The involvement of U-type dicentric chromosomes in the formation of terminal deletions with or without adjacent inverted duplications

Kato, Takema; Inagaki, Hidehito; Miyai, Shunsuke; Suzuki, Fujio; Naru, Yuki; Shinkai, Yasuko; Kato, Atsushi; Kanyama, Kazuo; Mizuno, Seiji; Muramatsu, Yoshiyuki; Yamamoto, Toshiyuki; Shinya, Mitsuhisa; Tazaki, Yukiko; Hiwatashi, Sayuri; Ikeda, Tsutomu; Ozaki, Mamoru; Kurahashi, Hiroki

doi:10.1007/s00439-020-02186-8

Cited by 12 publications

(17 citation statements)

References 23 publications

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“…An inverted duplication associated with a terminal deletion of the short arm of chromosome 8 is a rare chromosomal rearrangement, but it is one of the most frequent among all inverted duplications with an adjacent deletion [7,9,11]. This is due to the presence of two clusters of olfactory receptor genes or defensin repeats (ORDRs) localized in the 8p23.1 region-REPD (REPeat Distal) is a distal repeat and REPP (REPeat Proximal) is a proximal repeat.…”

Section: Discussionmentioning

confidence: 99%

“…Such rearrangements are formed because of two consecutive events. The first (required) event is the formation of a symmetric dicentric chromosome in which breaks occur due to functional instability, and this leads to the formation of a monocentric chromosome with an inverted duplication having an adjacent deletion and a chromosome with a terminal deletion [11]. Dicentric chromosome 8 formation can occur by two different mechanisms: U-type exchange and non-allelic homologous recombination mediated by parental paracentric inversion inv(8)(p23.1) [4,12,13].…”

Section: Introductionmentioning

confidence: 99%

“…The latter mechanism is a consequence of ectopic recombination, which is most characteristic of inv dup del(8p); as a result of this mechanism, a chromosomal imbalance with an intervening disomic spacer is formed [1]. The formation of inverted 8p duplications/deletions due to U-type exchange occurs according to the "breakage-fusion-bridge" cycle mechanism that prevents the formation of the spacer [9,[11][12][13]. Considering the characteristics of all previously described mechanisms of formation of inv dup del(8p), namely the presence or absence of a spacer and the size of duplication and deletion, it is obvious that different mechanisms of formation of chromosomal rearrangements lead to different molecular cytogenetic variants of inverted duplications/deletions of the short arm of chromosome 8.…”

Section: Introductionmentioning

confidence: 99%

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Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of “8p Inverted Duplication/Deletion Syndrome”

et al. 2022

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Inverted duplication syndrome with an adjacent terminal deletion of the short arm of chromosome 8—inv dup del(8p)—is a rare complex structural chromosomal rearrangement with a wide range of clinical manifestations. Molecular cytogenetic variants of chromosomal imbalance depend on the mechanism of rearrangement formation. We analyzed the clinical–genetic and molecular cytogenetic characteristics of the 8p inverted duplication/deletion syndrome, as well as the genotype–phenotype correlation in eight unrelated cases with the rearrangement of inv dup del(8p). The main clinical manifestations in all cases are psychomotor and language delay, muscle hypotonia, and dysmorphic facial features. Malformations of the central nervous system, such as corpus callosum agenesis, were found in five cases. Seizures were reported in only one case. We found that the cause of the formation of the rearrangement was generally ectopic recombination (seven out of eight cases) and this was due to U-type exchange in only one case. Depending on the mechanism of formation, the characteristics of the genomic imbalance were different, which made it possible to identify two molecular cytogenetic variants in the cases we describe here. No association between molecular cytogenetic variants and clinical manifestations was found.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of “8p Inverted Duplication/Deletion Syndrome”

et al. 2022

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“…This mechanism is supported by the mosaicism detected in an analysis of a fetal loss, in which an intermediate allele dosage plot suggested a mixture of two cell lines: one with an inverted duplication contiguous with a terminal deletion of 8p and the other, in which a triplication and terminal segUPD replaced the duplication and deletion (Case 46). Since the distal end of the duplication is inverted relative to the normal homologue, it is reasonable that microhomology mediates homologue strand annealing, which has been shown by breakpoint junction sequencing [ 33 , 38 ] between the normal homologue and the distal end of the inverted duplication (Fig. 16 ).…”

Section: Discussionmentioning

confidence: 99%

Clinical significance and mechanisms associated with segmental UPD

et al. 2021

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Whole chromosome uniparental disomy (UPD) has been well documented with mechanisms largely understood. However, the etiology of segmental limited UPD (segUPD) is not as clear. In a 10-year period of confirming (> 300) cases of whole chromosome UPD, we identified 86 segmental cases in both prenatal and postnatal samples. Thirty-two of these cases showed mosaic segmental UPD at 11p due to somatic selection associated with Beckwith–Wiedemann syndrome. This study focuses on apparent mechanisms associated with the remaining cases, many of which appear to represent corrections of genomic imbalance such as deletions and derivative chromosomes. In some cases, segmental UPD was associated with the generation of additional genomic imbalance while in others it apparently resulted in restoration of euploidy. Multiple tests utilizing noninvasive prenatal testing (NIPT), chorionic villus sampling (CVS) and amniotic fluid samples from the same pregnancy revealed temporal evidence of correction and a “hotspot” at 1p. Although in many cases the genomic imbalance was dosage “repaired” in the analyzed tissue, clinical effects could be sustained due to early developmental effects of the original imbalance or due to its continued existence in other tissues. In addition, if correction did not occur in the gametes there would be recurrence risks for the offspring of those individuals. Familial microarray allele patterns are presented that differentiate lack of gamete correction from somatic derived gonadal mosaicism. These results suggest that the incidence of segUPD mediated correction is underestimated and may explain the etiology of some clinical phenotypes which are undetected by routine microarray analysis and many exome sequencing studies.

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“…Deletions of the distal region of the short arm of chromosome 8 have been frequently reported in the literature as either isolated terminal/interstitial deletions or terminal deletions associated with more proximal duplications [ 1 ]. These rearrangements are mainly due to the architecture of the 8p23.1 region, characterized by the presence of two olfactory receptor gene clusters and defensin repeats, named REPD (repeat-distal) and REPP (repeat-proximal), that mediate chromosomal rearrangements through a U-type exchange mechanism [ 2 , 3 , 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature

Catusi

Garzo

Capra

et al. 2021

Genes

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To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype.

show abstract

The involvement of U-type dicentric chromosomes in the formation of terminal deletions with or without adjacent inverted duplications

Cited by 12 publications

References 23 publications

Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of “8p Inverted Duplication/Deletion Syndrome”

Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of “8p Inverted Duplication/Deletion Syndrome”

Clinical significance and mechanisms associated with segmental UPD

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature

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