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Background <p>Heterozygous variants in <i>FBXW7</i> have recently been recognized as a cause of a rare neurodevelopmental disorder with variable developmental delay, neurological manifestations, and multisystem involvement. The breadth of clinical variability and penetrance remains incompletely defined.</p> Cases presentation <p>We report a retrospective multicenter case series of seven previously unreported individuals (five males, two females) with heterozygous <i>FBXW7</i> variants identified through clinical genetic testing, aged 5–9 years at last evaluation (median 6 years). Six variants occurred de novo and one was inherited. Neurodevelopmental involvement was present in six individuals and was characterized by global developmental delay and language impairment; hypotonia was observed in all seven. Formal intellectual disability was documented in four cases, while one individual showed preserved cognitive functioning with predominant behavioral difficulties. Epileptic seizures occurred in four individuals, whereas three had no history of epilepsy. Brain MRI was available for six individuals and was normal in four, whereas two showed structural anomalies involving the corpus callosum. Extracerebral features were variably reported, most commonly constipation and recurrent respiratory/otolaryngological infections. Comparison with previously reported individuals confirmed the core neurodevelopmental phenotype and further refined the spectrum.</p> Conclusions <p>This case series expands the phenotypic spectrum associated with <i>FBXW7</i>-related neurodevelopmental disorder and highlights variable expressivity and incomplete penetrance, including clinically relevant variants presenting with mild or atypical phenotypes. These findings support considering <i>FBXW7</i> across a broad range of neurodevelopmental presentations and inform genetic counseling.</p>

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Expanding clinical variability in FBXW7-related neurodevelopmental disorder: a multicenter case series

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Salvatore Savasta,
  • Francesco Fabrizio Comisi,
  • Giovanni Battista Dell’Isola,
  • Gabriele Di Pasquale,
  • Ivy Johnson,
  • Isabella Herman,
  • Andrea Maria Comisi,
  • Francesca Felicia Operto,
  • Giuditta Bargiacchi,
  • Daniëla Q.C.M. Barge-Schaapveld,
  • Giuseppe Donato Mangano,
  • Marco Carotenuto,
  • Vincenzo Salpietro,
  • Alberto Verrotti

摘要

Background

Heterozygous variants in FBXW7 have recently been recognized as a cause of a rare neurodevelopmental disorder with variable developmental delay, neurological manifestations, and multisystem involvement. The breadth of clinical variability and penetrance remains incompletely defined.

Cases presentation

We report a retrospective multicenter case series of seven previously unreported individuals (five males, two females) with heterozygous FBXW7 variants identified through clinical genetic testing, aged 5–9 years at last evaluation (median 6 years). Six variants occurred de novo and one was inherited. Neurodevelopmental involvement was present in six individuals and was characterized by global developmental delay and language impairment; hypotonia was observed in all seven. Formal intellectual disability was documented in four cases, while one individual showed preserved cognitive functioning with predominant behavioral difficulties. Epileptic seizures occurred in four individuals, whereas three had no history of epilepsy. Brain MRI was available for six individuals and was normal in four, whereas two showed structural anomalies involving the corpus callosum. Extracerebral features were variably reported, most commonly constipation and recurrent respiratory/otolaryngological infections. Comparison with previously reported individuals confirmed the core neurodevelopmental phenotype and further refined the spectrum.

Conclusions

This case series expands the phenotypic spectrum associated with FBXW7-related neurodevelopmental disorder and highlights variable expressivity and incomplete penetrance, including clinically relevant variants presenting with mild or atypical phenotypes. These findings support considering FBXW7 across a broad range of neurodevelopmental presentations and inform genetic counseling.