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American Journal of Medical Genetics Jun 2000
Topics: Abnormalities, Multiple; Female; Humans; Infant, Newborn; Syndrome
PubMed: 10861670
DOI: 10.1002/1096-8628(20000619)92:5<366::aid-ajmg15>3.0.co;2-u -
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 -
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.... Dec 2015Bohring-Opitz syndrome (BOS) was first described by Bohring et al. [1999]. The authors reported four cases which had several features in common, including a prominent... (Review)
Review
Bohring-Opitz syndrome (BOS) was first described by Bohring et al. [1999]. The authors reported four cases which had several features in common, including a prominent metopic suture, hypertelorism, exophthalmos, cleft lip and palate, limb anomalies, as well as difficulty feeding with severe developmental delays. In almost 50% of cases that meet the clinical criteria for BOS, de novo frameshift and nonsense mutations in the ASXL1 gene have been detected, suggesting that loss of function of this gene is a major cause. We report on the clinical characterization of one young female patient who was evaluated because of severe developmental delays, failure to thrive, and multiple minor anomalies and was clinically diagnosed with BOS. Whole exome sequencing analysis detected one novel disruptive frameshift mutation in the ASXL1 gene and we were also able to confirm the presence of two CFTR mutations associated with her chronic pancreatitis with acute severe breakthrough attacks requiring multiple ICU admissions. This latter complication of pancreatitis further contributed to the complexity of the clinical presentation and represents an independent genetic finding. Our case report emphasizes the importance of highly specific phenotypic characterization of patients with complex phenotypes before proceeding with molecular studies. That approach will lead to more accurate molecular data interpretation and better clinical genetic diagnosis, particularly for those patients with rare, difficult-to-diagnose disorders.
Topics: Abnormalities, Multiple; Adolescent; Adult; Craniosynostoses; Exome; Female; Frameshift Mutation; High-Throughput Nucleotide Sequencing; Humans; Intellectual Disability; Prognosis; Repressor Proteins
PubMed: 26364555
DOI: 10.1002/ajmg.a.37342 -
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.... May 2018Bohring-Opitz syndrome (BOS) is characterized clinically by severe developmental delays, microcephaly, failure to thrive, and characteristic facial features (prominent...
Bohring-Opitz syndrome (BOS) is characterized clinically by severe developmental delays, microcephaly, failure to thrive, and characteristic facial features (prominent eyes, facial nevus simplex [flammeus], and others). Most patients meeting the clinical criteria for BOS (MIM: 605039) have a de novo nonsense or frameshift variant in ASXL1. We report a case of BOS caused by a pathogenic ASXL1 variant inherited from a germline mosaic mother. The ASXL1 mutation was detected via trio exome sequencing. The sequencing data demonstrated that the variant was inherited maternally but that the maternal variant was underrepresented in comparison to the normal allele. These results suggested maternal mosaicism for the variant. Additional testing on the mother was performed on buccal cell DNA, which was also consistent with mosaicism. The mother had been reported to be healthy and the family history is unremarkable. This is the first report of BOS caused by a mutation inherited from an unaffected, presumed germline mosaic parent. This phenomenon has been reported for other traditionally de novo dominant disorders like CHARGE syndrome and Cornelia de Lange syndrome. This case emphasizes the need for accurate low but non-negative recurrence risk counseling for families with children with BOS and it impacts exome interpretation strategy.
Topics: Alleles; Child, Preschool; Craniosynostoses; DNA Mutational Analysis; Exons; Facies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Germ-Line Mutation; Humans; Intellectual Disability; Male; Maternal Inheritance; Mutation; Phenotype; Polymorphism, Single Nucleotide; Repressor Proteins
PubMed: 29681100
DOI: 10.1002/ajmg.a.38686 -
Clinical Genetics Jan 2020Crisponi/cold-induced sweating syndrome (CS/CISS) is an autosomal recessive disease characterized by hyperthermia, camptodactyly, feeding and respiratory difficulties... (Review)
Review
Crisponi/cold-induced sweating syndrome (CS/CISS) is an autosomal recessive disease characterized by hyperthermia, camptodactyly, feeding and respiratory difficulties often leading to sudden death in the neonatal period. The affected individuals who survived the first critical years of life, develop cold-induced sweating and scoliosis in early childhood. The disease is caused by variants in the CRLF1 or in the CLCF1 gene. Both proteins form a heterodimeric complex that acts on cells expressing the ciliary neurotrophic factor receptor (CNTFR). CS/CISS belongs to the family of "CNTFR-related disorders" showing a similar clinical phenotype. Recently, variants in other genes, including KLHL7, NALCN, MAGEL2 and SCN2A, previously linked to other diseases, have been associated with a CS/CISS-like phenotype. Therefore, retinitis pigmentosa and Bohring-Optiz syndrome-like (KLHL7), Congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome (NALCN), Chitayat-Hall/Schaaf-Yang syndrome (MAGEL2), and early infantile epileptic encephalopathy-11 syndrome (SCN2A) all share an overlapping phenotype with CS/CISS, especially in the neonatal period. This review aims to summarize the existing literature on CS/CISS, focusing on the current state of differential diagnosis, pathogenesis and treatment concepts in order to achieve an accurate and rapid diagnosis. This will improve patient management and enable specific treatments for the affected individuals.
Topics: Ciliary Neurotrophic Factor Receptor alpha Subunit; Craniosynostoses; Cytokines; Death, Sudden; Diagnosis, Differential; Facies; Hand Deformities, Congenital; Humans; Hyperhidrosis; Intellectual Disability; Receptors, Cytokine; Retinitis Pigmentosa; Scoliosis; Trismus
PubMed: 31497877
DOI: 10.1111/cge.13639 -
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 -
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