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Epigenetics Nov 2012Heterozygous germline mutations in components of switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes were recently identified in patients with... (Review)
Review
Heterozygous germline mutations in components of switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes were recently identified in patients with non-syndromic intellectual disability, Coffin-Siris syndrome and Nicolaides-Baraitser syndrome. The common denominator of the phenotype of these patients is severe intellectual disability and speech delay. Somatic and germline mutations in SWI/SNF components were previously implicated in tumor development. This raises the question whether patients with intellectual disability caused by SWI/SNF mutations in the germline are exposed to an increased risk of developing cancer. Here we compare the mutational spectrum of SWI/SNF components in intellectual disability syndromes and cancer, and discuss the implications of the results of this comparison for the patients.
Topics: Abnormalities, Multiple; Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone; Face; Facies; Foot Deformities, Congenital; Genes, Switch; Genetic Predisposition to Disease; Germ-Line Mutation; Hand Deformities, Congenital; Humans; Hypotrichosis; Intellectual Disability; Language Development Disorders; Micrognathism; Neck; Neoplasms; Transcription Factors
PubMed: 23010866
DOI: 10.4161/epi.22299 -
Disease Models & Mechanisms Aug 2022Ciliopathies represent a disease class characterized by a broad range of phenotypes including polycystic kidneys and skeletal anomalies. Ciliopathic skeletal phenotypes...
Ciliopathies represent a disease class characterized by a broad range of phenotypes including polycystic kidneys and skeletal anomalies. Ciliopathic skeletal phenotypes are among the most common and most difficult to treat due to a poor understanding of the pathological mechanisms leading to disease. Using an avian model (talpid2) for a human ciliopathy with both kidney and skeletal anomalies (orofaciodigital syndrome 14), we identified disruptions in the FGF23-PTH axis that resulted in reduced calcium uptake in the developing mandible and subsequent micrognathia. Although pharmacological intervention with the U.S. Food and Drug Administration (FDA)-approved pan-FGFR inhibitor AZD4547 alone rescued expression of the FGF target SPRY2, it did not significantly rescue micrognathia. In contrast, treatment with a cocktail of AZD4547 and teriparatide acetate, a PTH agonist and FDA-approved treatment for osteoporosis, resulted in molecular, cellular and phenotypic rescue of ciliopathic micrognathia in talpid2 mutants. Together, these data provide novel insight into pathological molecular mechanisms associated with ciliopathic skeletal phenotypes and a potential therapeutic strategy for a pleiotropic disease class with limited to no treatment options.
Topics: Cilia; Ciliopathies; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Micrognathism; Phenotype; Proteins
PubMed: 35818799
DOI: 10.1242/dmm.049611 -
Neurology India 2022Coffin-Siris syndrome (CSS) (OMIM #135900) involves multiple congenital malformations, including hypotonia, short stature, sparse scalp hair, a coarse face, prominent...
Coffin-Siris syndrome (CSS) (OMIM #135900) involves multiple congenital malformations, including hypotonia, short stature, sparse scalp hair, a coarse face, prominent eyebrows, a wide mouth, delayed bone age, and hypoplastic or absent fifth fingers/toes or nails, together with developmental delay. The cause of CSS is suggested to be related to alterations in the BRG- or HRBM-associated factor (BAF) pathway in humans. In this gene family, pathogenic variations in the AT-rich interactive domain-containing protein 1B (ARID1B) gene are revealed to be a significant element causing neurodevelopmental disability in patients with CSS. Herein, we describe the clinical features and gene variations in four Chinese patients with CSS. All the patients shared common features of short fifth fingers/toes or hypoplastic nails, coarse facial features, thick eyebrows, long cilia, a flat nasal bridge, a broad nose, a wide mouth, a high palate, and hypotonia. Besides, they had an intellectual disability, language, and motor developmental delay. Candidate genes were screened for variations using polymerase chain reaction (PCR) and sequencing. The variations were sequenced by next-generation sequencing and confirmed by first-generation sequencing. Exome sequencing suggested four de novo variations in the ARID1B gene in four unrelated patients. These included two frameshift variations (c.3581delC, c.6661_6662insG) and two nonsense variations (c.1936C>T, c.2248C>T). Of the four variations, three variations were novel. The results in our present study broaden the understanding of the disease and further interpret the molecular genetic mechanism of these rare variations in CSS.
