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Precise modulation of transcription factor levels identifies features underlying dosage sensitivity.Nature Genetics May 2023Transcriptional regulation exhibits extensive robustness, but human genetics indicates sensitivity to transcription factor (TF) dosage. Reconciling such observations...
Transcriptional regulation exhibits extensive robustness, but human genetics indicates sensitivity to transcription factor (TF) dosage. Reconciling such observations requires quantitative studies of TF dosage effects at trait-relevant ranges, largely lacking so far. TFs play central roles in both normal-range and disease-associated variation in craniofacial morphology; we therefore developed an approach to precisely modulate TF levels in human facial progenitor cells and applied it to SOX9, a TF associated with craniofacial variation and disease (Pierre Robin sequence (PRS)). Most SOX9-dependent regulatory elements (REs) are buffered against small decreases in SOX9 dosage, but REs directly and primarily regulated by SOX9 show heightened sensitivity to SOX9 dosage; these RE responses partially predict gene expression responses. Sensitive REs and genes preferentially affect functional chondrogenesis and PRS-like craniofacial shape variation. We propose that such REs and genes underlie the sensitivity of specific phenotypes to TF dosage, while buffering of other genes leads to robust, nonlinear dosage-to-phenotype relationships.
Topics: Humans; SOX9 Transcription Factor; Pierre Robin Syndrome; Gene Expression Regulation; Regulatory Sequences, Nucleic Acid; Phenotype
PubMed: 37024583
DOI: 10.1038/s41588-023-01366-2 -
Molecular Syndromology Apr 2021Pierre Robin syndrome/sequence (PRS) is associated with a triad of symptoms that includes micrognathia, cleft palate, and glossoptosis that may lead to respiratory... (Review)
Review
Pierre Robin syndrome/sequence (PRS) is associated with a triad of symptoms that includes micrognathia, cleft palate, and glossoptosis that may lead to respiratory obstruction. The syndrome occurs in 2 forms: nonsyndromic PRS (nsPRS), and PRS associated with other syndromes (sPRS). Studies have shown varying genetic mutations associated with both nsPRS and sPRS. The present systematic review aims to provide a comprehensive collection of published literature reporting genetic mutations in PRS. Web of Science, PubMed, and Scopus were searched using the keywords: "Pierre Robin syndrome/sequence AND gene mutation." The search resulted in 208 articles, of which 93 were excluded as they were duplicates/irrelevant. The full-text assessment led to the further exclusion of 76 articles. From the remaining 39 articles included in the review, details of 324 cases were extracted. 56% of the cases were sPRS, and 22% of the cases were associated with other malformations and the remaining were nsPRS. Genetic mutations were noted in 30.9% of the 300 cases. Based on the review, was found to be the most common gene associated with both nsPRS and sPRS. The gene mutation in sPRS was specific to the associated syndrome. Due to the lack of original studies, a quantitative analysis was not possible. Thus, future studies must focus on conducting large-scale cohort studies. Along with generating data on genetic mutation, future studies must also conduct pedigree analysis to assess potential familial inheritance, which in turn could provide valuable insights into the etiopathogenesis of PRS.
PubMed: 34012376
DOI: 10.1159/000513217 -
Sleep Medicine Reviews Jun 2016Children with craniofacial syndromes are at risk of sleep disordered breathing, the most common being obstructive sleep apnea. Midface hypoplasia in children with... (Review)
Review
Children with craniofacial syndromes are at risk of sleep disordered breathing, the most common being obstructive sleep apnea. Midface hypoplasia in children with craniosynostosis and glossoptosis in children with Pierre Robin syndrome are well recognized risk factors, but the etiology is often multifactorial and many children have multilevel airway obstruction. We examine the published evidence and explore the current management strategies in these complex patients. Some treatment modalities are similar to those used in otherwise healthy children such as adenotonsillectomy, positive pressure ventilation and in the refractory cases, tracheostomy. However, there are some distinct approaches such as nasopharyngeal airways, tongue lip adhesion, mandibular distraction osteogenesis in children with Pierre Robin sequence, and midface advancement in children with craniosynostoses. Clinicians should have a low threshold for referral for evaluation of sleep-disordered-breathing in these patients.
Topics: Airway Obstruction; Child; Cleft Palate; Craniofacial Abnormalities; Craniosynostoses; Humans; Pierre Robin Syndrome; Sleep Apnea, Obstructive; Tonsillectomy; Tracheostomy
PubMed: 26454241
DOI: 10.1016/j.smrv.2015.05.010 -
American Journal of Human Genetics Jun 2021ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a...
ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.
Topics: Adolescent; Adult; Child; Child, Preschool; Craniofacial Abnormalities; Female; Haploinsufficiency; Heterozygote; Humans; Infant; Intellectual Disability; Language Development Disorders; Loss of Function Mutation; Male; Pedigree; Phenotype; RNA-Binding Proteins; Signal Transduction; Syndrome; Young Adult
PubMed: 33909992
DOI: 10.1016/j.ajhg.2021.04.007 -
Indian Journal of Otolaryngology and... Sep 2021Hereditary hearing loss accounts for nearly 60% of deafness in developed countries and about 30% of them are syndromic. Pierre Robin Syndrome is one such condition. The...
