Bohring-Opitz Research Articles

Role of Nasopharyngeal Airway in Management of Craniofacial Syndrome-Associated Upper Airway Obstruction in Children.

Upper airway obstruction (UAO) management in children, particularly those with associated anatomical mid-face structural differences, poses a significant challenge. This study describes using a nasopharyngeal airway (NPA) in managing infants with severe upper airway obstruction. Infants discharged home from Queensland Children's Hospital with an NPA insitu for the management of upper airway obstruction were retrospectively evaluated for clinical and demographic parameters, underlying diagnoses and respiratory support, including NPA insertion details and comorbidities. Sixty-seven children (24 male) were included with a median age at NPA insertion of 24 (IQR 7-59) days and a median duration of NPA use of 229.1 (IQR 151.50-297.75) days. Fifty-two (77.6%) had Pierre Robin sequence. Other diagnoses included CHARGE syndrome, Treacher Collins syndrome, Stickler syndrome, Crouzon syndrome, Bohring-Opitz syndrome, isolated cleft palate, Beckwith-Wiedemann syndrome, Chromosome 3 deletion and VACTERL association. Four infants required tracheostomy, and no complications related to NPA use were reported. Those with oximetry and polysomnography data showed improving indices following NPA insertion [pre NPA median (IQR) SpO2: 95.9% (94.73-97.73), AHI: 51.40 (44.50-69.45), OAHI 65.9 (56.45-73.35) and TcCO2 (mmHg) 65.70 (61.95-67.30) vs. post-NPA median (IQR) SpO2: 97.1% (96.19-97.9), AHI: 12.20 (11.25-24.35), OAHI 10.20 (6.12-5.62) and TcCO2 (mmHg) 52.40 (47.90-58.40)]. Our findings highlight the effectiveness and safety of NPA as a noninvasive management option for severe upper airway obstruction in children, particularly in those with anatomical midface structural differences. Further research and larger studies are warranted to confirm these findings and optimise management strategies for these patients.

Bohring–Opitz syndrome: Unraveling neonatal hypoglycemia and early detection through whole exome sequencing

Bohring–Opitz syndrome: Unraveling neonatal hypoglycemia and early detection through whole exome sequencing

Examining the neurodevelopmental and motor phenotypes of Bohring-Opitz syndrome (ASXL1) and Bainbridge-Ropers syndrome (ASXL3).

Chromatin Modifying Disorders (CMD) have emerged as one of the most rapidly expanding genetic disorders associated with autism spectrum disorders (ASD). Motor impairments are also prevalent in CMD and may play a role in the neurodevelopmental phenotype. Evidence indicates that neurodevelopmental outcomes in CMD may be treatable postnatally; thus deep phenotyping of these conditions can improve clinical screening while improving the development of treatment targets for pharmacology and for clinical trials. Here, we present developmental phenotyping data on individuals with Bohring-Optiz Syndrome (BOS - ASXL1) and Bainbridge-Ropers Syndrome (BRS - ASXL3) related disorders, two CMDs highly penetrant for motor and developmental delays. To phenotype the motor and neurodevelopmental profile of individuals with ASXL1 and ASXL3 related disorders (BOS and BRS). To provide a preliminary report on the association of motor impairments and ASD. Neurodevelopmental and motor phenotyping was conducted on eight individuals with pathogenic ASXL1 variants and seven individuals with pathogenic ASXL3 variants, including medical and developmental background intake, movement and development questionnaires, neurological examination, and quantitative gait analysis. Average age of first developmental concerns was 4 months for individuals with BOS and 9 months in BRS. 100% of individuals who underwent the development questionnaire met a diagnosis of developmental coordination disorder. 71% of children with BOS and 0% of children with BRS noted movement difficulty greatly affected classroom learning. Participants with BRS and presumed diagnoses of ASD were reported to have more severe motor impairments in recreational activities compared to those without ASD. This was not the case for the individuals with BOS. Motor impairments are prevalent and pervasive across the ASXL disorders with and without ASD, and these impairments negatively impact engagement in school-based activities. Unique neurodevelopmental and motor findings in our data include a mixed presentation of hypo and hypertonia in individuals with BOS across a lifespan. Individuals with BRS exhibited hypotonia and greater variability in motor skills. This deep phenotyping can aid in appropriate clinical diagnosis, referral to interventions, and serve as meaningful treatment targets in clinical trials.

