Abstract
FBXW7 (F-box and WD-repeat domain-containing 7) is a tumor suppressor gene, and its germline variants have been causally linked to Wilms tumors. Furthermore, germline variants of FBXW7 have also been implicated in a neurodevelopmental syndrome. However, little is known regarding the occurrence of Wilms tumor in patients with FBXW7-related neurodevelopmental syndrome. We identified a novel constitutional pathogenic variant of FBXW7 in a patient with intellectual disability, who also developed Wilms tumor. The variant was derived from his apparently normal mother, and was also detected in his sister who exhibited developmental delay. Furthermore, we detected a somatic nonsense variant on the paternal allele of FBXW7 in the tumor DNA. These results suggest that the development of Wilms tumor along with FBXW7-related neurodevelopmental syndrome follows the two-hit model, which needs to be validated to establish appropriate follow-up management and tumor surveillance.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available because of privacy and ethics restrictions.
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Acknowledgements
We thank the patient and his family for their cooperation. We are grateful to the physicians and staff of cancer genomic medicine in the C-CAT system. We also thank Mrs. Naoko Omotani for her technical support.
Funding
This study was supported by The Initiative on Rare and Undiagnosed Diseases (Grant number 23ek0109549) from the Japan Agency for Medical Research and Development; a Grant-in-Aid for Research on rare and intractable diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan; and the Japan Society for the Promotion of Science, KAKENHI Grant Numbers 23K07283 (KK), 23K14966 (YK), and 22K07835 (YE).
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Saito, Y., Keino, D., Kuroda, Y. et al. Two-hit mutation causes Wilms tumor in an individual with FBXW7-related neurodevelopmental syndrome. J Hum Genet 70, 121–123 (2025). https://doi.org/10.1038/s10038-024-01299-6
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DOI: https://doi.org/10.1038/s10038-024-01299-6