Hereditary hearing loss accounts for nearly 60% of deafness in developed countries and about 30% of them are syndromic. Pierre Robin Syndrome is one such condition. The patient with this syndrome usually presnts with triad of micrognathia, glossoptosis and cleft palate. Hearing loss is mostly conductive but there can be sensorineural hearing loss also. Here we present a case of Pierre Robin Syndrome who presented with congenital hearing loss. He also had bilateral serous otitis media. He underwent cochlear implant surgery and was prescribed antihistaminics and steroid spray for middle ear effusion. Therefore, proper clinical evaluation is required.
PubMed: 34471629
DOI: 10.1007/s12070-020-02331-9 -
Polymers Sep 2022This paper introduces a complex novel concept and methodology for the creation of personalized biomedical appliances 3D-printed from certified biocompatible photopolymer...
This paper introduces a complex novel concept and methodology for the creation of personalized biomedical appliances 3D-printed from certified biocompatible photopolymer resin Dental LT Clear (V2). The explained workflow includes intraoral and CT scanning, patient virtualization, digital appliance design, additive manufacturing, and clinical application with evaluation of the appliance intended for patients with cranio-facial syndromes. The presented concept defines virtual 3D fusion of intraoral optical scan and segmented CT as sufficient and accurate data defining the 3D surface of the face, intraoral and airway morphology necessary for the 3D design of complex personalized intraoral and extraoral parts of the orthopedic appliance. A central aspect of the concept is a feasible utilization of composite resin for biomedical prototyping of the sequence of marginally different appliances necessary to keep the pace with the patient rapid growth. Affordability, noninvasiveness, and practicality of the appliance update process shall be highlighted. The methodology is demonstrated on a particular case of two-year-old infant with Pierre Robin sequence. Materialization by additive manufacturing of this photopolymer provides a highly durable and resistant-to-fracture two-part appliance similar to a Tübingen palatal plate, for example. The paper concludes with the viability of the described method and material upon interdisciplinary clinical evaluation of experts from departments of orthodontics and cleft anomalies, pediatric pneumology and phthisiology, and pediatric otorhinolaryngology.
PubMed: 36146014
DOI: 10.3390/polym14183858 -
Molecular Cell May 2023Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied...
Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. We observed pronounced changes in locus topology between cell types. Subsequent analysis of single-chromatin fiber traces revealed that these ensemble-average differences arise through changes in the frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which promote stripe formation, are positioned near the domain's 3D geometric center, and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multi-loop, centrally clustered geometry. Together, we provide mechanistic insights into architectural stripe formation and gene regulation over ultra-long genomic ranges.
Topics: Humans; Chromatin; Regulatory Sequences, Nucleic Acid; Promoter Regions, Genetic; Gene Expression Regulation; Genome; Cell Cycle Proteins; Enhancer Elements, Genetic; CCCTC-Binding Factor
PubMed: 36996812
DOI: 10.1016/j.molcel.2023.03.009 -
Journal of Developmental Biology Dec 2020The phenotype currently accepted as Pierre Robin syndrome/sequence/anomalad/complex (PR) is characterized by mandibular dysmorphology, glossoptosis, respiratory... (Review)
Review
The phenotype currently accepted as Pierre Robin syndrome/sequence/anomalad/complex (PR) is characterized by mandibular dysmorphology, glossoptosis, respiratory obstruction, and in some cases, cleft palate. A causative sequence of developmental events is hypothesized for PR, but few clear causal relationships between discovered genetic variants, dysregulated gene expression, precise cellular processes, pathogenesis, and PR-associated anomalies are documented. This review presents the current understanding of PR phenotypes, the proposed pathogenetic processes underlying them, select genes associated with PR, and available animal models that could be used to better understand the genetic basis and phenotypic variation of PR.
PubMed: 33291480
DOI: 10.3390/jdb8040030 -
Seminars in Fetal & Neonatal Medicine Aug 2016In infants with craniofacial disorders, upper airway obstruction is one of the primary causes for morbidity and mortality in the neonatal period. Infants with... (Review)
Review
In infants with craniofacial disorders, upper airway obstruction is one of the primary causes for morbidity and mortality in the neonatal period. Infants with craniofacial disorders, including Pierre Robin sequence, are at high risk for obstructive sleep apnea syndrome. Because of the complexity of their care, these neonates are usually followed by a multidisciplinary team to ensure timely evaluation and optimal treatment. In addition to history and physical examination, clinical evaluation may include genetic testing, imaging, endoscopy, and polysomnography. There are various treatment options, both surgical and non-surgical, that may be used depending on clinical assessment, underlying condition, and severity of disease. Recent advances have led to better assessment and treatment of these patients, but many questions remain. This review outlines the available literature pertaining to the evaluation and management of upper airway obstruction in the neonate with craniofacial conditions, with a particular focus on Pierre Robin sequence.
Topics: Achondroplasia; Airway Obstruction; Cleft Lip; Cleft Palate; Craniosynostoses; Down Syndrome; Humans; Infant; Infant, Newborn; Pierre Robin Syndrome
PubMed: 26997148
DOI: 10.1016/j.siny.2016.03.001