Genomic Balancing Act: Deciphering DNA rearrangements in the Complex Chromosomal Aberration involving 5p15.2, 2q31.1 and 18q21.32
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1104260 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Despite extensive research into the genetic underpinnings of neurodevelopmental disorders (NDD), many clinical cases remain unresolved. We studied a female proband with a NDD, mildly dysmorphic facial features, and brain stem hypoplasia on neuroimaging. Comprehensive genomic analyses revealed a terminal 5p loss and terminal 18q gain in the proband while a diploid copy number for chromosomes 5 and 18 in both parents. Genomic investigations in the proband identified an unbalanced translocation t(5;18) with additional genetic material from chromosome 2 (2q31.3) inserted at the breakpoint, pointing to a complex chromosomal rearrangement (CCR) involving 5p15.2, 2q31.3, and 18q21.32. Breakpoint junction analyses enabled by long read genome sequencing unveiled the presence of four distinct junctions in the father, who is carrier of a balanced CCR. The proband inherited from the father both the abnormal chromosome 5 resulting in segmental aneusomies of chr5 (loss) and chr18 (gain) and a der(2) homologue. Evidences suggest a chromoplexy mechanism for this CCR derivation, involving double-strand breaks (DSBs) repaired by non-homologous end joining (NHEJ) or alternative end joining (alt-EJ). The complexity of the CCR and the segregation of homologues elucidate the genetic model for this family. This study demonstrates the importance of combining multiple genomic technologies to uncover genetic causes of complex neurodevelopmental syndrome and to better understand genetic disease mechanisms.
2025-02-26 | GSE265815 | GEO
Project description:Despite extensive research into the genetic underpinnings of neurodevelopmental disorders (NDD), many clinical cases remain unresolved. We studied a female proband with a NDD, mildly dysmorphic facial features, and brain stem hypoplasia on neuroimaging. Comprehensive genomic analyses revealed a terminal 5p loss and terminal 18q gain in the proband while a diploid copy number for chromosomes 5 and 18 in both parents. Genomic investigations in the proband identified an unbalanced translocation t(5;18) with additional genetic material from chromosome 2 (2q31.3) inserted at the breakpoint, pointing to a complex chromosomal rearrangement (CCR) involving 5p15.2, 2q31.3, and 18q21.32. Breakpoint junction analyses enabled by long read genome sequencing unveiled the presence of four distinct junctions in the father, who is carrier of a balanced CCR. The proband inherited from the father both the abnormal chromosome 5 resulting in segmental aneusomies of chr5 (loss) and chr18 (gain) and a der(2) homologue. Evidences suggest a chromoplexy mechanism for this CCR derivation, involving double-strand breaks (DSBs) repaired by non-homologous end joining (NHEJ) or alternative end joining (alt-EJ). The complexity of the CCR and the segregation of homologues elucidate the genetic model for this family. This study demonstrates the importance of combining multiple genomic technologies to uncover genetic causes of complex neurodevelopmental syndrome and to better understand genetic disease mechanisms.