Topics: Humans; DNA-Binding Proteins; Muscle Hypotonia; Micrognathism; Hand Deformities, Congenital; Intellectual Disability; Transcription Factors
PubMed: 36352633
DOI: 10.4103/0028-3886.359283 -
Lin Chuang Er Bi Yan Hou Tou Jing Wai... Aug 2023To explore the perioperative airway management and treatment of newborns with micrognathia and laryngomalacia. From January to December 2022, a total of 6 newborns with...
To explore the perioperative airway management and treatment of newborns with micrognathia and laryngomalacia. From January to December 2022, a total of 6 newborns with micrognathia and laryngomalacia were included. Preoperative laryngoscopy revealed concomitant laryngomalacia. These micrognathia were diagnosed as Pierre Robin sequences. All patients had grade Ⅱ or higher symptoms of laryngeal obstruction and required oxygen therapy or non-invasive ventilatory support. All patients underwent simultaneous laryngomalacia surgery and mandibular distraction osteogenesis. The shortened aryepiglottic folds were ablated using a low-temperature plasma radiofrequency during the operation. Tracheal intubation was maintained for 3-5 days postoperatively. Polysomnography(PSG) and airway CT examination were performed before and 3 months after the surgery. Among the 6 patients, 4 required oxygen therapy preoperatively and 2 required non-invasiveventilatory support. The mean age of patients was 40 days at surgery. The inferior alveolar nerve bundle was not damaged during the operation, and there were no signs of mandibular branch injury such as facial asymmetry after the surgery. Laryngomalacia presented as mixed type: type Ⅱ+ type Ⅲ. The maximum mandibular distraction distance was 20 mm, the minimum was 12 mm, and the mean was 16 mm. The posterior airway space increased from a preoperative average of 3.5 mm to a postoperative average of 9.5 mm. The AHI decreased from a mean of 5.65 to 0.85, and the lowest oxygen saturation increased from a mean of 78% to 95%. All patients were successfully extubated after the surgery, and symptoms of laryngeal obstruction such as hypoxia and feeding difficulties disappeared. Newborns with micrognathia and laryngomalacia have multi-planar airway obstruction. Simultaneous laryngomalacia surgery and mandibular distraction osteogenesis are safe and feasible, and can effectively alleviate symptoms of laryngeal obstruction such as hypoxia and feeding difficulties, while significantly improving the appearance of micrognathia.
Topics: Humans; Infant, Newborn; Infant; Micrognathism; Laryngomalacia; Treatment Outcome; Mandible; Airway Obstruction; Intubation, Intratracheal; Laryngeal Diseases; Osteogenesis, Distraction; Oxygen; Retrospective Studies
PubMed: 37551568
DOI: 10.13201/j.issn.2096-7993.2023.08.004 -
Frontiers in Immunology 2022The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has created an urgent global situation. Therefore, it is necessary to...
Differential gene expression profiling reveals potential biomarkers and pharmacological compounds against SARS-CoV-2: Insights from machine learning and bioinformatics approaches.
