The involvement of U-type dicentric chromosomes in the formation of terminal deletions with or without adjacent inverted duplications

Kato, Takema; Inagaki, Hidehito; Miyai, Syunsuke; Suzuki, Fumihiko; Naru, Yuki; Shinkai, Yasuko; Kato, Asuka; Kanyama, Kazuo; Mizuno, Seiji; Muramatsu, Yukako; Yamamoto, Toshiyuki; Shinya, Mitsuhisa; Tazaki, Yukiko; Hiwatashi, Sayuri; Ikeda, Toshiro; Ozaki, Mamoru; Kurahashi, Hiroki

doi:10.1007/s00439-020-02186-8

Original Investigation
Published: 02 June 2020

The involvement of U-type dicentric chromosomes in the formation of terminal deletions with or without adjacent inverted duplications

Takema Kato¹,
Hidehito Inagaki¹,
Syunsuke Miyai¹,
Fumihiko Suzuki¹,
Yuki Naru¹,
Yasuko Shinkai¹,
Asuka Kato¹,
Kazuo Kanyama¹,
Seiji Mizuno²,
Yukako Muramatsu³,
Toshiyuki Yamamoto⁴,
Mitsuhisa Shinya^5,6,
Yukiko Tazaki^5,6,
Sayuri Hiwatashi^5,6,
Toshiro Ikeda^5,6,
Mamoru Ozaki⁷ &
Hiroki Kurahashi^1,2

Human Genetics volume 139, pages 1417–1427 (2020)Cite this article

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Abstract

An inverted duplication with a terminal deletion (inv-dup-del) is one of the complex constitutional structural rearrangements that can occur in a chromosome. Although breakages of dicentric chromosome have been suggested, the precise mechanism of this is yet to be fully understood. In our present study, we investigated the genomic structure of 10 inv-dup-del cases to elucidate this mechanism. Two recurrent 8p inv-dup-del cases harbored a large copy-number-neutral region between the duplication and deletion in common. Although the other non-recurrent cases did not appear to have this copy-number-neutral region, refined sequencing analysis identified that they contained a small intervening region at the junction between the inverted and non-inverted segment. The size of this small intervening region ranged from 1741 to 3728 bp. Combined with a presence of microhomology at the junction, a resolution of the replication fork stalling through template switching within the same replication fork is suggested. We further observed two cases with mosaicism of the dicentric chromosome and various structural rearrangements related to the dicentric chromosome. Refined analysis allowed us to identify different breakpoints on the same chromosome in the same case, implicating multiple rounds of U-type formation and its breakage. From these results, we propose that a replication-based mechanism generates unstable dicentric chromosomes and that their breakage leads to the formation of inv-dup-dels and other related derivative chromosomes.

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Acknowledgements

We thank the patients and their families for participating in this study.

Funding

This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (17K11259 to T.K., 15H04710 and 24390085 to H.K.) and from the Ministry of Health, Welfare and Labor (16ek0109067h0003 to H.K.).

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Authors and Affiliations

Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
Takema Kato, Hidehito Inagaki, Syunsuke Miyai, Fumihiko Suzuki, Yuki Naru, Yasuko Shinkai, Asuka Kato, Kazuo Kanyama & Hiroki Kurahashi
Department of Clinical Genetics, Central Hospital, Aichi Developmental Disability Center, Kasugai, Kasugai, Japan
Seiji Mizuno & Hiroki Kurahashi
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Yukako Muramatsu
Institute of Medical Genetics, Tokyo Women’s Medical University, Shinjuku, Japan
Toshiyuki Yamamoto
Genetic Counseling Room, Kagoshima University Hospital, Kagoshima, Japan
Mitsuhisa Shinya, Yukiko Tazaki, Sayuri Hiwatashi & Toshiro Ikeda
Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima, Japan
Mitsuhisa Shinya, Yukiko Tazaki, Sayuri Hiwatashi & Toshiro Ikeda
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan
Mamoru Ozaki

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Takema Kato
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Hidehito Inagaki
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Fumihiko Suzuki
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Yuki Naru
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Yasuko Shinkai
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Asuka Kato
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Kazuo Kanyama
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Seiji Mizuno
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Yukako Muramatsu
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Toshiyuki Yamamoto
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Mitsuhisa Shinya
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Yukiko Tazaki
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Sayuri Hiwatashi
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Toshiro Ikeda
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Contributions

TK—participated in the design of the study, carried out the molecular biology work, and drafted the manuscript. HI—participated in the design of the study, carried out the molecular biology work. SuM—participated in the design of the study, carried out the molecular biology work. FS—participated in the design of the study, carried out the molecular biology work. YN—participated in the design of the study, carried out the molecular biology work. YS—participated in the design of the study, carried out the molecular biology work. AK—participated in the design of the study, carried out the molecular biology work. KK—participated in the design of the study, carried out the molecular biology work. SeM—participated in the design of the study. YM—participated in the design of the study. TY—participated in the design of the study. MS—participated in the design of the study. YT—participated in the design of the study, carried out the molecular biology work. SH—participated in the design of the study. TI—participated in the design of the study. MO—participated in the design of the study. HK—Coordinated and conceived the study, being involved in the critical revision of the manuscript for important intellectual content.

Corresponding author

Correspondence to Hiroki Kurahashi.

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The authors declare no competing interests.

Ethical approval

This study was approved by the Ethical Review Board for Human Genome Studies at Fujita Health University. The written informed consent was obtained from patients. All experiments were carried out in accordance with the relevant guidelines and regulations.

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We have obtained consent to participate in the study. We have obtained consent to publication in the study.

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Kato, T., Inagaki, H., Miyai, S. et al. The involvement of U-type dicentric chromosomes in the formation of terminal deletions with or without adjacent inverted duplications. Hum Genet 139, 1417–1427 (2020). https://doi.org/10.1007/s00439-020-02186-8

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Received: 07 April 2020
Accepted: 22 May 2020
Published: 02 June 2020
Issue Date: November 2020
DOI: https://doi.org/10.1007/s00439-020-02186-8