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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alu Elements
  • Chromosome Breakpoints
  • Chromothripsis
  • DNA Copy Number Variations*
  • DNA Replication / genetics*
  • Gene Rearrangement
  • Genome, Human
  • Humans
  • Long Interspersed Nucleotide Elements
  • Oligonucleotide Array Sequence Analysis
  • Whole Genome Sequencing

Grant support

This work was supported by the SciLifeLab national sequencing projects grant; the Swedish Research Council [2013-2603, 2017-02936]; the Swedish Society for Medical Research big grant; the Marianne and Marcus Wallenberg foundation [2014.0084]; the Stockholm City Council; the Ulf Lundahl memory fund through the Swedish Brain Foundation; the Erik Rönnberg Foundation and the Danish Council for Independent Research; the Danish Council for Independent Research - Medical Sciences [4183-00482B]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript