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Combining cytogenetic and genomic technologies for deciphering challenging complex chromosomal rearrangements

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Abstract

Complex chromosomal rearrangements (CCRs), a class of structural variants (SVs) involving more than two chromosome breaks, were classically thought to be extremely rare. As advanced technologies become more available, it has become apparent that CCRs are more common than formerly thought, and are a substantial cause of genetic disorders. We attempted a novel approach for solving the mechanism of challenging CCRs, which involve repetitive sequences, by precisely identifying sequence-level changes and their order. Chromosomal microarray (CMA) and FISH analyses were used for interpretation of SVs detected by whole exome sequencing (WES). Breakpoint junctions were analyzed by Nanopore sequencing, a novel long-read whole genome sequencing tool. A large deletion identified by WES, encompassing the FOXF1 enhancer, was the cause of alveolar capillary dysplasia and respiratory insufficiency, resulting in perinatal death. CMA analysis of the newborn’s mother revealed two duplications encompassing the deleted region in the proband, raising our hypothesis that the deletion resulted from the mother’s CCR. Breakpoint junctions of complex SVs were determined at the nucleotide level using Nanopore long-read sequencing. According to sequencing results of breakpoint junctions, the CCR in the newborn was considered the consequence of at least one double-strand break during meiosis, and reassembly of DNA fragments by intra-chromosomal homologous recombination. Our comprehensive approach, combining cytogenetics and long-read sequencing, enabled delineation of the exact breakpoints in a challenging CCR, and proposal of a mechanism in which it arises. We suggest applying our integrative approach combining technologies for deciphering future challenging CCRs, enabling risk assessment in families.

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RM-C was responsible for planning, conduct, reporting, acquisition of data, analysis and interpretation of data, and drafting of the manuscript for intellectual content. OM was responsible for planning, conduct, reporting, conception and design, analysis and interpretation of data. SZ was responsible for analysis and interpretation of data. OL was responsible for analysis and interpretation of data. OW was responsible for analysis and interpretation of data. EP was responsible for conduct and reporting of data. TM was responsible for analysis and interpretation of data. HM-S was responsible for analysis and interpretation of data. DZ was responsible for planning, conduct, reporting, conception and design, analysis and interpretation of data, and drafting of the manuscript for intellectual content. RS was responsible for planning, conduct, reporting, acquisition of data and analysis interpretation of data, and drafting of the manuscript for intellectual content.

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Correspondence to Rachel Michaelson-Cohen.

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There are no competing interests for any of the authors.

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This study does not involve any research on human participants, their involvement was strictly for clinical purpose and this is an article summarizing the clinical findings. This study does not involve animal subjects.

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All authors whose names appear on this submission: made substantial contributions to the conception of the work, and/or the acquisition, analysis, or interpretation of data. Revised the work critically for important intellectual content; and approved the version to be published. Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Communicated by Shuhua Xu.

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Michaelson-Cohen, R., Murik, O., Zeligson, S. et al. Combining cytogenetic and genomic technologies for deciphering challenging complex chromosomal rearrangements. Mol Genet Genomics 297, 925–933 (2022). https://doi.org/10.1007/s00438-022-01898-y

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  • DOI: https://doi.org/10.1007/s00438-022-01898-y

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