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JCI Insight May 2023ASXL1 (additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression. De novo protein-truncating mutations in ASXL1 cause...
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.
Topics: Humans; Intellectual Disability; Mutation; Epigenesis, Genetic; Multiomics; Wnt Signaling Pathway; Repressor Proteins; Transcription Factors; Kidney Neoplasms
PubMed: 37053013
DOI: 10.1172/jci.insight.167744 -
European Journal of Human Genetics :... May 2011Bohring-Opitz syndrome (BOS) is a rare congenital disorder of unknown etiology diagnosed on the basis of distinctive clinical features. We suggest diagnostic criteria... (Review)
Review
Bohring-Opitz syndrome (BOS) is a rare congenital disorder of unknown etiology diagnosed on the basis of distinctive clinical features. We suggest diagnostic criteria for this condition, describe ten previously unreported patients, and update the natural history of four previously reported patients. This is the largest series reported to date, providing a unique opportunity to document the key clinical features and course through childhood. Investigations undertaken to try and elucidate the underlying pathogenesis of BOS using array comparative genomic hybridization and tandem mass spectrometry of cholesterol precursors did not show any pathogenic changes responsible.
Topics: Child, Preschool; Cholesterol; Comparative Genomic Hybridization; Craniosynostoses; Female; Humans; Infant; Intellectual Disability; Male
PubMed: 21368916
DOI: 10.1038/ejhg.2010.234 -
American Journal of Medical Genetics.... Sep 2015Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia,...
Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe intellectual disability, and feeding issues. Nine patients with Bohring-Opitz syndrome have been identified as having a mutation in ASXL1. We report on eight previously unpublished patients with Bohring-Opitz syndrome caused by an apparent or confirmed de novo mutation in ASXL1. Of note, two patients developed bilateral Wilms tumors. Somatic mutations in ASXL1 are associated with myeloid malignancies, and these reports emphasize the need for Wilms tumor screening in patients with ASXL1 mutations. We discuss clinical management with a focus on their feeding issues, cyclic vomiting, respiratory infections, insomnia, and tumor predisposition. Many patients are noted to have distinctive personalities (interactive, happy, and curious) and rapid hair growth; features not previously reported.
Topics: Abnormalities, Multiple; Bone Marrow Neoplasms; Child; Child, Preschool; Craniosynostoses; Female; Genetic Predisposition to Disease; Humans; Infant; Intellectual Disability; Male; Mutation; Repressor Proteins; Wilms Tumor
PubMed: 25921057
DOI: 10.1002/ajmg.a.37131 -
Stem Cell Reports Jun 2016De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood mortality. The underlying...
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.
Topics: Adipocytes; Animals; Bone Marrow Cells; Cell Differentiation; Cell Proliferation; Craniosynostoses; Disease Models, Animal; Gene Expression; Genetic Complementation Test; Humans; Intellectual Disability; Lentivirus; Mesenchymal Stem Cells; Mice; Nanog Homeobox Protein; Octamer Transcription Factor-3; Osteoblasts; Osteogenesis; Primary Cell Culture; Repressor Proteins; Sequence Analysis, RNA; Transduction, Genetic
PubMed: 27237378
DOI: 10.1016/j.stemcr.2016.04.013 -
The Medical Journal of Malaysia Aug 2017The diagnostic challenge of Bohring-Opitz Syndrome, a rare genetic disorder has haunted clinicians for ages. Our patient was born at term via caesarean-section with a...
The diagnostic challenge of Bohring-Opitz Syndrome, a rare genetic disorder has haunted clinicians for ages. Our patient was born at term via caesarean-section with a birth weight of 1.95 kilograms. She had mild laryngomalacia, gastroesophageal reflux disease and seizures. Physical signs included microcephaly, hemangioma, low set ears, cleft palate, micrognatia and the typical BOS posture. Chromosomal analysis showed 46 xx -Bohring-Opitz Syndrome overlapped with C- syndrome. Goal-directed holistic care with integration of parent/carer training was started very early. She succumbed to a Respiratory- Syncitial-Virus and Pseudomonas pneumonia complicated with sepsis at the age of two years and 11 months.
Topics: Child, Preschool; Craniosynostoses; Fatal Outcome; Female; Gastroesophageal Reflux; Humans; Intellectual Disability; Seizures
PubMed: 28889139
DOI: No ID Found -
European Journal of Human Genetics :... Jun 2022The 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...
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.
Topics: Animals; Craniosynostoses; DNA Methylation; Epigenesis, Genetic; Humans; Intellectual Disability; Mammals; Syndrome; Transcription Factors
PubMed: 35361921
DOI: 10.1038/s41431-022-01083-0 -
European Journal of Medical Genetics Jun 2019Biallelic pathogenic variants in KLHL7 are known to result in Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) like phenotype and Bohring-Opitz-like...
