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PLoS Genet. 2018 Nov 12;14(11):e1007780. doi: 10.1371/journal.pgen.1007780. eCollection 2018 Nov.

Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization.

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Wilhelm Johannsen Center for Functional Genome Research, Institute of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Clinical Genetics, Linköping University Hospital, Linköping, Sweden.
Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Folkhälsan Institute of Genetics, Helsinki, Finland.
SciLifeLab, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
SciLifeLab, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden.
SciLifeLab, Department of Microbiology, Tumor and Cell biology, Karolinska Institutet, Stockholm, Sweden.
Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.


Clustered copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) are often reported as germline chromothripsis. However, such cases might need further investigations by massive parallel whole genome sequencing (WGS) in order to accurately define the underlying complex rearrangement, predict the occurrence mechanisms and identify additional complexities. Here, we utilized WGS to delineate the rearrangement structure of 21 clustered CNV carriers first investigated by CMA and identified a total of 83 breakpoint junctions (BPJs). The rearrangements were further sub-classified depending on the patterns observed: I) Cases with only deletions (n = 8) often had additional structural rearrangements, such as insertions and inversions typical to chromothripsis; II) cases with only duplications (n = 7) or III) combinations of deletions and duplications (n = 6) demonstrated mostly interspersed duplications and BPJs enriched with microhomology. In two cases the rearrangement mutational signatures indicated both a breakage-fusion-bridge cycle process and haltered formation of a ring chromosome. Finally, we observed two cases with Alu- and LINE-mediated rearrangements as well as two unrelated individuals with seemingly identical clustered CNVs on 2p25.3, possibly a rare European founder rearrangement. In conclusion, through detailed characterization of the derivative chromosomes we show that multiple mechanisms are likely involved in the formation of clustered CNVs and add further evidence for chromoanagenesis mechanisms in both "simple" and highly complex chromosomal rearrangements. Finally, WGS characterization adds positional information, important for a correct clinical interpretation and deciphering mechanisms involved in the formation of these rearrangements.

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Conflict of interest statement

The authors have declared that no competing interests exist.

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