Bohring opitz syndrome: a rare case report

Bohring- Opitz syndrome (BOS) first described by Bohring et al in 1999, is a rare congenital disorder of unknown etiology. He described 4 cases with characteristic features. This syndrome is characterized by distinctive facial features and posture, growth failure, variable intellectual disability, and variable anomalies. The diagnosis of BOS is established in a proband with suggestive clinical features and/or Identification of constitutional heterozygous pathogenic variant in ASXL1 by molecular genetic testing. We presented a case which phenotypically and genetically matches the findings of this syndrome.

Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.

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.

Clinical findings in 39 individuals with Bohring-Opitz syndrome from a global patient-driven registry with implications for tumor surveillance and recurrence risk.

Bohring-Opitz syndrome (BOS) is a rare genetic condition caused by pathogenic variants in ASXL1, which is a gene involved in chromatin regulation. BOS is characterized by severe intellectual disabilities, distinctive facial features, hypertrichosis, facial nevus simplex, severe myopia, a typical posture in infancy, variable anomalies, and feeding issues. Wilms tumor has also been reported in two individuals. We report survey data from the largest known cohort of individuals with BOS with 34 participants from the ASXL Patient-Driven Registry and data on five additional individuals with notable findings. Important or novel findings include hepatoblastoma (n= 1), an additional individual with Wilms tumor, two families with a parent who is mosaic including a pair of siblings, birth weights within the normal range for the majority of participants, as well as presence of craniosynostosis and hernias. Data also include characterization of communication, motor skills, and care level including hospitalization frequency and surgical interventions. No phenotype-genotype correlation could be identified. The ASXL Registry is also presented as a crucial tool for furthering ASXL research and to support the ASXL community.

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

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.

De novo nonsense variant in ASXL3 in a Chinese girl causing Bainbridge-Ropers syndrome: A case report and review of literature.

BackgroundBainbridge‐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.MethodsIn 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.ResultsA 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.ConclusionThe 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.

Preterm Infant with Craniofacial Dysmorphic Features and Posture.

Preterm Infant with Craniofacial Dysmorphic Features and Posture.

Variant of bohring-opitz syndrome: A rare case report

Bohring–Opitz syndrome also known as Opitz C syndrome or Oberklaid–Danks syndrome is a rare syndrome. We are reporting a 2 months old male child with Bohring-Opitz like syndrome with all classical features and eventration of diaphragm (left side) which has not been reported yet with this syndrome. To our knowledge, a total of 23 cases with this syndrome have been reported in the medical literature to date and this is probably the first case report from India. Although there is overlap, a clinical distinction from the Bohring-Opitz syndrome and other syndromes seems possible, and thus a specific causal entity may be postulated.

Loss of ASXL1 in the Bone Marrow Niche Dysregulates Hematopoietic Stem Cell Fates through RNA Polymerase II Complex

