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

TY - JOUR

T1 - Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization

AU - Nazaryan-Petersen, Lusine

AU - Eisfeldt, Jesper

AU - Pettersson, Maria

AU - Lundin, Johanna

AU - Nilsson, Daniel

AU - Wincent, Josephine

AU - Lieden, Agne

AU - Lovmar, Lovisa

AU - Ottosson, Jesper

AU - Gacic, Jelena

AU - Mäkitie, Outi

AU - Nordgren, Ann

AU - Vezzi, Francesco

AU - Wirta, Valtteri

AU - Käller, Max

AU - Hjortshøj, Tina Duelund

AU - Jespersgaard, Cathrine

AU - Houssari, Rayan

AU - Pignata, Laura

AU - Bak, Mads

AU - Tommerup, Niels

AU - Lundberg, Elisabeth Syk

AU - Tümer, Zeynep

AU - Lindstrand, Anna

PY - 2018/11

Y1 - 2018/11

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pgen.1007780

DO - 10.1371/journal.pgen.1007780

M3 - Journal article

C2 - 30419018

SN - 1553-7390

VL - 14

JO - P L o S Genetics

JF - P L o S Genetics

IS - 11

M1 - e1007780

ER -