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Multi-omics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and non-canonical Wnt signaling dysregulation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230696 | GEO | 2023/04/27

REPOSITORIES: GEO

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Multi-omics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and non-canonical Wnt signaling dysregulation [CUT&RUN Fibro]

Project description:We performed genome-wide analysis of protein-DNA binding using data obtained from CUT&RUN of BOS patient and control individual fibroblast samples to dissect the effects of truncating ASXL1 mutations. We performed genome-wide analysis of protein-DNA binding using data obtained from CUT&RUN of BOS patient and control individual fibroblast samples.

2023-04-27 | GSE230695 | GEO

Multi-omics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and non-canonical Wnt signaling dysregulation [ATAC-seq Fibro]

Project description:We performed genome-wide chromatin accessibility analysis using data obtained from ATAC-seq of BOS patient and control individual fibroblast samples to dissect the chromatin regulating effects of truncating ASXL1 mutations. We performed genome-wide chromatin accessibility analysis using data obtained from ATAC-seq of BOS patient and control individual fibroblast samples.

2023-04-27 | GSE230688 | GEO

Multi-omics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and non-canonical Wnt signaling dysregulation [RNA-seq Fibro]

Project description:We performed gene expression profiling analysis using data obtained from RNA-seq of BOS patient and control individual fibroblast samples to dissect the transcriptomic effects of truncating ASXL1 mutations. We performed gene expression profiling analysis using data obtained from RNA-seq of BOS patient and control individual fibroblast samples.

2023-04-27 | GSE230686 | GEO

Multi-omics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and non-canonical Wnt signaling dysregulation [RNA-seq blood]

Project description:We performed gene expression profiling analysis using data obtained from RNA-seq of BOS patient and control individual blood samples to dissect the transcriptomic effects of truncating ASXL1 mutations. We performed gene expression profiling analysis using data obtained from RNA-seq of BOS patient and control individual blood samples.

2023-04-27 | GSE230685 | GEO

The ASXL1 mutation p.Gly646Trpfs*12 found in a Turkish boy with Bohring-Opitz Syndrome.

Project description:In line with a recent study showing that ASXL1 mutations found in the common population cannot be ruled out as pathogenic, we have identified the ASXL1 p.Gly646Trpfs*12 mutation-present in 132 individuals in ExAC-as a very probable cause of the disease in a Bohring-Opitz syndrome patient.

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Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome.

Project description:The clinical interpretation of genetic variants has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC) database. Pathogenic variants in genes associated with severe, pediatric-onset, highly penetrant, autosomal dominant conditions are assumed to be absent or rare in these databases. Exome sequencing of a 6-year-old female patient with seizures, developmental delay, dysmorphic features, and failure to thrive identified an ASXL1 variant previously reported as causative of Bohring-Opitz syndrome (BOS). Surprisingly, the variant was observed seven times in the ExAC database, presumably in individuals without BOS. Although the BOS phenotype fit, the presence of the variant in reference population databases introduced ambiguity in result interpretation. Review of the literature revealed that acquired somatic mosaicism of ASXL1 variants (including pathogenic variants) during hematopoietic clonal expansion can occur with aging in healthy individuals. We examined all ASXL1 truncating variants in the ExAC database and determined most are likely somatic. Failure to consider somatic mosaicism may lead to the inaccurate assumption that conditions like BOS have reduced penetrance, or the misclassification of potentially pathogenic variants.

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De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome.

Project description:Molecular diagnostics can resolve locus heterogeneity underlying clinical phenotypes that may otherwise be co-assigned as a specific syndrome based on shared clinical features, and can associate phenotypically diverse diseases to a single locus through allelic affinity. Here we describe an apparently novel syndrome, likely caused by de novo truncating mutations in ASXL3, which shares characteristics with Bohring-Opitz syndrome, a disease associated with de novo truncating mutations in ASXL1.We used whole-genome and whole-exome sequencing to interrogate the genomes of four subjects with an undiagnosed syndrome.Using genome-wide sequencing, we identified heterozygous, de novo truncating mutations in ASXL3, a transcriptional repressor related to ASXL1, in four unrelated probands. We found that these probands shared similar phenotypes, including severe feeding difficulties, failure to thrive, and neurologic abnormalities with significant developmental delay. Further, they showed less phenotypic overlap with patients who had de novo truncating mutations in ASXL1.We have identified truncating mutations in ASXL3 as the likely cause of a novel syndrome with phenotypic overlap with Bohring-Opitz syndrome.

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Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice.

Project description:De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood mortality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models, we found that Asxl1 global loss as well as conditional deletion in osteoblasts and their progenitors led to significant bone loss and a markedly decreased number of bone marrow stromal cells (BMSCs) compared with wild-type littermates. Asxl1(-/-) BMSCs displayed impaired self-renewal and skewed differentiation, away from osteoblasts and favoring adipocytes. RNA-sequencing analysis revealed altered expression of genes involved in cell proliferation, skeletal development, and morphogenesis. Furthermore, gene set enrichment analysis showed decreased expression of stem cell self-renewal gene signature, suggesting a role of Asxl1 in regulating the stemness of BMSCs. Importantly, re-introduction of Asxl1 normalized NANOG and OCT4 expression and restored the self-renewal capacity of Asxl1(-/-) BMSCs. Our study unveils a pivotal role of ASXL1 in the maintenance of BMSC functions and skeletal development.

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Measurable residual disease of canonical versus non-canonical DNMT3A, TET2, or ASXL1 mutations in AML at stem cell transplantation.

Project description: Not available

| S-EPMC8486652 | biostudies-literature

Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies.

Project description:Additional Sex Combs-Like 1 (ASXL1) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter-driven Flag-Asxl1Y588X transgenic mouse model, Asxl1Y588X Tg, to express a truncated FLAG-ASXL1aa1-587 protein in the hematopoietic system. The Asxl1Y588X Tg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with ASXL1 mutations. ATAC- and RNA-sequencing analyses revealed that the ASXL1aa1-587 truncating protein expression results in more open chromatin in cKit+ cells compared with wild-type cells, accompanied by dysregulated expression of genes critical for HSC self-renewal and differentiation. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation experiments showed that ASXL1aa1-587 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Asxl1Y588X Tg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1aa1-587 plays a gain-of-function role in promoting myeloid malignancies. Our model provides a powerful platform to test therapeutic approaches of targeting the ASXL1 truncation mutations in myeloid malignancies.

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