RT Journal Article SR Electronic T1 Detection of cryptic balanced chromosomal rearrangements using high-resolution optical genome mapping JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 274 OP 284 DO 10.1136/jmedgenet-2022-108553 VO 60 IS 3 A1 Shuo Zhang A1 Zhenle Pei A1 Caixia Lei A1 Saijuan Zhu A1 Ke Deng A1 Jing Zhou A1 Jingmin Yang A1 Daru Lu A1 Xiaoxi Sun A1 Chenming Xu A1 Congjian Xu YR 2023 UL http://jmg.bmj.com/content/60/3/274.abstract AB 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.The original contributions presented in the study are included in the article/Supplemental Materials, further inquiries can be directed to the corresponding author/s.