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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 -
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 -
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 -
Nature Communications Jun 2015ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature...
ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring-Opitz syndrome. Here we demonstrate that ASXL1 truncations confer enhanced activity on the ASXL1-BAP1 complex. Stable expression of truncated, hyperactive ASXL1-BAP1 complexes in a haematopoietic precursor cell line results in global erasure of H2AK119Ub, striking depletion of H3K27me3, selective upregulation of a subset of genes whose promoters are marked by both H2AK119Ub and H3K4me3, and spontaneous differentiation to the mast cell lineage. These outcomes require the catalytic activity of BAP1, indicating that they are downstream consequences of H2AK119Ub erasure. In bone marrow precursors, expression of truncated ASXL1-BAP1 complex cooperates with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo. Our data raise the possibility that ASXL1 truncation mutations confer gain-of-function on the ASXL-BAP1 complex.
Topics: Animals; Bone Marrow Cells; Cell Differentiation; Craniosynostoses; HEK293 Cells; Hematopoietic Stem Cells; Histones; Humans; Intellectual Disability; Leukemia, Myeloid; Mast Cells; Mice; Mice, Inbred C57BL; Mutation; Promoter Regions, Genetic; Repressor Proteins; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 26095772
DOI: 10.1038/ncomms8307 -
Acta Orthopaedica Apr 2017Background and purpose - Studies have indicated that one-third of children with cerebral palsy (CP) develop dislocation of the hip that needs surgical intervention. When...
Background and purpose - Studies have indicated that one-third of children with cerebral palsy (CP) develop dislocation of the hip that needs surgical intervention. When hip dislocation occurs during childhood surgical treatment consists of tenotomies, femoral varus derotation osteotomy (VDRO), and acetabuloplasty. Relapse is observed in one-fifth of cases during adolescence. In this prospective cohort study, we performed a descriptive evaluation of translation and rotation across VDROs in children with neuromuscular disorders and syndromes by radiostereometric analysis (RSA). We assessed "RSA stability" and migration across the VDROs. Patients and methods - Children with a neuromuscular disorder were set up for skeletal corrective surgery of the hip. RSA follow-ups were performed postoperatively, at 5 weeks, and 3, 6, and 12 months after surgery. Results - 27 femoral VDROs were included; 2 patients were excluded during the study period. RSA data showed stability across the VDRO in the majority of cases within the first 5 weeks. At the 1-year follow-up, the mean translations (SD) of the femoral shaft distal to the VDRO were 0.51 (1.12) mm medial, 0.69 (1.61) mm superior, and 0.21 (1.28) mm posterior. The mean rotations were 0.39° (2.90) anterior tilt, 0.02° (3.07) internal rotation, and 2.17° (2.29) varus angulation. Interpretation - The migration stagnates within the first 5 weeks, indicating stability across the VDRO in most patients.
Topics: Acetabulum; Adolescent; Angelman Syndrome; Cerebral Palsy; Child; Child, Preschool; Cohort Studies; Craniosynostoses; Female; Femur; Hip Dislocation; Humans; Intellectual Disability; Joint Instability; Male; Osteotomy; Prospective Studies; Plastic Surgery Procedures; Rett Syndrome; Rotation; Tenotomy; Treatment Outcome
PubMed: 27892801
DOI: 10.1080/17453674.2016.1263110 -
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