Abstract
The chromosomal region critical in Down syndrome has long been analyzed through genotype–phenotype correlation studies using data from many patients with partial trisomy 21. Owing to that, a relatively small region of human chromosome 21 (35.9 ~ 38.0 Mb) has been considered as Down syndrome critical region (DSCR). In this study, microarray-based comparative genomic hybridization analysis identified complex rearrangements of chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome. Although the patient did not show up-slanting palpebral fissures and single transverse palmar creases, other symptoms were consistent with Down syndrome. Rearrangements were analyzed by whole-genome sequencing using Nanopore long-read sequencing. The analysis revealed that chromosome 21 was fragmented into seven segments and reassembled by six connected points. Among 12 breakpoints, 5 are located within the short region and overlapped with repeated segments. The rearrangement resulted in a maximum gain of five copies, but no region showed loss of genomic copy numbers. Breakpoint-junctions showed no homologous region. Based on these findings, chromoanasynthesis was considered as the mechanism. Although the distal 21q22.13 region was not included in the aberrant regions, some of the genes located on the duplicated regions, SOD1, SON, ITSN1, RCAN1, and RUNX1, were considered as possible candidate genes for clinical features of the patient. We discussed the critical region for Down syndrome, with the literature review.
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Acknowledgements
We would like to express our gratitude to the patient and her parents for their cooperation. We thank GeneBay, Inc. (Yokohama, Japan) for supports to analyze whole-genome sequence using Nanopore long-read sequencer.
Funding
This work was supported by the Practical Research Project for Rare/Intractable Diseases (18ek0109270) from the Japan Agency for Medical Research and Development (AMED, TY), JSPS KAKENHI JP18K07803, and Research on Measures for Intractable Diseases from the Ministry of Health Labour and Welfare (TY). We are also thankful for the support from the Initiative on Rare and Undiagnosed Diseases (IRUD) via AMED. This study was partially supported by a Grant-in-Aid for Young Scientists (B) (17K18133) and a Restart Postdoctoral Fellowship (17J40108) from the Japan Society for the Promotion of Science (JSPS) for KY. The data obtained in this study are available on request due to privacy/ethical restrictions.
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Imaizumi, T., Yamamoto-Shimojima, K., Yanagishita, T. et al. Complex chromosomal rearrangements of human chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome. Hum Genet 139, 1555–1563 (2020). https://doi.org/10.1007/s00439-020-02196-6
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DOI: https://doi.org/10.1007/s00439-020-02196-6