The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has created an urgent global situation. Therefore, it is necessary to identify the differentially expressed genes (DEGs) in COVID-19 patients to understand disease pathogenesis and the genetic factor(s) responsible for inter-individual variability and disease comorbidities. The pandemic continues to spread worldwide, despite intense efforts to develop multiple vaccines and therapeutic options against COVID-19. However, the precise role of SARS-CoV-2 in the pathophysiology of the nasopharyngeal tract (NT) is still unfathomable. This study utilized machine learning approaches to analyze 22 RNA-seq data from COVID-19 patients (n = 8), recovered individuals (n = 7), and healthy individuals (n = 7) to find disease-related differentially expressed genes (DEGs). We compared dysregulated DEGs to detect critical pathways and gene ontology (GO) connected to COVID-19 comorbidities. We found 1960 and 153 DEG signatures in COVID-19 patients and recovered individuals compared to healthy controls. In COVID-19 patients, the DEG-miRNA, and DEG-transcription factors (TFs) interactions network analysis revealed that E2F1, MAX, EGR1, YY1, and SRF were the highly expressed TFs, whereas hsa-miR-19b, hsa-miR-495, hsa-miR-340, hsa-miR-101, and hsa-miR-19a were the overexpressed miRNAs. Three chemical agents (Valproic Acid, Alfatoxin B1, and Cyclosporine) were abundant in COVID-19 patients and recovered individuals. Mental retardation, mental deficit, intellectual disability, muscle hypotonia, micrognathism, and cleft palate were the significant diseases associated with COVID-19 by sharing DEGs. Finally, the detected DEGs mediated by TFs and miRNA expression indicated that SARS-CoV-2 infection might contribute to various comorbidities. Our results provide the common DEGs between COVID-19 patients and recovered humans, which suggests some crucial insights into the complex interplay between COVID-19 progression and the recovery stage, and offer some suggestions on therapeutic target identification in COVID-19 caused by the SARS-CoV-2.
Topics: Biomarkers; COVID-19; Computational Biology; Gene Expression Profiling; Humans; Machine Learning; MicroRNAs; Pandemics; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 36059456
DOI: 10.3389/fimmu.2022.918692 -
Ultrasound in Obstetrics & Gynecology :... Feb 2012To describe a new ultrasound technique that may be useful for the diagnosis of micrognathia in the first trimester of pregnancy. (Review)
Review
OBJECTIVE
To describe a new ultrasound technique that may be useful for the diagnosis of micrognathia in the first trimester of pregnancy.
METHODS
The retronasal triangle (RNT) view is a technique that captures the coronal plane of the face in which the primary palate and the frontal processes of the maxilla are visualized simultaneously. Normal first-trimester fetuses display a characteristic gap between the right and left body of the mandible in this view (the 'mandibular gap'). The presence or absence of this gap was evaluated and measured prospectively during real-time scanning (n = 154) and retrospectively by analyzing three-dimensional (3D) datasets (n = 50) in normal first-trimester fetuses undergoing screening for aneuploidy at 11-13 weeks' gestation. 3D datasets from 12 fetuses with suspected micrognathia were also collected and examined retrospectively for the same features.
RESULTS
The mandibular gap was identified in all 204 normal fetuses and increased linearly with increasing crown-rump length (y = 0.033x + 0.435; R(2) = 0.316), with no statistically significant differences between measurements obtained by two-dimensional ultrasound and 3D offline analysis. Among fetuses with suspected micrognathia, three 3D datasets were excluded from analysis because of poor image quality in one and the diagnosis of a normal chin in two. In the remaining nine fetuses, the mandibular gap was absent and was replaced by a bony structure representing the receding chin in seven (77.8%) cases and was not visualized due to severe retrognathia in the remaining two (22.2%) cases. All fetuses with micrognathia had associated anomalies, including seven with aneuploidy and two with skeletal dysplasia.
CONCLUSIONS
The RNT view may be a helpful technique for detecting micrognathia in the first trimester. The absence of the mandibular gap or failure to identify the mandible in this view is highly suggestive of micrognathia and should prompt a targeted ultrasound scan to assess for other anomalies. Further research is needed to determine the false-positive and false-negative rates of this technique.
