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

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 rearr...

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Bibliographic Details
Published in:PLoS genetics 2018-11, Vol.14 (11), p.e1007780-e1007780
Main Authors: Nazaryan-Petersen, Lusine, Eisfeldt, Jesper, Pettersson, Maria, Lundin, Johanna, Nilsson, Daniel, Wincent, Josephine, Lieden, Agne, Lovmar, Lovisa, Ottosson, Jesper, Gacic, Jelena, Mäkitie, Outi, Nordgren, Ann, Vezzi, Francesco, Wirta, Valtteri, Käller, Max, Hjortshøj, Tina Duelund, Jespersgaard, Cathrine, Houssari, Rayan, Pignata, Laura, Bak, Mads, Tommerup, Niels, Lundberg, Elisabeth Syk, Tümer, Zeynep, Lindstrand, Anna
Format: Article
Language:English
Subjects:
Alu Elements
Bioinformatics
Biology
Biology and Life Sciences
Biotechnology
Cell cycle
Chromosome Breakpoints
Chromosome rearrangements
Chromosomes
Chromothripsis
Copy number
Copy number variations
DNA Copy Number Variations
DNA microarrays
DNA Replication - genetics
DNA sequencing
Engineering schools
Gene Rearrangement
Genetic research
Genetics
Genome, Human
Genomes
Genomics
Hospitals
Humans
Ionizing radiation
Laboratories
Long Interspersed Nucleotide Elements
Medicin och hälsovetenskap
Medicine
Oligonucleotide Array Sequence Analysis
Research and Analysis Methods
Software
Supervision
Surgery
Whole Genome Sequencing
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1007780