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Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization
Univ Copenhagen, Wilhelm Johannsen Ctr Funct Genome Res, Inst Cellular & Mol Med, Copenhagen, Denmark..
Karolinska Inst, Dept Mol Med & Surg, Ctr Mol Med, Stockholm, Sweden.;Karolinska Inst Sci Pk, Sci Life Lab, Solna, Sweden..
Karolinska Inst, Dept Mol Med & Surg, Ctr Mol Med, Stockholm, Sweden..
Karolinska Inst, Dept Mol Med & Surg, Ctr Mol Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
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2018 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 11, article id e1007780Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Public Library of Science , 2018. Vol. 14, no 11, article id e1007780
National Category
Genetics
Identifiers
URN: urn:nbn:se:kth:diva-240782DOI: 10.1371/journal.pgen.1007780ISI: 000452454300037PubMedID: 30419018Scopus ID: 2-s2.0-85057212366OAI: oai:DiVA.org:kth-240782DiVA, id: diva2:1277420
Funder
Swedish Research Council, 2013-2603 2017-02936Marianne and Marcus Wallenberg Foundation, 2014.0084Swedish Society for Medical Research (SSMF)Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20190110

Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-01-10Bibliographically approved

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Wirta, ValtteriKäller, Max

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