| S-EPMC10925411 | biostudies-literature
Project description:Using high-resolution array comparative genomic hybridization, we mapped del(14)(q) in a series of 23 B-cell leukemia/lymphoma cases. Interestingly, 14 cases with interstitial del(14)(q) showed involvement of IGH at 14q32.33. Whereas the proximal breakpoints of these deletions varied in 6 cases, they clustered in the 14q24.1/ZFP36L1 region in the 8 remaining cases. The latter del(14)(q24.1q32.33) covering approximately 36 Mb was further demonstrated in 12 additional patients by FISH. The majority of cases harboring this deletion were diagnosed as chronic lymphocytic leukemia (CLL) (75%), particularly atypical CLL, and were frequently associated with trisomy 12 (40%) and unmutated VH region (75%). Further analysis of the 14q32.33 breakpoints showed clustering in the constant region of IGH, proximal to the 5’ (Eµ) enhancer sequences. These findings therefore suggest that the del(14)(q24.1q32.33), and other analogous IGH-involving del(14)(q), might represent a novel aberration leading to activation of unknown oncogene(s) at 14q by its juxtaposition with regulatory elements of IGH. Extensive expression analysis via quantitative PCR and microarray profiling, however, failed to identify a gene uniformly upregulated in cases with del(14)(q24.1q32.33). Further investigations are needed to unravel the mechanism(s) and role of IGH-involving del(14)(q) in B-cell malignancies. Keywords: comparative genomic hybridization
2007-05-01 | GSE6713 | GEO
Project description:A balancing act: Interactions within NuA4/TIP60 regulate picNuA4 function in Saccharomyces cerevisiae and humans
| PRJNA564953 | ENA
Project description:The goal of this experiment was to determine the size, genomic extent and gene content of complex rearrangements involving chromosome 9q
2015-01-29 | GSE65376 | GEO
Project description:The goal of this experiment was to determine the size, genomic extent and gene content of complex rearrangements involving multiple chromosomes
2015-01-29 | GSE65375 | GEO
Project description:Distinct lineages of T cells can act in response to various environmental cues to either drive or restrict immune-mediated pathology. Immunotherapy involving the block of cell surface immune checkpoints CTLA-4 and PD-1/PD-L1 has revolutionized cancer treatment across a wide spectrum of malignancies. However, additional immune regulatory mechanisms remain to be discovered, and will facilitate development of next generation agents to overcome resistance to current therapies. We now report that the RNA-binding protein, PCBP1, is critical for stabilizing effector T cell functions by limiting expression of T effector cell-intrinsic Treg-commitment programs and subverting expression of immune-suppressive signals. Indeed, T cell-specific deletion of Pcbp1 increased Treg development, enlisted multiple inhibitory checkpoint molecules including PD-1, TIGIT and VISTA on TILs, and thwarted anti-tumor immunity. Our results demonstrate a critical role for PCBP1 as an intracellular checkpoint for balancing effector versus Treg cells and also suggest PCBP1 as a novel target for cancer immunotherapy.
2020-06-16 | GSE131826 | GEO
Project description:Chromothripsis represents a novel phenomenon in the structural variation landscape of cancer genomes. Here, we analyzed the genomes of ten patients with congenital disease that were preselected to carry complex chromosomal rearrangements (CCRs) with more than two breakpoints. The rearrangements displayed unanticipated complexity resembling chromothripsis. We find that eight of them contain hallmarks of multiple clustered double-stranded DNA breaks (DSBs) on one or more chromosomes. In addition, nucleotide resolution analysis of 98 breakpoint-junctions indicates that break-repair involves non-homologous or microhomology mediated end-joining. We observed that these eight rearrangements are balanced or contain sporadic deletions ranging in size between a few hundred bp and several Mb. The two remaining complex rearrangements did not display signs of DSBs and contain duplications, indicative of rearrangement processes involving template-switching. Our work provides detailed insight in the characteristics of chromothripsis and supports a role for clustered DSBs driving some constitutional chromothripsis rearrangements. We analyzed five patient-parent trios with Illumina BeadChip arrays to test for (de novo) copy number variants and to analyze the parental origin of the complex rearrangements in these patients.
2012-05-10 | E-GEOD-37906 | biostudies-arrayexpress
Project description:Chromothripsis represents a novel phenomenon in the structural variation landscape of cancer genomes. Here, we analyzed the genomes of ten patients with congenital disease that were preselected to carry complex chromosomal rearrangements (CCRs) with more than two breakpoints. The rearrangements displayed unanticipated complexity resembling chromothripsis. We find that eight of them contain hallmarks of multiple clustered double-stranded DNA breaks (DSBs) on one or more chromosomes. In addition, nucleotide resolution analysis of 98 breakpoint-junctions indicates that break-repair involves non-homologous or microhomology mediated end-joining. We observed that these eight rearrangements are balanced or contain sporadic deletions ranging in size between a few hundred bp and several Mb. The two remaining complex rearrangements did not display signs of DSBs and contain duplications, indicative of rearrangement processes involving template-switching. Our work provides detailed insight in the characteristics of chromothripsis and supports a role for clustered DSBs driving some constitutional chromothripsis rearrangements.
2012-05-11 | GSE37906 | GEO