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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230695 | 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 [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 [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 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

Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.

Project description:ASXL1 (additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression. De novo protein-truncating mutations in ASXL1 cause Bohring-Opitz syndrome (BOS; OMIM #605039), a rare neurodevelopmental condition characterized by severe intellectual disabilities, distinctive facial features, hypertrichosis, increased risk of Wilms tumor, and variable congenital anomalies, including heart defects and severe skeletal defects giving rise to a typical BOS posture. These BOS-causing ASXL1 variants are also high-prevalence somatic driver mutations in acute myeloid leukemia. We used primary cells from individuals with BOS (n = 18) and controls (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations using comprehensive multiomics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral blood and skin fibroblasts. Our data show that regardless of cell type, ASXL1 mutations drive strong cross-tissue effects that disrupt multiple layers of the epigenome. The data showed a broad activation of canonical Wnt signaling at the transcriptional and protein levels and upregulation of VANGL2, which encodes a planar cell polarity pathway protein that acts through noncanonical Wnt signaling to direct tissue patterning and cell migration. This multiomics approach identifies the core impact of ASXL1 mutations and therapeutic targets for BOS and myeloid leukemias.

| S-EPMC10322691 | biostudies-literature

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-04-27 | GSE230696 | GEO

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

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

| PRJNA962140 | ENA

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.

| S-EPMC5487276 | biostudies-literature

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

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

| PRJNA962136 | ENA

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

Project description:BackgroundMolecular 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.MethodsWe used whole-genome and whole-exome sequencing to interrogate the genomes of four subjects with an undiagnosed syndrome.ResultsUsing 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.ConclusionWe have identified truncating mutations in ASXL3 as the likely cause of a novel syndrome with phenotypic overlap with Bohring-Opitz syndrome.

| S-EPMC3707024 | biostudies-literature

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