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Analyses of breakpoint junctions of complex genomic rearrangements comprising multiple consecutive microdeletions by nanopore sequencing


The widespread use of genomic copy number analysis has revealed many previously unknown genomic structural variations, including some which are more complex. In this study, three consecutive microdeletions were identified in the same chromosome by microarray-based comparative genomic hybridization (aCGH) analysis for a patient with a neurodevelopmental disorder. Subsequent fluorescence in situ hybridization (FISH) analyses unexpectedly suggested complicated translocations and inversions. For better understanding of the mechanism, breakpoint junctions were analyzed by nanopore sequencing, as a new long-read whole-genome sequencing (WGS) tool. The results revealed a new chromosomal disruption, giving rise to four junctions in chromosome 7. According the sequencing results of breakpoint junctions, all junctions were considered as the consequence of multiple double-strand breaks and the reassembly of DNA fragments by nonhomologous end-joining, indicating chromothripsis. KMT2E, located within the deletion region, was considered as the gene responsible for the clinical features of the patient. Combinatory usage of aCGH and FISH analyses would be recommended for interpretation of structural variations analyzed through WGS.

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We would like to express our gratitude to the patient and her family for their cooperation. This work was supported by the Practical Research Project for Rare/Intractable Diseases (18ek0109270) and the Acceleration Program for Intractable Diseases Research utilizing Disease-specific iPS cells from Japan Agency for Medical Research and development (AMED), a Grant-in-Aid for Scientific Research from Health Labor Sciences Research Grants from the Ministry of Health, Labor and Welfare, Japan, and JSPS KAKENHI (TY). This work was also supported by a Grant-in-Aid for Young Scientists (B) (17K18133) and a Restart Postdoctoral Fellowship (17J40108) from the Japan Society for the Promotion of Science (JSPS) (KY-S). We are also thankful for the support from the Initiative on Rare and Undiagnosed Diseases (IRUD) via AMED.

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Correspondence to Toshiyuki Yamamoto.

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Imaizumi, T., Yamamoto-Shimojima, K., Yanagishita, T. et al. Analyses of breakpoint junctions of complex genomic rearrangements comprising multiple consecutive microdeletions by nanopore sequencing. J Hum Genet 65, 735–741 (2020).

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