Introduction: Somatic or de novo mutations of Additional Sex Combs-like 1 (ASXL1) frequently occur in patients with myeloid malignancies or Bohring-Opitz syndrome, respectively. Conditional deletion of Asxl1 in hematopoietic system (Asxl1Δ/Δ, Abdel-Wahab et al. J Exp Med 2013) or global loss of Asxl1 (Asxl1-/-, Wang et al. Blood 2014) resulted in myeloid malignancies in mice. Interestingly, hematopoietic disease phenotypes are severer in Asxl1-/- mice than that in Asxl1Δ/Δ mice. The difference in disease severity between the two different mouse models led us to hypothesize that ASXL1 plays an important role in the function of marrow niche for normal hematopoiesis and deletion of Asxl1 in the niche contributes to the hematopoietic defect in vivo.Methods: In the current study, we performed a serial hematopoietic phenotypic analyses in OsxCre;Asxl1fl/fl mice, in which Asxl1 is only deleted in the mesenchymal stromal cells (MSCs) and preosteoblasts. Bone marrow (BM) transplantation was performed to identify the biological effects of ASXL1 loss in the niche on hematopoietic stem cell (HSC) functions. Convergent analyses of RNA-seq and ChIP-seq data were performed to survey ASXL1 target genes that are critical for HSC maintenance.Results:OsxCre;Asxl1fl/fl mice had a reduced LT-HSC pool and skewed cell differentiation favoring granulocytic/monocytic lineages in the BM by flow cytometric analyses. Co-culture of MSC with Lin-cKit+ (LK) cells revealed that Asxl1-/- MSCs induced a preferential myeloid differentiation of LK cells compared with WT MSCs. BM transplantation assay further confirmed that deletion of Asxl1 in MSCs/preosteoblasts resulted in a reduced HSC pool and a preferential myeloid lineage increment. Gene set enrichment analysis of RNA-seq data showed that downregulated genes in Asxl1-/- MSCs were enriched in cell cycle, stem cell division/proliferation, and cell surface receptor signaling pathway. Gene ontology analysis revealed that some of the differentially expressed genes were associated with cell cycle, cell division/proliferation, extracellular matrix organization, and cell adhesion. Protein mass spectrometry analysis and immunoprecipitation demonstrated a novel interaction of ASXL1 with multiple core subunits of RNA polymerase II (RNAPII) complex. Gel filtration chromatography assay verified the interaction between ASXL1 and RNAPII. ChIP-seq analysis using ASXL1 and RNAPII antibodies showed a high degree of the overlap peaks between ASXL1 and RNAPII bound genes. Convergent analyses of RNA-seq and ChIP-seq data revealed that loss of Asxl1 deregulated RNAPII transcriptional function and altered the expression of genes critical for HSC maintenance, such as Cxcl1, Cxcl2, and Vcam1 . Importantly, ASXL1 expression decreased markedly in MSCs of patients with chronic myelomonocytic leukemia (CMML-MSCs) compared with that in healthy donors. Consistently, co-culture of CMML-MSCs with cord blood CD34+ cells revealed that CMML-MSCs had a reduced hematopoietic supportive activity and induced a myeloid differentiation bias of CD34+ cells.Conclusion: Our in vivo studies demonstrate that Asxl1 in MSCs/preosteoblasts is required for normal hematopoiesis through regulating RNAPII transcriptional function. This study provides a mechanistic insight into the function of ASXL1 in the niche to maintain normal hematopoiesis; and ASXL1 alteration in, at least, a subset of the niche cells induces myeloid differentiation bias, thus, contributes the progression of myeloid malignancies. DisclosuresNo relevant conflicts of interest to declare.

Modeling ASXL1 Mutation Revealed Myelodysplasia Caused By Derepression of p16Ink4a through Aberrant PRC1-Mediated Histone Modification