Topics: Adult; Crown-Rump Length; Female; Gestational Age; Humans; Mandible; Maxilla; Micrognathism; Nasal Bone; Palate; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Ultrasonography, Prenatal
PubMed: 22009662
DOI: 10.1002/uog.10121 -
Development (Cambridge, England) Feb 2021Ciliopathies represent a growing class of diseases caused by defects in microtubule-based organelles called primary cilia. Approximately 30% of ciliopathies are...
Ciliopathies represent a growing class of diseases caused by defects in microtubule-based organelles called primary cilia. Approximately 30% of ciliopathies are characterized by craniofacial phenotypes such as craniosynostosis, cleft lip/palate and micrognathia. Patients with ciliopathic micrognathia experience a particular set of difficulties, including impaired feeding and breathing, and have extremely limited treatment options. To understand the cellular and molecular basis for ciliopathic micrognathia, we used the ( ), a bona fide avian model for the human ciliopathy oral-facial-digital syndrome subtype 14. Histological analyses revealed that the onset of ciliopathic micrognathia in embryos occurred at the earliest stages of mandibular development. Neural crest-derived skeletal progenitor cells were particularly sensitive to a ciliopathic insult, undergoing unchecked passage through the cell cycle and subsequent increased proliferation. Furthermore, whereas neural crest-derived skeletal differentiation was initiated, osteoblast maturation failed to progress to completion. Additional molecular analyses revealed that an imbalance in the ratio of bone deposition and resorption also contributed to ciliopathic micrognathia in embryos. Thus, our results suggest that ciliopathic micrognathia is a consequence of multiple aberrant cellular processes necessary for skeletal development, and provide potential avenues for future therapeutic treatments.
Topics: Animals; Bone Remodeling; Bone Resorption; Cell Cycle; Ciliopathies; Craniofacial Abnormalities; Disease Susceptibility; Embryo, Nonmammalian; Gene Expression Regulation, Developmental; Genetic Association Studies; Hedgehog Proteins; Micrognathism; Organogenesis; Osteoblasts; Phenotype; Zinc Finger Protein GLI1
PubMed: 33589509
DOI: 10.1242/dev.194175 -
Journal of Medical Genetics Aug 2022Replication of the nuclear genome is an essential step for cell division. Pathogenic variants in genes coding for highly conserved components of the DNA replication...
INTRODUCTION
Replication of the nuclear genome is an essential step for cell division. Pathogenic variants in genes coding for highly conserved components of the DNA replication machinery cause Meier-Gorlin syndrome (MGORS).
OBJECTIVE
Identification of novel genes associated with MGORS.
METHODS
Exome sequencing was performed to investigate the genotype of an individual presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. The analysis of the candidate variants employed bioinformatic tools, structural protein analysis and modelling in budding yeast.
RESULTS
A novel homozygous missense variant NM_016095.2:c.341G>T, p.(Arg114Leu), in was identified. Both non-consanguineous healthy parents carried this variant. Bioinformatic analysis supports its classification as pathogenic. Functional analyses using yeast showed that this variant increases sensitivity to nicotinamide, a compound that interferes with DNA replication processes. The phylogenetically highly conserved residue p.Arg114 localises at the docking site of CDC45 and MCM5 at GINS2. Moreover, the missense change possibly disrupts the effective interaction between the GINS complex and CDC45, which is necessary for the CMG helicase complex (Cdc45/MCM2-7/GINS) to accurately operate. Interestingly, our patient's phenotype is strikingly similar to the phenotype of patients with -related MGORS, particularly those with craniosynostosis, mild short stature and patellar hypoplasia.
CONCLUSION
is a new disease-associated gene, expanding the genetic aetiology of MGORS.
Topics: Cell Cycle Proteins; Chromosomal Proteins, Non-Histone; Congenital Microtia; Craniosynostoses; Growth Disorders; Humans; Micrognathism; Patella; Saccharomyces cerevisiae
PubMed: 34353863
DOI: 10.1136/jmedgenet-2020-107572 -
American Journal of Medical Genetics.... Sep 2023Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia,...
Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia, hypertrichosis, and sparse scalp hair. Most reported cases are due to ARID1B loss of function variants. We report a boy with developmental delay, feeding difficulties, aspiration, recurrent respiratory infections, slow growth, and hypotonia without a clinical diagnosis, where a previously unreported ARID1B missense variant was classified as a variant of uncertain significance. The pathogenicity of this variant was refined through combined methodologies including genome-wide methylation signature analysis (EpiSign), Machine Learning (ML) facial phenotyping, and LIRICAL. Trio exome sequencing and EpiSign were performed. ML facial phenotyping compared facial images using FaceMatch and GestaltMatcher to syndrome-specific libraries to prioritize the trio exome bioinformatic pipeline gene list output. Phenotype-driven variant prioritization was performed with LIRICAL. A de novo heterozygous missense variant, ARID1B p.(Tyr1268His), was reported as a variant of uncertain significance. The ACMG classification was refined to likely pathogenic by a supportive methylation signature, ML facial phenotyping, and prioritization through LIRICAL. The ARID1B genotype-phenotype has been expanded through an extended analysis of missense variation through genome-wide methylation signatures, ML facial phenotyping, and likelihood-ratio gene prioritization.
Topics: Male; Humans; DNA-Binding Proteins; Muscle Hypotonia; Transcription Factors; Face; Abnormalities, Multiple; Micrognathism; Intellectual Disability; Hand Deformities, Congenital; Neck
PubMed: 37654076
DOI: 10.1002/ajmg.c.32056 -
American Journal of Medical Genetics.... Aug 2016Coffin-Siris syndrome (CSS, MIM 135900), is a well-described, multiple congenital anomaly syndrome characterized by coarse facial features, hypertrichosis, sparse scalp... (Review)
Review
Coffin-Siris syndrome (CSS, MIM 135900), is a well-described, multiple congenital anomaly syndrome characterized by coarse facial features, hypertrichosis, sparse scalp hair, and hypo/aplastic digital nails and phalanges, typically of the 5th digits. Mutations in the BAF (SWI/SNF)-complex subunits (SMARCA4, SMARCE1, SMARCB1, SMARCA2, ARID1B, and ARID1A) have been shown to cause not only CSS, but also related disorders including Nicolaides-Baraitser (MIM 601358) syndrome and ARID1B-intellectual disability syndrome (MIM 614562). At least 200 individuals with CSS have been found to have a mutation in the BAF pathway. However, to date, only three individuals with CSS have been reported to have pathogenic variants in SMARCE1. We report here three additional individuals with clinical features consistent with CSS and alterations in SMARCE1, one of which is novel. The probands all exhibited dysmorphic facial features, moderate developmental and cognitive delay, poor growth, and hypoplastic digital nails/phalanges, including digits not typically affected in the other genes associated with CSS. Two of the three probands had a variety of different organ system anomalies, including cardiac disease, genitourinary abnormalities, feeding difficulties, and vision abnormalities. The 3rd proband has not had further investigative studies. Although an increasing number of individuals are being diagnosed with disorders in the BAF pathway, SMARCE1 is the least common of these genes. This report doubles the number of probands with these mutations, and allows for better phenotypic information of this rare syndrome. © 2016 Wiley Periodicals, Inc.
Topics: Abnormalities, Multiple; Alleles; Child; Child, Preschool; Chromosomal Proteins, Non-Histone; DNA-Binding Proteins; Exome; Exons; Face; Facies; Female; Genetic Association Studies; Genotype; Hand Deformities, Congenital; High-Throughput Nucleotide Sequencing; Humans; Infant; Intellectual Disability; Male; Micrognathism; Mutation; Neck; Phenotype
PubMed: 27264197
DOI: 10.1002/ajmg.a.37722