Abstract
Reciprocal chromosomal translocation is one of genomic variations. When cytogenetically de novo reciprocal translocations are identified in patients with some clinical manifestations, the genes in the breakpoints are considered to be related to the clinical features. In this study, we encountered a patient with severe developmental delay, intractable epilepsy, growth failure, distinctive features, and skeletal manifestations. Conventional karyotyping revealed a de novo translocation described as 46,XY,t(3;4)(q27;q31.2). Chromosomal microarray testing detected a 1.25-Mb microdeletion at 3q27.3q28. Although the skeletal manifestations may have been affected by this deletion, the neurological features of this patient were severe and could not be fully explained by this deletion. Since no genomic copy number aberration was detected on chromosome 4, long-read whole-genome sequencing analysis was performed and a precise breakpoint was confirmed. A 460-bp deletion was detected between the two breakpoints; however, no gene was disrupted. FBXW7, the gene responsible for developmental delay, hypotonia, and impaired language, is in the 0.5-Mb telomeric region. Most of the patient’s clinical features were considered consistent with symptoms of FBXW7-related disorders, but were more severe. FBXW7 expression in the immortalized lymphoblasts of the patient was reduced compared to that in controls. Based on these findings, we suspect that FBXW7 is affected by downstream position effects of chromosomal translocations. The severe neurological features of the patient may have been affected not only by the 3q27-q28 deletion but also by impaired expression of FBXW7 derived from the breakage of chromosome 4.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
We would like to express our gratitude to the patient and his parents for their cooperation. We thank GeneBay, Inc. for their support with long-read WGS.
Funding
This work was supported by the Initiative on Rare and Undiagnosed Diseases (Grant Number 22ek0109549) from the Japan Agency for Medical Research and Development (AMED), Grants-in-Aid for Scientific Research from Health Labor Sciences Research Grants from the Ministry of Health, Labor, and Welfare, Japan (22FC1005), and Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS) (Grant Number 21K07873).
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Toshiyuki Yamamoto designed this study. Takeaki Tamura involved in organizing this study and drafting the manuscript. Keiko Shimojima Yamamoto and Jun Tohyama have contributed to acquisition of data. Ichiro Morioka and Hitoshi Kanno critically reviewed the manuscript. All authors contributed to the analysis and interpretation of data. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Tamura, T., Shimojima Yamamoto, K., Tohyama, J. et al. Reciprocal chromosome translocation t(3;4)(q27;q31.2) with deletion of 3q27 and reduced FBXW7 expression in a patient with developmental delay, hypotonia, and seizures. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01286-x
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DOI: https://doi.org/10.1038/s10038-024-01286-x
