Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Abstract

Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.

Heterogeneity of a Constitutional Complex Chromosomal Rearrangement in 2q

“…In contrast to the present de novo CCR localized in a small region of chromosome 2, most constitutional CCRs involve 2 or more chromosomes [Kloosterman and Cuppen, 2013]. To date, only a few cases of CCRs involving only a single (2) none ( chromosome have been described [López-Expósito et al, 2008;Kloosterman et al, 2012;Poot and Haaf, 2015]. The CCR in our patient is responsible of the 2q37.3 deletion (2.580 Mb) and the heterogeneity of partial trisomies involving the 2q34q37.2 region.…”

“…In one of the cases, the CCR involved 5 chromosomes and 5-15 breakpoints [Houge et al, 2003]; in the other case, the CCR, at the PLP1 locus, included triplication and quadruplication [Beck et al, 2015]. Recently, the review of Poot and Haaf [2015] provided some guidance as to how current molecular cytogenetic techniques can be used to resolve constitutional CCRs and to determine their respective mechanisms of origin. Array-CGH is a powerful tool to identify the breakpoints involved in complex rearrangements; however, this methodology may not be appropriate for the characterization of heterogeneous rearrangements.…”

Chromothripsis in Oncology: Literature Review and Case Report

“…Несмотря на большой клинический и эксперимен-тальный материал, посвященный феномену хромо-трипсиса, механизмы его возникновения и развития остаются неясными [50,74]. Поскольку подавляющее число поломок ДНК при хромотрипсисе по своей сути является микрогомологичным [45], есть все основания считать, что репарация возникших в клетке повреж-дений ДНК осуществляется путем негомологичного концевого спаривания [75,76], что успешно исполь-зуется для его выявления.…”

From Telomere Crisis via Dicentric Chromosomes to Kataegis and Chromothripsis

“…Thereupon, the authors isolated cell clones and confirmed in clones with aneuploidy and/ or marker chromosomes by telomere fusion PCR that telomere fusion had indeed taken place. By whole-genome sequencing clusters of genomic rearrangements, affecting one or more chromosomes and exhibiting hallmarks of chromothripsis, such as close spatial clustering, random fragment orientation and oscillating copy number states were found [Korbel and Campbell, 2013;Poot and Haaf, 2015]. Those were in particular terminal deleAll linear chromosomes are capped at their ends, the telomeres, by special telomeric repeat sequences [Riethman, 2008].…”

“…Loss of TERT activity may cause a few rare autosomal recessive, dominant and X-linked syndromes, such as dyskeratosis congenita 1, idiopathic pulmonary fibrosis and myelodysplastic syndrome, and may be involved in ageing [Armanios and Blackburn, 2013;Vermeij et al, 2015]. Single chromosomes undergo, upon loss of their telomeric repeat sequences, breakage-fusion-bridge cycles, producing dicentric chromosomes, which may subsequently be degraded into mitotically stable dicentric supernumerary marker chromosomes [Murnane, 2012;Spittel et al, 2014;Poot and Haaf, 2015]. Products of breakage-fusionbridge cycles are rarely observed, since cell cycle checkpoints prevent their proliferation.…”