GATA2 deficiency phenotype associated with tandem duplication of the GATA2 locus linked to a common structural variant
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ABSTRACT:
PROVIDER: PRJNA699578 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13633388_1.fastq.gz | Fastqsanger.gz | |||
| SRR13633388_2.fastq.gz | Fastqsanger.gz | |||
| SRR13633389_1.fastq.gz | Fastqsanger.gz | |||
| SRR13633389_2.fastq.gz | Fastqsanger.gz | |||
| SRR13633390_1.fastq.gz | Fastqsanger.gz |
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Project description:Typical features of GATA2 deficiency were observed in a individual with wild-type GATA2 sequence. The patient had a de novo tandem duplication of 187Kb spanning GATA2 and RPN1 containing a deletion of 25Kb 5’ of RPN1, inherited from the mother. The deletion is a copy number variant present in about 4% of Europeans (GRCh37: esv2725896 and nsv513733; GRCh38: esv3597711) and removes an alternative 5’ start site of RPN1 at 128,400Kb, associated with CTCF and H3K27ac binding peaks. A second copy of GATA2 is translocated to this region by the tandem duplication. RNA-Seq was underatken in order to identify any gene fussion events resulting from the mutation and to inverstigate differences in gene expression between the patient and controls.
2021-05-10 | GSE166201 | GEO
Project description:UBTF tandem duplication AMLs are sensitive to menin inhibition
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Project description:UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition
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Project description:A 3-year-old girl of nonconsanguineous healthy parents presented with cervical and mediastinal lymphadenopathy due to Mycobacterium fortuitum infection. Routine blood analysis showed normal hemoglobin, neutrophils, and platelets but profound mononuclear cell deficiency (monocytes < 0.1 × 109/L; B cells 78/μL; NK cells 48/μL). A 548 902-bp region containing GATA2 was sequenced by targeted capture and deep sequencing. This revealed a de novo 187-kb duplication of the entire GATA2 locus, containing a maternally inherited copy number variation deletion of 25 kb (GRCh37: esv2725896 and nsv513733). Many GATA2-associated phenotypes have been attributed to amino acid substitution, frameshift/deletion, loss of intronic enhancer function, or aberrant splicing. Gene deletion has been described, but other structural variation has not been reported in the germline configuration. In this case, duplication of the GATA2 locus was paradoxically associated with skewed diminished expression of GATA2 messenger RNA and loss of GATA2 protein. Chimeric RNA fusion transcripts were not detected. A possible mechanism involves increased transcription of the anti-sense long noncoding RNA GATA2-AS1 (RP11-472.220), which was increased several fold. This case further highlights that evaluation of the allele count is essential in any case of suspected GATA2-related syndrome.
| S-EPMC8714714 | biostudies-literature
Project description:We here describe the first successful construction of a targeted tandem duplication of a large chromosomal segment in Aspergillus oryzae. The targeted tandem chromosomal duplication was achieved by using strains that had 5’ΔpyrG upstream of the region targeted for tandem chromosomal duplication and 3’ΔpyrG downstream of the target region. Consequently, strains bearing a 210-kb targeted tandem chromosomal duplication near the centromeric region of chromosome 8 and strains bearing a targeted tandem chromosomal duplication of a 700-kb region of chromosome 2 were successfully constructed. The strains bearing the tandem chromosomal duplication were efficiently obtained from the regenerated protoplast of the parental strains. However, the generation of the chromosomal duplication did not depend on the introduction of double-stranded breaks (DSBs) by I-SceI. The chromosomal duplications of these strains were stably maintained after five generations of culture under non-selective conditions. The strains bearing the tandem chromosomal duplication in the 700-kb region of chromosome 2 showed highly increased protease activity in solid-state culture, indicating that the duplication of large chromosomal segments could be a useful new breeding technology and gene analysis method.
