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Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization
Univ Copenhagen, Denmark.
Karolinska Inst, Sweden; Karolinska Inst Sci Pk, Sweden.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden; Karolinska Univ Hosp, 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 SCIENCE , 2018. Vol. 14, no 11, article id e1007780
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Medical Genetics
Identifiers
URN: urn:nbn:se:liu:diva-153703DOI: 10.1371/journal.pgen.1007780ISI: 000452454300037PubMedID: 30419018OAI: oai:DiVA.org:liu-153703DiVA, id: diva2:1276197
Note

Funding Agencies|SciLifeLab national sequencing projects grant; Swedish Research Council [2013-2603, 2017-02936]; Swedish Society for Medical Research big grant; Marianne and Marcus Wallenberg foundation [2014.0084]; Stockholm City Council; Ulf Lundahl memory fund through the Swedish Brain Foundation; Erik Ronnberg Foundation; Danish Council for Independent Research; Danish Council for Independent Research - Medical Sciences [4183-00482B]

Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-05-02

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Gacic, Jelena

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