in affected individuals.

Main Results:

  • Germline FBXW7 variants, including missense, frameshift, and structural changes, primarily affect the WD40 domain, impairing substrate recognition.
  • Affected individuals exhibit early developmental delay, hypotonia, language impairment, brain anomalies, dysmorphisms, and growth issues.
  • A subset of individuals with germline or mosaic FBXW7 variants developed Wilms tumor, suggesting a role in tumorigenesis with a second hit.

Conclusions:

  • Germline FBXW7 variants cause a distinct neurodevelopmental disorder with a recognizable phenotype.
  • Impaired degradation of FBXW7 targets like cyclin E, MYC, and NOTCH1 underlies the observed developmental deficits.
  • FBXW7 variants represent a rare predisposition factor for Wilms tumor, highlighting the gene's dual role in development and cancer.

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