Complex chromosomal rearrangements of human chromosome 21 in a patient manifesting clinical features partially overlappe
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ORIGINAL INVESTIGATION
Complex chromosomal rearrangements of human chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome Taichi Imaizumi1,2 · Keiko Yamamoto‑Shimojima1,3,4,5 · Tomoe Yanagishita1,6 · Yumiko Ondo1 · Eriko Nishi7 · Nobuhiko Okamoto7 · Toshiyuki Yamamoto1,2,5,6 Received: 14 April 2020 / Accepted: 6 June 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00439-020-02196-6) contains supplementary material, which is available to authorized users. * Toshiyuki Yamamoto [email protected] 1
Institute of Medical Genetics, Tokyo Women’s Medical University, 8‑1 Kawada‑cho, Shinjuku‑ward, Tokyo 162‑8666, Japan
2
Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan
3
Japan Society for the Promotion of Science (RPD), Tokyo, Japan
4
Department of Transfusion Medicine and Cell Processing, Tokyo Women’s Medical University, Tokyo, Japan
5
Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Tokyo, Japan
6
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
7
Department of Medical Genetics, Osaka Women’s and Children’s Hospital, Osaka, Japan
Introduction Previously, many patients with partial trisomy of human chromosome 21 (Hsa21) have been reported (Korbel et al. 2009). The existence of such patients
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