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Chromosomal rearrangements
Original research
Detection of cryptic balanced chromosomal rearrangements using high-resolution optical genome mapping
  1. Shuo Zhang1,
  2. Zhenle Pei1,
  3. Caixia Lei1,
  4. Saijuan Zhu1,
  5. Ke Deng1,
  6. Jing Zhou1,
  7. Jingmin Yang2,3,
  8. Daru Lu2,3,
  9. Xiaoxi Sun1,
  10. Chenming Xu1,
  11. Congjian Xu1
  1. 1 Shanghai Ji Ai Genetics & IVF Institute, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
  2. 2 State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
  3. 3 NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning, Science and Technology Research Institute, Chongqing, China
  1. Correspondence to Professor Congjian Xu, Shanghai Ji Ai Genetics & IVF Institute, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China; pghunion{at}163.com

Abstract

Background Chromosomal rearrangements have profound consequences in diverse human genetic diseases. Currently, the detection of balanced chromosomal rearrangements (BCRs) mainly relies on routine cytogenetic G-banded karyotyping. However, cryptic BCRs are hard to detect by karyotyping, and the risk of miscarriage or delivering abnormal offspring with congenital malformations in carrier couples is significantly increased. In the present study, we aimed to investigate the potential of single-molecule optical genome mapping (OGM) in unravelling cryptic chromosomal rearrangements.

Methods Eleven couples with normal karyotypes that had abortions/affected offspring with unbalanced rearrangements were enrolled. Ultra-high-molecular-weight DNA was isolated from peripheral blood cells and processed via OGM. The genome assembly was performed followed by variant calling and annotation. Meanwhile, multiple detection strategies, including FISH, long-range-PCR amplicon-based next-generation sequencing and Sanger sequencing were implemented to confirm the results obtained from OGM.

Results High-resolution OGM successfully detected cryptic reciprocal translocation in all recruited couples, which was consistent with the results of FISH and sequencing. All high-confidence cryptic chromosomal translocations detected by OGM were confirmed by sequencing analysis of rearrangement breakpoints. Moreover, OGM revealed additional complex rearrangement events such as inverted aberrations, further refining potential genetic interpretation.

Conclusion To the best of our knowledge, this is the first study wherein OGM facilitate the rapid and robust detection of cryptic chromosomal reciprocal translocations in clinical practice. With the excellent performance, our findings suggest that OGM is well qualified as an accurate, comprehensive and first-line method for detecting cryptic BCRs in routine clinical testing.

  • chromosome aberrations
  • reproductive health
  • genetic testing
  • in situ hybridization, fluorescence
  • chromosome banding

Data availability statement

The original contributions presented in the study are included in the article/Supplemental Materials, further inquiries can be directed to the corresponding author/s.

https://doi.org/10.1136/jmedgenet-2022-108553

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    Data availability statement

    The original contributions presented in the study are included in the article/Supplemental Materials, further inquiries can be directed to the corresponding author/s.

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    Footnotes

    • SZ and ZP contributed equally.

    • Contributors CJX and SZ conceived the hypothesis and designed the study. SZ, CL and XS collected the cases. SZ, ZP, SJZ, JZ, and JY performed experiment and data analysis. SZ and ZP wrote the manuscript. CJX, CMX, DL and KD revised the manuscript and provided edits. All authors contributed to the final manuscript and approved the submitted version.

    • Funding The research was supported by Shanghai Science and Technology Innovation Action Plan Program (18411953800, 20Y11907200), Shanghai 'Rising Stars of Medical Talents' Youth Development Program and Natural Science Foundation of Chongqing (grants cstc2020jcyj-zdxmX0011 and cstc2020jcyj-msxmX0012).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.