Delineation of complex chromosomal rearrangements: evidence for increased complexity

Astbury, Caroline; Christ, Laurie A.; Aughton, David J.; Cassidy, Suzanne B.; Fujimoto, Atsuko; Pletcher, Beth A.; Schafer, Irwin A.; Schwartz, Stuart

doi:10.1007/s00439-003-1079-1

Cited by 32 publications

(21 citation statements)

References 24 publications

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“…4 . otic multivalent confi guration whose resolution resulted in this highly chaotic CCR (Houge et al, 2003). Indeed, the remarkable complexity of the present case agrees with the observation by other authors (Astbury et al, 2004;Lespinasse et al, 2004;Vermeulen et al, 2004;Borg et al, 2005;Gribble et al, 2005) that CCRs may actually be more complex than they seem when further characterized by sophisticated molecular cytogenetic techniques such as array-painting and micro-array CGH. That the 2q32 and 3q13 partial insertions were overlooked after hybridization with the chromosome 11 WCP can mainly be attributed to an excess of signal that obscured these relatively small insertions.…”

Section: Discussionsupporting

confidence: 80%

A highly complex rea(2;3;11) and aniridia by position effect

Rivera

Ayala-Madrigal

Barros-Núñez

et al. 2006

Cytogenet Genome Res

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A two-year-old boy presenting with bilateral aniridia and psychomotor retardation had a de novo (2;3;11) highly complex rearrangement which was characterized as far as possible by means of G-banding and FISH assays with multiple probes including cosmids for the Wilms, Aniridia, Genital anomalies and Retardation (WAGR) region, alphoid repeats for chromosomes 2, 3 and 11, subtelomere probes for 2p/2q, 3p/3q and 11q and BACs for 2q32 and 3q13. We identified ∼15 breakpoints with at least three interchromosomal and three intrachromosome anomalies involving chromosome 11. Both parents had normal karyotypes and no cryptic 11p rearrangements revealed by the chromosome 11 cosmid panel. The lack of a deletion of PAX6 pointed to the direct insertion of an ∼300-kb segment involving the cosmids FO2121 and AO4160, and more specifically the insertion’s proximal breakpoint in the ∼150-kb segment between FO2121 and FAT5 (PAX6), as the responsible factor for the patient’s aniridia via a position effect resulting in functional haploinsufficiency of the PAX6 gene. This case illustrates the importance of recognizing that de novo complex chromosomal rearrangements found in patients with diverse clinical features may contribute to the phenotype, but that multiple mechanisms and higher levels of complexity may be unmasked by high resolution molecular cytogenetic studies.

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Section: Discussionsupporting

confidence: 80%

A highly complex rea(2;3;11) and aniridia by position effect

Rivera

Ayala-Madrigal

Barros-Núñez

et al. 2006

Cytogenet Genome Res

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“…Due to the increased complexity of this de novo rearrangement, this patient will be discussed in more detail in a separate article. 23 Briefly, although no deletions were found at any of the breakpoints, at least 14 genes spanned the breakpoint regions and, therefore, might have been disrupted.…”

Section: Patient Lwmentioning

confidence: 98%

“…The complexity and resolution of the abnormality in this patient are discussed in more detail in a separate article. 23 Briefly, two nonconsecutive deletions in 18q were delineated (18q12.22-18q21.1 and 18q21.22-18q22.2), with the loss of 11 Mb and 6.5 Mb of DNA, respectively, as well as two nonconsecutive regions of 18q insertion into 11q. genes.…”

Section: Patient Hbmentioning

confidence: 99%

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Detection of deletions in de novo “balanced” chromosome rearrangements: Further evidence for their role in phenotypic abnormalities

Astbury

Christ

Aughton

et al. 2004

Genetics in Medicine

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Purpose: The purpose of this study was to test the hypothesis that deletions of varying sizes in de novo apparently balanced chromosome rearrangements are a significant cause of phenotypic abnormalities. Methods: A total of fifteen patients, with seemingly balanced de novo rearrangements by routine cytogenetic analysis but with phenotypic anomalies, were systematically analyzed. We characterized the breakpoints in these fifteen cases (two of which were ascertained prenatally), using a combination of high-resolution GTG-banding, fluorescence in situ hybridization (FISH) with bacterial artificial chromosomes (BACs), and data from the Human Genome Project.Results: Molecular cytogenetic characterization of the 15 patients revealed nine with deletions, ranging in size from 0.8 to 15.3 Mb, with the number of genes lost ranging from 15 to 70. In five of the other six cases, a known or putative gene(s) was potentially disrupted as a result of the chromosomal rearrangement. In the remaining case, no deletions were detected, and no known genes were apparently disrupted. Conclusions: Our study suggests that the use of molecular cytogenetic techniques is a highly effective way of systematically delineating chromosomal breakpoints, and that the presence of deletions of varying size is an important cause of phenotypic abnormalities in patients with "balanced" de novo rearrangements. Genet Med 2004:6(2):81-89.

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“…However, the development of fluorescence in situ hybridization (FISH) with different probes in combination with the data available from the Human Genome Project has permitted greater understanding of these cases and led to an ability of delineate such rearrangements [Astbury et al, 2004]. In addition, these techniques permit the attribution of chromosomal origin and also provide better genotype-phenotype correlations [Sirko-Osadsa et al, 1999].…”

Section: Introductionmentioning

confidence: 98%

Breakpoint mapping in a case of mosaicism with partial monosomy 9p23 → pter and partial trisomy 1q41 → qter suggests neo‐telomere formation in stabilizing the deleted chromosome

Kulikowski

Christ

Nogueira

et al. 2005

American J of Med Genetics Pt A

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We report on a clinical and molecular cytogenetic study of a patient who presents a complex chromosomal rearrangement with two different cell lines. Using high-resolution GTG banding and fluorescence in situ hybridization (FISH) with several probes, including bacterial artificial chromosomes (BACs), the karyotype was defined as 46,XX,del(9)(p23)[54]/46,XX,der(9)t(1;9)(q41;p23)[46], indicating the presence of monosomy 9p23 in all cells and trisomy 1q41 in approximately 50% of the cells. The patient studied presents most of the manifestations of the 9p deletion and 1q duplication syndromes. The breakpoint was mapped at 9p23 with a loss of approximately 13.9-Mb of DNA. The duplicated segment consists of approximately 35 Mb from 1q41-qter region. We also suggest that a mechanism for telomere capture and interstitial telomeric sequences (ITs) is involved in a neo-telomere formation in one of the cell lines. This study highlights the importance of combining high-resolution chromosome and FISH with BACs in order to make genotype-phenotype correlations and to understand the mechanisms involved chromosomal aberrations.

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Delineation of complex chromosomal rearrangements: evidence for increased complexity

Cited by 32 publications

References 24 publications

A highly complex rea(2;3;11) and aniridia by position effect

A highly complex rea(2;3;11) and aniridia by position effect

Detection of deletions in de novo “balanced” chromosome rearrangements: Further evidence for their role in phenotypic abnormalities

Breakpoint mapping in a case of mosaicism with partial monosomy 9p23 → pter and partial trisomy 1q41 → qter suggests neo‐telomere formation in stabilizing the deleted chromosome

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