Biallelic pathogenic variants in KLHL7 are known to result in Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) like phenotype and Bohring-Opitz-like syndrome. In this report, a trio whole-exome sequencing (WES) was performed in proband with cold-induced sweating, microcephaly, facial dysmorphism, spasticity, failure to thrive, pigmentary abnormalities of the retina, hypoplasia of corpus callosum and periventricular nodular heterotopia. A novel homozygous in-frame deletion was identified in exon 2 of KLHL7, affecting the BTB domain of the protein. Our findings expand the clinical and molecular spectrum of KLHL7-related disorders.
Topics: Autoantigens; Craniosynostoses; Death, Sudden; Facies; Gene Deletion; Hand Deformities, Congenital; Homozygote; Humans; Hyperhidrosis; Infant; Intellectual Disability; Male; Phenotype; Protein Domains; Trismus
PubMed: 30142437
DOI: 10.1016/j.ejmg.2018.08.009 -
Human Mutation May 2017The clinical interpretation of genetic variants has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC) database.... (Review)
Review
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.
Topics: Aged; Aged, 80 and over; Alleles; Amino Acid Substitution; Child, Preschool; Craniosynostoses; Databases, Genetic; Facies; Female; Genetic Association Studies; Germ-Line Mutation; Humans; Infant; Intellectual Disability; Male; Middle Aged; Mutation; Phenotype; Repressor Proteins
PubMed: 28229513
DOI: 10.1002/humu.23203 -
American Journal of Medical Genetics.... Jun 2021Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but...
Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes. Bohring-Opitz syndrome (BOPS) was first described as a clinical syndrome and later found to be associated with pathogenic variants in ASXL1. This syndrome is characterized by developmental delay, microcephaly, characteristic facies, hypotonia, and feeding difficulties. Subsequently, pathogenic variants in ASXL2 were found to lead to Shashi-Pena syndrome (SHAPNS) and in ASXL3 to lead to Bainbridge-Ropers syndrome (BRPS). While SHAPNS and BRPS share many core features with BOPS, there also seem to be emerging clear differences. Here, we present five cases of BOPS, one case of SHAPNS, and four cases of BRPS. By adding our cohort to the limited number of previously published patients, we review the overlapping features of ASXL-related diseases that bind them together, while focusing on the characteristics that make each neurodevelopmental syndrome unique. This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families.
Topics: Adolescent; Adult; Child; Child, Preschool; Craniosynostoses; Developmental Disabilities; Female; Genetic Predisposition to Disease; Humans; Infant; Intellectual Disability; Male; Microcephaly; Muscle Hypotonia; Mutation; Phenotype; Repressor Proteins; Transcription Factors; Young Adult
PubMed: 33751773
DOI: 10.1002/ajmg.a.62156 -
Medicine Feb 2022Bohring-Opitz syndrome is a severe congenital disorder associated with a de novo mutation in the additional sex combs-like 1 (ASXL1) gene, and it is characterized by...
RATIONALE
Bohring-Opitz syndrome is a severe congenital disorder associated with a de novo mutation in the additional sex combs-like 1 (ASXL1) gene, and it is characterized by symptoms that include developmental delay and musculoskeletal and neurological features.
PATIENT CONCERNS
The patient was a girl, an in vitro fertilization (IVF) baby, with delayed motor development, drooling, short stature, slow growth, low muscle tone, image diagnosis of hypoplasia of the corpus callosum, delayed tooth eruption, high palatal arch, adduction of the thumb, drooling, not chewing, excessive joint activity, and ligament relaxation.
DIAGNOSIS
Whole-exome sequencing analysis detected 1 novel disruptive frameshift mutation in ASXL1 in the proband but wild-type ASXL1 in both parents.
INTERVENTIONS
Approximately 1 year of rehabilitation training, which included exercise therapy, toy imitation operation, cognition of daily objects, daily living skills training, gesture language training, oral muscle training, and hand movement training.
OUTCOMES
After approximately 1 year of training, the patient was 3 years old and able to eat normally without drooling. She was able to grasp objects and pick them up after they fell. She was able to grasp small objects and actively played with toys. In addition, she was able to crawl on the floor (at slow speed, with poor initiative), stand with assistance, and walk with assistance; she was unstable when standing unassisted (standing unassisted for 8 seconds at most during training).
LESSON
ASXL1 c.3762delT is a novel mutation that may be caused by IVF. This finding suggests that appropriate gene mutation detection approaches may be necessary for IVF technology.
Topics: Child, Preschool; Craniosynostoses; Female; Fertilization in Vitro; Humans; Infant; Intellectual Disability; Mutation; Phenotype; Repressor Proteins; Sialorrhea
PubMed: 35119035
DOI: 10.1097/MD.0000000000028759