Molecular Mechanisms for Constitutional Chromosomal Rearrangements in Humans

Shaffer, Lisa G.; Lupski, James R.

doi:10.1146/annurev.genet.34.1.297

Cited by 340 publications

(253 citation statements)

References 128 publications

(216 reference statements)

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“…36 This mechanism for recurrent rearrangements is also postulated to occur in other genomic disorders and predicts that microdeletions and their reciprocal microduplications should occur with similar frequency. 1,10 In this investigation, we present results from a clinical aCGH test designed to detect chromosomal abnormalities across the whole genome including 22q11.2. Placement of seven BACs flanking the major LCRs within 22q11.2 enables this assay to detect a variety of microdeletions and microduplications that occur between the LCR22s in this region.…”

Section: Discussionmentioning

confidence: 99%

Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes

Berg

Yonath

et al. 2008

Genetics in Medicine

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174

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Purpose: Genomic rearrangements of chromosome 22q11.2, including the microdeletion associated with DiGeorge/velocardiofacial syndrome, are mediated by nonallelic homologous recombination between region-specific low-copy repeats. To date, only a small number of patients with 22q11.2 microduplication have been identified. Methods:We report the identification by array-comparative genomic hybridization of 14 individuals from eight families who harbor microduplications within the 22q11.2 region. Results: We have now observed a variety of microduplications, including the typical common ϳ3-Mb microduplication, ϳ1.5-Mb nested duplication, and smaller microduplications within and distal to the DiGeorge/velocardiofacial syndrome region, consistent with nonallelic homologous recombination using distinct low-copy repeats in the 22q11.2 DiGeorge/velocardiofacial syndrome region. These microduplications likely represent the predicted reciprocal rearrangements to the microdeletions characterized in the 22q11.2 region. The phenotypes seen in these individuals are generally mild and highly variable; familial transmission is frequently observed. Conclusions: These findings highlight the unbiased ability of array-comparative genomic hybridization to identify genomic imbalances and further define the molecular etiology and clinical phenotypes seen in microduplication 22q11.2 syndrome. Our findings also further support that the 22q11.2 region is highly dynamic with frequent rearrangements using alternative low-copy repeats as recombination substrates. Genet Med 2008:10(4):267-277.

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Section: Discussionmentioning

confidence: 99%

Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes

Berg

Yonath

et al. 2008

Genetics in Medicine

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“…Conversely, the human genome assembly clone indicated the presence of only two such repeats, suggesting that expansion may have predisposed that individual to instability, possibly by increasing the propensity (and/or stability) for cruciform formation. Recombination events between highly homologous (97-98%) sequences within LCR-A to -D are associated with recurrent deletions and duplications (ϳ1:3,000 live births), leading to the DiGeorge, velocardiofacial, conotruncal anomaly face and cat-eye syndromes (20,21,25) (Table I), suggesting that non-B DNA conformations may also be involved in these conditions.…”

Section: Chromosomal Rearrangementsmentioning

confidence: 99%

Non-B DNA Conformations, Genomic Rearrangements, and Human Disease

Bacolla

Wells

2004

Journal of Biological Chemistry

300

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The history of investigations on non-B DNA conformations as related to genetic diseases dates back to the mid-1960s. Studies with high molecular weight DNA polymers of defined repeating nucleotide sequences demonstrated the role of sequence in their properties and conformations (1). Investigations with repeating homo-, di-, tri-, and tetranucleotide repeating motifs revealed the powerful role of sequence in molecular behaviors. At that time, this concept was heretical because numerous prior investigations with naturally occurring DNA sequences masked the effect of sequence (1). It may be noted that these studies in the 1960s predated DNA sequencing by at least a decade.Early studies were followed by a number of innovative discoveries on DNA conformational features in synthetic oligomers, restriction fragments, and recombinant DNAs. The DNA polymorphisms were a function of sequence, topology (supercoil density), ionic conditions, protein binding, methylation, carcinogen binding, and other factors (2). A number of non-B DNA structures have been discovered (approximately one new conformation every 3 years for the past 35 years) and include the following: triplexes, left-handed DNA, bent DNA, cruciforms, nodule DNA, flexible and writhed DNA, G4 tetrad (tetraplexes), slipped structures, and sticky DNA (Fig. 1). From the outset, it was realized (1, 2) that these sequence effects probably have profound biological implications, and indeed their role in transcription (3) and in the maintenance of telomere ends (4) has recently been reviewed.However, in the past few years dramatic advances from genomics, human genetics, medicine, and DNA structural biology have revealed the role of non-B conformations in the etiology of at least 46 human genetic diseases ( Table I) that involve genomic rearrangements as well as other types of mutation events. Non-B DNA ConformationsSegments of DNA are polymorphic. A large number of simple DNA repeat sequences can exist in at least two conformations. All of these sequences adopt the orthodox right-handed B form, probably for the majority of the time, with Watson-Crick (WC) 1 A⅐T and G⅐C bp. However, at least 10 non-B conformations (5-7) are formed, perhaps transiently, at specific sequence motifs as a function of negative supercoil density, generated in part by transcription, protein binding, and other factors.Non-B DNA structures (Fig.

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“…1 Among these, chromosome duplications have an approximate frequency of 1:4000 in the general population 2 and are found in about 2% of subjects with a typical chromosomal phenotype. 3 According to the orientation of the duplicated segment, duplications may be either in tandem or inverted. 4 Segmental duplications have a primary function in both types of rearrangement by causing non-allelic homologous recombination (NAHR).…”

Section: Introductionmentioning

confidence: 99%

A familial inverted duplication/deletion of 2p25.1–25.3 provides new clues on the genesis of inverted duplications

et al. 2008

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We studied a family in which the same 10 Mb inverted duplication of 2p25.3 -p25.1 segregates in two children and their father, all showing a trisomy phenotype. As FISH analysis demonstrated that the duplication was inverted, we suspected that a contiguous terminal deletion was also present, according to the classical inv dup del type of rearrangements. Although FISH with 2p and 2q subtelomeric probes gave normal results, 100 kb resolution array-C\GH (aCGH) showed that, beside the duplication, a 273 kb deletion was also present. The presence of a single-copy region between the deleted and duplicated regions was further suspected through high-resolution aCGH analysis (B20 kb), although only one informative spot having a normal log ratio was detected. The precise structure of the rearrangement was re-defined by real-time PCR and breakpoint cloning, demonstrating the presence of a 2680 bp single-copy sequence between deleted and duplicated regions and the involvement of a simple repeat with the potential for forming a non-B DNA structure. The rearrangement was not mediated by segmental duplications or short inverted repeats, and the double-strand break might have been repaired by nonhomologous end joining or microhomology-mediated intrastrand repair. These data highlight the fact that concomitant deletions associated with inverted duplications are very likely to be more frequent than classical cytogenetic methods alone have been able to demonstrate. The phenotypic effects of the trisomy and of the terminal 2p deletion are discussed.

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Molecular Mechanisms for Constitutional Chromosomal Rearrangements in Humans

Cited by 340 publications

References 128 publications

Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes

Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes

Non-B DNA Conformations, Genomic Rearrangements, and Human Disease

A familial inverted duplication/deletion of 2p25.1–25.3 provides new clues on the genesis of inverted duplications

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