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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 :... 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 -
Molecular Genetics & Genomic Medicine May 2022Bainbridge-Ropers syndrome (BRPS, OMIM #615485) was first identified in 2013 by Bainbridge et al. and is a neurodevelopment disorder characterized by failure to thrive,...
BACKGROUND
Bainbridge-Ropers syndrome (BRPS, OMIM #615485) was first identified in 2013 by Bainbridge et al. and is a neurodevelopment disorder characterized by failure to thrive, facial dysmorphism and severe developmental delay. BRPS is caused by heterozygous loss-of-function (LOF) variants in the additional sex combs-like 3 (ASXL3) gene. Due to the limited specific recognizable features and overlapping symptoms with Bohring-Opitz syndrome (BOS, OMIM #612990), clinical diagnosis of BRPS is challenging.
METHODS
In this study, a 2-year-8-month-old Chinese girl was referred for genetic evaluation of severe developmental delay. The reduced fetal movement was found during the antenatal period and bilateral varus deformity of feet was observed at birth. Whole-exome sequencing and Sanger sequencing were used to detect and confirm the variant.
RESULTS
A novel nonsense variant c.1063G>T (p.E355*) in the ASXL3 gene (NM_030632.3) was identified in the proband and the clinical symptoms were compatible with BRPS. The parents were physical and genetic normal and prenatal diagnosis was requested for her pregnant mother with a negative Sanger sequencing result.
CONCLUSION
The study revealed a de novo LOF variant in the ASXL3 gene and expanded the mutation spectrum for this clinical condition. By performing a literature review, we summarized genetic results and the clinical phenotypes of all BPRSs reported so far. More cases study may help to elucidate the function of the ASXL3 gene may be critical to understand the genetic aetiology of this syndrome and assist in accurate genetic counselling, informed decision making and prenatal diagnosis.
Topics: Child, Preschool; China; Craniosynostoses; Developmental Disabilities; Female; Humans; Intellectual Disability; Pregnancy; Transcription Factors
PubMed: 35276034
DOI: 10.1002/mgg3.1924 -
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 -
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 -
Cold Spring Harbor Molecular Case... Apr 2020An 18-yr-old man with a history of intellectual disability, craniofacial dysmorphism, seizure disorder, and obesity was identified to carry a de novo, pathogenic variant...
An 18-yr-old man with a history of intellectual disability, craniofacial dysmorphism, seizure disorder, and obesity was identified to carry a de novo, pathogenic variant in (c.4198G>T; p.E1400X) associated with the diagnosis of Bohring-Opitz syndrome based on exome sequencing. In addition, he was identified to carry a maternally inherited and likely pathogenic variant in (c.817C>T; p.Q273X) associated with monogenic obesity. Dual genetic diagnosis occurs in 4%-6% of patients and results in unique clinical phenotypes that are a function of tissue-specific gene expression, involved pathways, clinical expressivity, and penetrance. This case highlights the utility of next-generation sequencing in patients with an unusual combination of clinical presentations for several pillars of precision medicine including (1) diagnosis, (2) prognosis and outcome, (3) management and therapy, and (4) utilization of resources.
Topics: Adolescent; Alleles; Craniosynostoses; Developmental Disabilities; Facies; Genetic Association Studies; Genotype; Growth Charts; Humans; Intellectual Disability; Male; Medical History Taking; Mutation; Obesity, Morbid; Pedigree; Phenotype; Receptor, Melanocortin, Type 4; Repressor Proteins; Exome Sequencing
PubMed: 31969346
DOI: 10.1101/mcs.a004846 -
Journal of Genetics Dec 2019Mutations in genes involved in chromatin remodelling have been implicated in broad phenotypes of congenital abnormalities and neurodevelopment. However, limited...
Mutations in genes involved in chromatin remodelling have been implicated in broad phenotypes of congenital abnormalities and neurodevelopment. However, limited genotype-phenotype correlations are available for some of the rarest genetic disorders that affect chromatin regulation. We hereby describe a 12-year-old girl presented at birth with severe hypotonia, developmental delay, a mid-line capillary malformation and distinctive craniofacial features. During the natural history of her disease, the girl developed severe spasticity and drug-resistant seizures, leading to a diagnosis of Bohring-Opitz syndrome (BOS). We performed whole-exome sequencing (WES) and identified a mutation in (c.2033dupG) which results in the introduction of a premature stop codon (p.R678fs*6). encodes a polycomb repressive complex protein implicated in chromatin regulation and mutations are a known cause of BOS. Phenotypes with segmental craniofacial overgrowth associated to midline capillary malformations enlarge the clinical spectrum of BOS at onset and further expand the differential diagnosis in mutation carriers.
Topics: Base Sequence; Brain; Child; Codon, Nonsense; Craniosynostoses; Female; Genetic Association Studies; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Humans; Intellectual Disability; Muscle Hypotonia; Mutation; Pedigree; Phenotype; Repressor Proteins; Exome Sequencing
PubMed: 31819025
DOI: 10.1007/s12041-019-1155-5 -
Stem Cell Reports May 2019The neural crest (NC) gives rise to a multitude of fetal tissues, and its misregulation is implicated in congenital malformations. Here, we investigated molecular...
The neural crest (NC) gives rise to a multitude of fetal tissues, and its misregulation is implicated in congenital malformations. Here, we investigated molecular mechanisms pertaining to NC-related symptoms in Bohring-Opitz syndrome (BOS), a developmental disorder linked to mutations in the Polycomb group factor Additional sex combs-like 1 (ASXL1). Genetically edited human pluripotent stem cell lines that were differentiated to NC progenitors and then xenotransplanted into chicken embryos demonstrated an impairment of NC delamination and emigration. Molecular analysis showed that ASXL1 mutations correlated with reduced activation of the transcription factor ZIC1 and the NC gene regulatory network. These findings were supported by differentiation experiments using BOS patient-derived induced pluripotent stem cell lines. Expression of truncated ASXL1 isoforms (amino acids 1-900) recapitulated the NC phenotypes in vitro and in ovo, raising the possibility that truncated ASXL1 variants contribute to BOS pathology. Collectively, we expand the understanding of truncated ASXL1 in BOS and in the human NC.
Topics: Animals; Cell Differentiation; Cell Line; Cells, Cultured; Chick Embryo; Craniosynostoses; Gene Expression Profiling; Gene Regulatory Networks; Human Embryonic Stem Cells; Humans; Induced Pluripotent Stem Cells; Intellectual Disability; Mutation; Neural Crest; Pluripotent Stem Cells; Repressor Proteins; Transplantation, Heterologous
PubMed: 31006630
DOI: 10.1016/j.stemcr.2019.03.006 -
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 -
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