2014-06-30 | GSE57246 | GEO
Project description:We here describe the first successful construction of a targeted tandem duplication of a large chromosomal segment in Aspergillus oryzae. The targeted tandem chromosomal duplication was achieved by using strains that had 5M-bM-^@M-^YM-NM-^TpyrG upstream of the region targeted for tandem chromosomal duplication and 3M-bM-^@M-^YM-NM-^TpyrG downstream of the target region. Consequently, strains bearing a 210-kb targeted tandem chromosomal duplication near the centromeric region of chromosome 8 and strains bearing a targeted tandem chromosomal duplication of a 700-kb region of chromosome 2 were successfully constructed. The strains bearing the tandem chromosomal duplication were efficiently obtained from the regenerated protoplast of the parental strains. However, the generation of the chromosomal duplication did not depend on the introduction of double-stranded breaks (DSBs) by I-SceI. The chromosomal duplications of these strains were stably maintained after five generations of culture under non-selective conditions. The strains bearing the tandem chromosomal duplication in the 700-kb region of chromosome 2 showed highly increased protease activity in solid-state culture, indicating that the duplication of large chromosomal segments could be a useful new breeding technology and gene analysis method. A. oryzae strain bearing a 210-kb targeted tandem chromosomal duplication, A. oryzae strain bearing a 700-kb targeted tandem chromosomal duplication, and A. oryzae RIB40 (wild type strain), were cultivated in Polypeptone-dextrin medium. After 3 days cultivation, genomic DNAs from the samples were extracted, and array CGH analysis was carried out to confirm the chromosomal duplications in the strains.
2014-06-30 | E-GEOD-57246 | biostudies-arrayexpress
Project description:UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition [Cut&Run]
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Project description:UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition [RNA-seq]
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Project description:Interpreting the genomic and phenotypic consequences of copy number variation (CNV) is essential to understand the etiology of genetic disorders. Whereas deletion CNVs obviously lead to haploinsufficiency, duplications may cause disease through triplosensitivity, gene disruption, or gene fusion at breakpoints. The mutational spectrum of duplications has been studied at certain loci and in some cases these copy number gains are complex chromosome rearrangements involving triplications and/or inversions. However, the organization of clinically relevant duplications throughout the genome has not been investigated on a large scale. Here, we fine mapped 184 germline duplications (14.7 kb-25.3 Mb; median 532 kb) ascertained from individuals referred for diagnostic cytogenetics testing. We performed next-generation sequencing (NGS) and whole-genome sequencing (WGS) to sequence 130 breakpoints from 112 subjects with 119 CNVs and found that most (83%) were tandem duplications in direct orientation. The remainder were triplications embedded within duplications (8.4%), adjacent duplications (4.2%), insertional translocations (2.5%), or other complex rearrangements (1.7%). In addition, we predicted six in-frame fusion genes at sequenced duplication breakpoints. Four gene fusions were formed by tandem duplications, one by two interconnected duplications, and one by duplication inserted at another locus. These novel fusion genes could be related to clinical phenotypes and warrant further study. Though most duplications are positioned head-to-tail adjacent to the original locus, those that are inverted, triplicated, or inserted can disrupt or fuse genes in a manner that may not be predicted by conventional copy number analysis. Thus, interpreting the genetic consequences of duplication CNVs requires breakpoint-level analysis.
2014-10-25 | GSE62657 | GEO
Project description:MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXLS families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ CNV breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated. To study the role of the genomic rearrangement structures on an individual’s clinical phenotypic variability, we employed a comprehensive genomics, transcriptomics, and deep phenotyping analysis approach on 137 individuals affected by MRXSL. Genomic structural information was correlated with transcriptomic and quantitative phenotypic analysis using Human Phenotype Ontology (HPO) semantic similarity scores. Duplication sizes in the cohort ranging from 64 kb to 16.5 Mb were classified into four categories comprising of tandem duplications (47%), terminal duplications (23%), inverted triplication structures (23%), and other CGRs (7%). A majority of the terminal duplication structures consist of translocations (65%) followed by recombinant chromosomes (23%). Notably, 67% of de novo events occurred in the terminal duplication group in contrast with 17% observed in tandem duplications. RNAseq data from lymphoblastoid cell lines indicated that the MECP2 transcript quantity in MECP2 triplications is statistically different from all duplications, but not between other classes of genomic structures. We also observed a significant (p < 0.05) correlation (Pearson R = 0.6, Spearman = 0.63) between the log-transformed MECP2 RNA levels and MeCP2 protein levels, demonstrating that genomic aberrations spanning MECP2 lead to altered MECP2 RNA and MeCP2 protein levels. Genotype-phenotype analyses indicated a gradual worsening of phenotypic features, including overall survival, developmental levels, microcephaly, epilepsy, and genitourinary/eye abnormalities in the following order: tandem duplications, other CGRs, terminal duplications/translocations, and triplications encompassing MECP2. In aggregate, this combined analysis uncovers an interplay between MECP2 dosage, genomic rearrangement structure and phenotypic traits. Whereas the level of MeCP2 is a key determinant of the phenotype, the DNA rearrangement structure can contribute to clinical severity and disease expression variability. Employing this type of analytical approach will advance our understanding of the impact of genomic rearrangements on genomic disorders and may help guide more targeted therapeutic approaches.
2024-08-12 | GSE256075 | GEO