Established and Novel Mechanisms Leading to de novo Genomic Rearrangements in the Human Germline

Hattori, Atsushi; Fukami, Maki

doi:10.1159/000507837

Cited by 23 publications

(21 citation statements)

References 66 publications

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“…Most constitutional genomic rearrangements are created through 1 of the 4 well-known mechanisms, i.e., nonallelic homologous recombination, erroneous repair after double-strand DNA breaks, replication errors, and retrotransposition [ 23 ]. According to the karyotyping analysis findings, we systematically evaluated the genomic sequence within the potentially breaking bands, 1q42 and 3q25.…”

Section: Discussionmentioning

confidence: 99%

De novo balanced reciprocal translocation mosaic t(1;3)(q42;q25) detected by prenatal genetic diagnosis: a fetus conceived using preimplantation genetic testing due to a t(12;14)(q22;q13) balanced paternal reciprocal translocation

Zhang

Zhu

et al. 2021

Mol Cytogenet

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Introduction De novo balanced reciprocal translocations mosaicism in fetus conceived using preimplantation genetic testing from a different balanced translocation carrier parent has been rarely reported. Methods Chromosomal microarray analysis, karyotype analysis and fluorescent in situ hybridization were performed to verify the type and heredity of the rearrangement. STR analysis was conducted to identify potential contamination and verify kinship. In addition, a local BLAST engine was performed to locate potentially homologous segments which might contribute to the translocation in breakpoints of chromosome. Results A rare de novo balanced reciprocal translocations mosaicism mos 46,XY,t(1;3)(q42;q25)[40]/46,XY[39] was diagnosed in a fetus conceived using preimplantation genetic testing due to a 46,XY,t(12;14)(q22;q13) balanced translocation carrier father through multiplatform genetic techniques. Two of the largest continuous high homology segments were identified in chromosomal band 1q42.12 and 3q25.2. At the 21-months follow up, infant has achieved all psychomotor development milestones as well as growth within the normal reference range. Conclusion We present a prenatal diagnosis of a rare de novo balanced reciprocal translocations mosaicism in a fetus who conceived by preimplantation genetic testing. The most reasonable driving mechanism was that a de novo mitotic error caused by nonallelic homologous recombination between 1q42.12 and 3q25.2 in a zygote within the first or early cell divisions, which results in a mosaic embryo with the variant present in a half proportion of cells.

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Section: Discussionmentioning

confidence: 99%

De novo balanced reciprocal translocation mosaic t(1;3)(q42;q25) detected by prenatal genetic diagnosis: a fetus conceived using preimplantation genetic testing due to a t(12;14)(q22;q13) balanced paternal reciprocal translocation

Zhang

Zhu

et al. 2021

Mol Cytogenet

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“…While balanced translocations and pericentric inversions have been reported in healthy individuals, it is notable that both are present in proband 4, and additional events on both chromosomes 6 and 7 were identified at or near one of the breakpoints of the large rearrangements. The local rearrangement of eight segments near 6q22.31-6q23.3 appears to represent chromothripsis, as the segments are localized, do not have microhomology at their breaks, and show no significant copy gain or loss in the region (Supplemental Figure 9) 53 . The location of this cluster near one of the breakpoints of the pericentric inversion is consistent with observations that missegregated chromosomes can undergo micronucleus formation and shattering 54 .…”

Section: Discussionmentioning

confidence: 99%

Long-read genome sequencing for the diagnosis of neurodevelopmental disorders

Lawlor

et al. 2020

Preprint

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AbstractExome and genome sequencing have proven to be effective tools for the diagnosis of neurodevelopmental disorders (NDDs), but large fractions of NDDs cannot be attributed to currently detectable genetic variation. This is likely, at least in part, a result of the fact that many genetic variants are difficult or impossible to detect through typical short-read sequencing approaches. Here, we describe a genomic analysis using Pacific Biosciences circular consensus sequencing (CCS) reads, which are both long (>10 kb) and accurate (>99% bp accuracy). We used CCS on six proband-parent trios with NDDs that were unexplained despite extensive testing, including genome sequencing with short reads. We identified variants and created de novo assemblies in each trio, with global metrics indicating these data sets are more accurate and comprehensive than those provided by short-read data. In one proband, we identified a likely pathogenic (LP), de novo L1-mediated insertion in CDKL5 that results in duplication of exon 3, leading to a frameshift. In a second proband, we identified a de novo translocation affecting DGKB and MLLT3, which we show disrupts MLLT3 transcript levels. We consider this a variant of uncertain significance (VUS). The breadth and quality of variant detection coupled to finding variants of clinical and research interest in two of six probands with unexplained NDDs strongly support the value of long-read genome sequencing for understanding rare disease.

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“…Replication forks can be subjected to breakage or stalling due to replication stress, including DNA lesions, interaction with RNA, and metabolic conditions [ 28 – 30 ]. Alternatively, replication forks can be disturbed by the presence of secondary DNA structures (non-B DNA), usually formed in regions containing repetitive sequences in the genome (Fig.…”

Section: Recurrent and Non-recurrent Rearrangementsmentioning

confidence: 99%

“…After detecting the DSB, both broken DNA ends are molecularly bridged, modified, and then rejoined [ 6 ]. C-NHEJ is known for being imprecise, which means that information scars (gain or loss of nucleotides) may be seen in the junction points [ 6 , 7 , 24 , 26 , 28 , 46 ]. To facilitate ligation of the broken ends, nucleotides can be added to mimic microhomology since most causes of DSB form blunt ends that do not share any.…”

Section: Mechanisms Of Structural Chromosomal Rearrangement Formationmentioning

confidence: 99%

Mechanisms of structural chromosomal rearrangement formation

et al. 2022

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Structural chromosomal rearrangements result from different mechanisms of formation, usually related to certain genomic architectural features that may lead to genetic instability. Most of these rearrangements arise from recombination, repair, or replication mechanisms that occur after a double-strand break or the stalling/breakage of a replication fork. Here, we review the mechanisms of formation of structural rearrangements, highlighting their main features and differences. The most important mechanisms of constitutional chromosomal alterations are discussed, including Non-Allelic Homologous Recombination (NAHR), Non-Homologous End-Joining (NHEJ), Fork Stalling and Template Switching (FoSTeS), and Microhomology-Mediated Break-Induced Replication (MMBIR). Their involvement in chromoanagenesis and in the formation of complex chromosomal rearrangements, inverted duplications associated with terminal deletions, and ring chromosomes is also outlined. We reinforce the importance of high-resolution analysis to determine the DNA sequence at, and near, their breakpoints in order to infer the mechanisms of formation of structural rearrangements and to reveal how cells respond to DNA damage and repair broken ends.

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Established and Novel Mechanisms Leading to de novo Genomic Rearrangements in the Human Germline

Cited by 23 publications

References 66 publications

De novo balanced reciprocal translocation mosaic t(1;3)(q42;q25) detected by prenatal genetic diagnosis: a fetus conceived using preimplantation genetic testing due to a t(12;14)(q22;q13) balanced paternal reciprocal translocation

De novo balanced reciprocal translocation mosaic t(1;3)(q42;q25) detected by prenatal genetic diagnosis: a fetus conceived using preimplantation genetic testing due to a t(12;14)(q22;q13) balanced paternal reciprocal translocation

Long-read genome sequencing for the diagnosis of neurodevelopmental disorders

Mechanisms of structural chromosomal rearrangement formation

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