Application of molecular cytogenetic techniques to clarify apparently balanced complex chromosomal rearrangements in two patients with an abnormal phenotype: case report

Vree, Paula Jp de; Simon, Marleen; Dooren, Marieke F. van; Stoevelaar, Gerda Ht; Hilkmann, José Tw; Rongen, Michel A; Huijbregts, Gido; Verkerk, Annemieke J.M.H.; Poddighe, Pino J.

doi:10.1186/1755-8166-2-15

Cited by 19 publications

(13 citation statements)

References 31 publications

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“…insertions, inversions, deletions, or duplications) from those involving several chromosomes at once [Lurie et al, 1994]. Meanwhile, several authors described complex inversions and insertion-translocations, which, depending on the definition applied, may or may not have been labeled CCRs [Madan and Menko, 1992;Bernardini et al, 2008;Jiang et al, 2008;Lybaek et al, 2008;de Vree et al, 2009;Poot et al, 2009;Kang et al, 2010]. A special case of a CCR involving a single chromosome is the inversion-duplication-distal deletion rearrangement [Hulick et al, 2009;van Binsbergen et al, 2012;Kowalczyk et al, 2013;Trachoo et al, 2013].…”

Section: Definition and Classification Of Ccrsmentioning

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: Definition and Classification Of Ccrsmentioning

confidence: 99%

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

Poot

Haaf

2015

Mol Syndromol

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“…In recent years, many apparently balanced chromosomal rearrangements associated with abnormal phenotypes have been analyzed using various approaches (FISH and chromosomal microarrays) and, in a significant proportion of these cases, the rearrangements were found to be more complex than had been predicted by the G‐banding karyotypes [Vissers et al, 2003; Sismani et al, 2008; de Vree et al, 2009]. In these cases, the breakpoints were not sequenced and the main emphasis was on whether the aberration was truly balanced or whether there were deletions and/or insertions.…”

Section: Discussionmentioning

confidence: 99%

Complex chromosomal rearrangement in a girl with psychomotor‐retardation and a de novo inversion: inv(2)(p15;q24.2)

Granot‐Hershkovitz

Raas‐Rothschild

Frumkin

et al. 2011

American J of Med Genetics Pt A

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Cytogenetic analysis of DNA from a girl with severe psychomotor retardation revealed a de novo pericentric inversion of chromosome 2: 46,XX,inv(2)(p15q24.2). In order to elucidate the possible role of the inversion in the girl's abnormal phenotype, we analyzed the inversion breakpoints. FISH analysis revealed BAC clones spanning the breakpoints at 2p and 2q of the inversion. Southern blot hybridization with DNA probes from the BAC regions was used to refine the localization of the breakpoints, followed by inverse-PCR which enabled us to sequence the inversion breakpoints. We found a complex chromosomal rearrangement, including five breakpoints, four at 2q and one at 2p joined with minor insertions/deletions of a few bases. The breakpoint at 2p was within the NRXN1 gene that has previously been associated with autism, intellectual disabilities, and psychiatric disorders. In 2q, the breakpoints disrupted two genes, TANC1 and RBMS1; the phenotypic effect of these genes is not currently known.

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“…Detailed structural analysis is indispensable to assess the function of such rearrangements in tumor development and to understand the mechanisms leading to such rearrangements. Although there have been a large number of reports on structure analysis of cancer chromosomes, most of these have dealt with relatively simple rearrangements (Albertson et al, 2003;de Vree et al, 2009;Zhang et al 2009;Gibaud et al, 2010). To analyze more complicated rearrangements, it would be necessary to simplify the complexity.…”

Section: Introductionmentioning

confidence: 98%

Chromosome‐specific segmentation revealed by structural analysis of individually isolated chromosomes

Kitada¹,

Taima²,

Ogasawara³

et al. 2011

Genes Chromosomes & Cancer

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Analysis of structural rearrangements at the individual chromosomal level is still technologically challenging. Here we optimized a chromosome isolation method using fluorescent marker-assisted laser-capture and laser-beam microdissection and applied it to structural analysis of two aberrant chromosomes found in a lung cancer cell line. A high-density array-comparative genomic hybridization (array-CGH) analysis of DNA samples prepared from each of the chromosomes revealed that these two chromosomes contained 296 and 263 segments, respectively, ranging from 1.5 kb to 784.3 kb in size, derived from different portions of chromosome 8. Among these segments, 242 were common in both aberrant chromosomes, but 75 were found to be chromosome-specific. Sequences of 263 junction sites connecting the ends of segments were determined using a PCR/Sanger-sequencing procedure. Overlapping microhomologies were found at 169 junction sites. Junction partners came from various portions of chromosome 8 and no biased pattern in the positional distribution of junction partners was detected. These structural characteristics suggested the occurrence of random fragmentation of the entire chromosome 8 followed by random rejoining of these fragments. Based on that, we proposed a model to explain how these aberrant chromosomes are formed. Through these structural analyses, it was demonstrated that the optimized chromosome isolation method described here can provide high-quality chromosomal DNA for high resolution array-CGH analysis and probably for massively parallel sequencing analysis.

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Application of molecular cytogenetic techniques to clarify apparently balanced complex chromosomal rearrangements in two patients with an abnormal phenotype: case report

Cited by 19 publications

References 31 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

Complex chromosomal rearrangement in a girl with psychomotor‐retardation and a de novo inversion: inv(2)(p15;q24.2)

Chromosome‐specific segmentation revealed by structural analysis of individually isolated chromosomes

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