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant condition in patients with blood cells that possess somatic mutations of genes known to be recurrently mutated in hematologic malignancies. Among them is additional sex combs like 1 (ASXL1), whose mutation is frequent in various myeloid malignancies and associated with poor prognosis, and ASXL1 is known to act as an epigenetic modulator. Despite the clinical impact of ASXL1 mutations in myeloid malignancies, lack of animal models expressing mutated Asxl1 at endogenous levels mimicking human ASXL1-mutated diseases hinders from dissecting precise molecular mechanisms of mutated Asxl1. Here in this study, with newly generated knock-in mice carrying a frameshift mutation at the exon 13 of the Asxl1 gene (Asxl1G643WfsX12), which is identical to the most frequent human ASXL1 G646WfsX12 mutation, we extensively investigated the biological effects of the mutant.Asxl1G643fs/+ mice showed decreased body size and weight, resembling hypomorphic features in patients with Bohring-Opitz syndrome carrying de novo constitutive ASXL1 mutation.Asxl1G643fs/+ mice developed slowly progressive peripheral leukopenia, and Wright-Giemsa stain of bone marrow (BM) cells from Asxl1G643fs/+ mice showed dysplastic myeloid cells represented by hypersegmented neutrophils, apoptotic neutrophils and hyposegmented neutrophils with fine nuclear bridging consistent with pseudo-Pelger-Huët anomaly. Flow cytometric analyses of Asxl1G643fs/+ BM cells confirmed aberrant myeloid differentiation with significant increase of granulocytic and monocytic cell fraction, significant decrease of hematopoietic stem cell (HSC) pool (c-kit+ Sca-1+ Lin- (LSK) cells and CD34- CD135- LSK cells), increased apoptosis in hematopoietic stem/progenitor cells (HSPC) and significant accumulation of G1-phase HSC in the cell cycle analysis, all of which were reminiscent of human myelodysplastic syndromes (MDS). Interestingly, Asxl1G643fs/+ mice became moribund about 600 days after birth when compared to Asxl1+/+ littermates with anemia, leukocytosis, neutrophilia/monocytosis and hepatosplenomegaly, suggesting the development of MDS/myeloproliferative neoplasm (MPN)-like disease, most relevant to human cases with chronic myelomonocytic leukemia.RNA sequencing and gene set enrichment analysis in Asxl1G643fs/+ mice identified derepression of sets of genes that are normally repressed by BMI1, a critical regulator of histone modification in polycomb repressive comprex 1 (PRC1). Among these genes were p16Ink4a, p21, and p15Ink4b all of which were significantly upregulated in Asxl1G643fs/+ LSK cells. We performed chromatin immunoprecipitation (ChIP) assay with an anti-H2AK119ub1 antibody using LSK cells from Asxl1G643fs/+ mice and found that H2AK119ub1 level around the promoter region of p16Ink4a was significantly decreased in Asxl1G643fs/+ LSK cells, suggesting perturbation of Bmi1-driven H2AK119ub1 histone modification by mutated Asxl1. Co-immunoprecipitation assay and in vitro pull-down assay revealed that the mutant form of ASXL1 had no ability to interact with BMI1 as opposed to wild type ASXL1 protein. In addition, we performed ChIP assay with an anti-BMI1 and anti-FLAG antibody using a cell line stably expressed FLAG-tagged wild-type (WT) ASXL1 or mutant form (MT), and found that BMI1 level around the promoter region of p16Ink4a was significantly decreased in the ASXL1 MT-expressed cell line, whereas no significant change in the FLAG level between WT and MT. Furthermore, we intercrossed Asxl1G643fs/+ mice with p16Ink4a heterozygous knock out mice to elucidate the effect of p16Ink4a up-regulation in Asxl1G643fs/+ mice, and found restoration of HSC pool and amelioration of increased apoptosis in HSPC obtained from Asxl1G643fs/+p16Ink4a+/- mice. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in MDS-like phenotypes represented by decreased HSC pool and aberrant myeloid differentiation in Asxl1G643fs/+ mice.Taken together, our Asxl1 G643fs mutation knock-in mouse line is useful as a model of CHIP or early stage MDS, and our detailed analysis highlights the functional role of ASXL1 mutation on MDS and MDS /MPN development. DisclosuresMasamoto:Astellas Pharma Inc.: Research Funding; Nippon Shinyaku Co., Ltd.: Other: Scholarship donations for the laboratory; Pfizer Inc.: Research Funding. Arai:Bristol-Myers Squibb: Research Funding. Kurokawa:Takeda Pharmaceutical Company Limited.: Research Funding, Speakers Bureau; Celgene Corporation: Speakers Bureau; Pfizer Inc.: Research Funding; Bristol-Myers Squibb: Speakers Bureau; Astellas Pharma Inc.: Research Funding; Nippon Shinyaku Co., Ltd.: Other: Scholarship donations for the laboratory, Speakers Bureau.

Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature.

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.

Novel truncating mutations in ASXL1 identified in two boys with Bohring-Opitz syndrome

Bohring-Opitz syndrome (BOS, or BOPS) is a rare congenital genetic disorder with multisystem abnormalities characterized by significant craniofacial dysmorphism, feeding difficulties, severe developmental delay, profound intellectual disability, flexion of elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints. Here, we report two Chinese BOS patients with distinctive phenotypes caused by novel truncating mutations. One was a boy aged 5 years 9 months who had a novel c.1049G>A/p.Trp350* mutation in ASXL1 and displayed relatively mild BOS symptoms with autism features. The other was a 16-month-old boy who carried a novel c.2689delC/p.His897Ilefs*11 mutation and displayed typical BOS symptoms. New cases with novel mutations, along with a detailed clinical and molecular analysis are important for a better diagnosis and understanding of BOS.

Further expanding the clinical phenotype in Bainbridge-Ropers syndrome and dissecting genotype-phenotype correlation in the ASXL3 mutational cluster regions

Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, intellectual disability with poor or absent speech, feeding difficulties, growth failure, specific craniofacial and minor skeletal features. It was firstly reported in 2013 by Bainbridge et al., who observed a group of individuals sharing overlapping features with Bohring-Opitz syndrome which were caused by pathogenic variant in ASXL1, who indeed carried truncating mutations in ASXL3. To date, 33 cases were described in the literature. BRPS is caused by loss-of-function mutations in ASXL3 which are mostly located in two mutational cluster regions (MCR). The exact molecular mechanism of these mutations resulting in the disease phenotype is still uncertain due to the observation of LOF mutations in healthy population. Here, we report four individuals with BRPS carrying de novo LOF mutations in ASXL3, comparing and summarizing the clinical phenotype of all BRPS reported so far. Furthermore, we try to dissect the genotype-phenotype correlation among the two well reported MCRs in all BRPS from the literature.

A de novo truncating mutation in ASXL1 associated with segmental overgrowth

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 de novo mutation in ASXL1 (c.2033dupG) which results in the introduction of a premature stop codon (p.R678fs*6). ASXL1 encodes a polycomb repressive complex protein implicated in chromatin regulation and de novo 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 ASXL1 mutation carriers.

Pathological ASXL1 Mutations and Protein Variants Impair Neural Crest Development.

SummaryThe 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.

New macular findings in individuals with biallelic KLHL7 gene mutation

ObjectiveThe ubiquitin-proteasome system pathway has been recognised as a crucial cellular mechanism for the proper function of photoreceptor cells. In particular, ubiquitin ligases (E3s) recognise and ubiquitinate specific proteins for...

Two siblings with a novel nonsense variant provide further delineation of the spectrum of recessive KLHL7 diseases

Mutations in Kelch-like family member 7 (KLHL7) have recently been described as a cause of a constellation of clinical findings with descriptions of both a Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1)-like, as well as a Bohring-Opitz syndrome (BOS)-like presentation. Here we report two siblings of Guatelmalan descent with a novel homozygous nonsense mutation (p.Arg326*) in KLHL7. These children have multiple dysmorphic features and developmental delay. Interestingly, their clinical traits inconsistently overlap both the CS/CISS1-like and BOS-like phenotypes, and the siblings also have subtle differences from each other, suggesting that clinicians need to be aware of the degree of variability in the presentations of these patients. Still, there is enough in common between patients with recessive KLHL7 mutations to define a novel multisystem disease that features various neurodevelopmental, musculoskeletal, dysmorphic, and other unique components. This report adds to the clinical features and disease-associated variants of the newly-recognized spectrum of KLHL7 mutations, and offers a new description, PERCHING, for the resulting syndrome.

Bi-allelic c.181_183delTGT in BTB domain of KLHL7 is associated with overlapping phenotypes of Crisponi/CISS1-like and Bohring-Opitz like syndrome

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.