Constitutional chromoanasynthesis: description of a rare chromosomal event in a patient

Plaisancié, Julie; Kleinfinger, Pascale; Cancés, Claude; Bazin, Anne; Julia, Sophie; Trost, Detlef; Lohmann, Laurence; Vigouroux, Adeline

doi:10.1016/j.ejmg.2014.07.004

Cited by 29 publications

(27 citation statements)

References 22 publications

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“…The eventual outcome of such a process would be a CCR. The molecular signature of such a FoSTeS-mediated CCR would be a set of closely interspersed joining points connecting multiple chromosomes or a set of interspersed duplications and triplications within a single chromosome, termed 'chromoanasynthesis' Hart and O'Driscoll, 2013;Plaisancié et al, 2014].…”

Section: Molecular Mechanisms: Fork Stalling and Template Switching mentioning

confidence: 99%

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

Poot

Haaf

2015

Mol Syndromol

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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.

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Section: Molecular Mechanisms: Fork Stalling and Template Switching mentioning

confidence: 99%

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

Poot

Haaf

2015

Mol Syndromol

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“…Other authors suggest that the complexity of constitutional CCRs is the result of a single meiotic event [Houge et al, 2003;Beck et al, 2015]. In recent years, extraordinary 1-step catastrophic genomic events characterized by the shattering of one, or a few, chromosome segments followed by chaotic reassembly of the fragments to explain a CCR have been proposed [Kloosterman et al, 2011[Kloosterman et al, , 2012Stephens et al, 2011;Chiang et al, 2012;Genesio et al, 2013;Gu et al, 2013;Kloosterman and Cuppen, 2013;Zhang et al, 2013;Plaisancié et al, 2014;Wang et al, 2015]. In agreement with the definition, the present CCRs (originating from 1 to 8 breakpoints) involving only a small portion of the 2q region could be caused by these catastrophic events.…”

Section: Discussionmentioning

confidence: 99%

“…Today, multiple molecular techniques such as array-based comparative genomic hybridization (array-CGH), bacterial artificial chromosome (BAC) FISH analyses, SNP oligonucleotide microarray, qPCR and whole-genome sequencing are the most useful techniques in order to characterize CCRs [López-Expósito et al, 2008;Wang et al, 2014;Macera et al, 2015;Wang et al, 2015]. It has been described that certain chromosomes, such as 1, 2, 5, 16, and 18, are prone to cause constitutional CCR [Houge et al, 2003;Vera-Carbonell et al, 2010;Genesio et al, 2013;Gu et al, 2013;Plaisancié et al, 2014;Wang et al, 2014;Gamba et al, 2015].…”

mentioning

confidence: 99%

“…However, new genome rearrangement mechanisms called chromosomal catastrophic events have been proposed to explain the CCRs frequently found in cancer cells [Stephens et al, 2011] and in patients with congenital disorders and/or intellectual disability [Kloosterman et al, 2011[Kloosterman et al, , 2012Liu et al, 2011;Chiang et al, 2012;Genesio et al, 2013;Gu et al, 2013;Kloosterman and Cuppen, 2013;Zhang et al, 2013Zhang et al, , 2015Nazaryan et al, 2014;Plaisancié et al, 2014;Gamba et al, 2015;Wang et al, 2015]. These mechanisms, produced in one unique event, are characterized by the shattering of one, or a few, chromosome segments followed by chaotic reassembly of the fragments resulting in a CCR affecting a limited portion of the genome, often a single chromosome or chromosome arm.…”

mentioning

confidence: 99%

“…Chromothripsis and chromoanasynthesis mechanisms are the most frequent types of chromosomal catastrophic events. Both processes are very similar, and several authors suggest that the main difference is that chromothripsis can only cause deletions, while chromoanasynthesis is characterized by amplifications of numerous segments [Kloosterman and Cuppen, 2013;Pellestor et al, 2014;Plaisancié et al, 2014]. However, recently, Wang et al [2015] reported constitutional chromothripsis involving chromosome 19 which includes interstitial tandem duplications, so the definition of this phenomenon is still confusing.…”

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confidence: 99%

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Heterogeneity of a Constitutional Complex Chromosomal Rearrangement in 2q

Rey¹,

Santos²,

González‐Meneses³

et al. 2016

Cytogenet Genome Res

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Complex chromosome rearrangements (CCRs) are unusual structural chromosome alterations found in humans, and to date only a few have been characterized molecularly. New mechanisms, such as chromothripsis, have been proposed to explain the presence of the CCRs in cancer cells and in patients with congenital disorders and/or mental retardation. The aim of the present study was the molecular characterization of a constitutional CCR in a girl with multiple congenital disorders and intellectual disability in order to determine the genotype-phenotype relation and to clarify whether the CCR could have been caused by chromosomal catastrophic events. The present CCR was characterized by G-banding, high-resolution CGH, multiplex ligation-dependent probe amplification and subtelomeric 2q-FISH analyses. Preliminary results indicate that the de novo CCR is unbalanced showing a 2q37.3 deletion and 2q34q37.2 partial trisomy. Our patient shows some of the typical traits and intellectual disability described in patients with 2q37 deletion and also in carriers of 2q34q37.2 partial trisomy; thus, the clinical disorders could be explained by additional effects of both chromosome alterations (deletions and duplications). A posterior, sequential FISH study using BAC probes revealed the unexpected presence of at least 17 different reorganizations affecting 2q34q37.2, suggesting the existence of chromosome instability in this region. The present CCR is the first case described in the literature of heterogeneity of unbalanced CCRs affecting a small region of 2q, indicating that the mechanisms involved in constitutional chromosome rearrangement may be more complex than previously thought.

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Chromoanasynthesis as a cause of Jacobsen syndrome

Anzick

Thurm

Burkett

et al. 2020

American J of Med Genetics Pt A

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Jacobsen syndrome (MIM #147791) is a rare multisystem genomic disorder involving craniofacial abnormalities, intellectual disability, other neurodevelopmental defects, and terminal truncation of chromosome 11q, typically deleting 170 to >340 genes. We describe the first case of Jacobsen syndrome caused by congenital chromoanasynthesis, an extreme form of complex chromosomal rearrangement. Six duplications and five deletions occurred on one copy of chromosome 11q with microhomology signatures in the breakpoint junctions, indicating an all-at-once replication-based rearrangement mechanism in a gametocyte or early post-zygotic cell. Eighteen genes were deleted from the Jacobsen region, including KIRREL3, which is associated with intellectual disability.

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Constitutional chromoanasynthesis: description of a rare chromosomal event in a patient

Cited by 29 publications

References 22 publications

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

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

Heterogeneity of a Constitutional Complex Chromosomal Rearrangement in 2q

Chromoanasynthesis as a cause of Jacobsen syndrome

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