Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

SUBMITTER: Urreizti R

PROVIDER: S-EPMC6099046 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

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

Urreizti Roser R Gürsoy Semra S Castilla-Vallmanya Laura L Cunill Guillem G Rabionet Raquel R Erçal Derya D Grinberg Daniel D Balcells Susana S

Clinical case reports 20180610 8

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. ...[more]

PMID: 30147881

Similar Datasets

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

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

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.

| S-EPMC4911496 | 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 [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

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

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

DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes.

Project description:The additional sex combs-like (ASXL) gene family-encoded by ASXL1, ASXL2, and ASXL3-is crucial for mammalian development. Pathogenic variants in the ASXL gene family are associated with three phenotypically distinct neurodevelopmental syndromes. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show consistent patterns of genome-wide DNA methylation (DNAm) alterations, i.e., DNAm signatures in peripheral blood. Given the role of ASXL1 in chromatin modification, we hypothesized that pathogenic ASXL1 variants underlying Bohring-Opitz syndrome (BOS) have a unique DNAm signature. We profiled whole-blood DNAm for 17 ASXL1 variants, and 35 sex- and age-matched typically developing individuals, using Illumina's Infinium EPIC array. We identified 763 differentially methylated CpG sites in individuals with BOS. Differentially methylated sites overlapped 323 unique genes, including HOXA5 and HOXB4, supporting the functional relevance of DNAm signatures. We used a machine-learning classification model based on the BOS DNAm signature to classify variants of uncertain significance in ASXL1, as well as pathogenic ASXL2 and ASXL3 variants. The DNAm profile of one individual with the ASXL2 variant was BOS-like, whereas the DNAm profiles of three individuals with ASXL3 variants were control-like. We also used Horvath's epigenetic clock, which showed acceleration in DNAm age in individuals with pathogenic ASXL1 variants, and the individual with the pathogenic ASXL2 variant, but not in individuals with ASXL3 variants. These studies enhance our understanding of the epigenetic dysregulation underpinning ASXL gene family-associated syndromes.

| S-EPMC9177544 | biostudies-literature