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Diagnostics (Basel, Switzerland) May 2020Elongation factor Tu guanosine-5'-triphosphate (GTP) binding domain containing 2 () encodes a major component of the spliceosomal GTPase and, if mutated, causes...
Elongation factor Tu guanosine-5'-triphosphate (GTP) binding domain containing 2 () encodes a major component of the spliceosomal GTPase and, if mutated, causes mandibulofacial dysostosis with microcephaly (MFDM; MIM#610536). Despite the increasing number of potentially pathogenic variants reported in the literature, most previous studies have relied solely on in silico prediction of the pathogenic potential of variants, which may result in misclassification of the variant's pathogenicity. Given the importance of the functional verification of variants, we identified a novel splice donor site variant, c.271+1G>A of , whose pathogenicity was clearly verified at the RNA level using a minigene assay. A child with MFDM, mixed hearing loss, microcephaly, and a congenital cardiac defect was identified with this variant, which arose in a de novo fashion. The minigene assay showed erroneous integration of the 118 bp IVS3 of exclusively among the c.271+1G>A variant clone. We first applied the minigene assay to identify the splice function of a splice site variant of , thereby allowing for in vitro functional verification of splice site variants in .
PubMed: 32408545
DOI: 10.3390/diagnostics10050296 -
American Journal of Medical Genetics.... Dec 2010Of all the babies born with birth defects, approximately one-third display anomalies of the head and face [Gorlin et al., 1990] including cleft lip, cleft palate, small... (Review)
Review
Of all the babies born with birth defects, approximately one-third display anomalies of the head and face [Gorlin et al., 1990] including cleft lip, cleft palate, small or absent facial and skull bones and improperly formed nose, eyes, ears, and teeth. Craniofacial disorders are a primary cause of infant mortality and have serious lifetime functional, esthetic, and social consequences that are devastating to both children and parents alike. Comprehensive surgery, dental care, psychological counseling, and rehabilitation can help ameliorate-specific problems but at great cost over many years which dramatically affects national health care budgets. For example, the Center for Disease Control and Prevention estimates that the lifetime cost of treating the children born each year with cleft lip and/or cleft palate alone to be US$697 million. Treating craniofacial malformations, of which in excess of 700 distinct syndromes have been described, through comprehensive, well-coordinated and integrated strategies can provide satisfactory management of individual conditions, however, the results are often variable and rarely fully corrective. Therefore, better techniques for tissue repair and regeneration need to be developed and therapeutic avenues of prevention need to be explored in order to eliminate the devastating consequences of head and facial birth defects. To do this requires a thorough understanding of the normal events that control craniofacial development during embryogenesis. This review therefore focuses on recent advances in our understanding of the basic etiology and pathogenesis of a rare craniofacial disorder known as Treacher Collins syndrome and emerging prospects for prevention that may have broad application to congenital craniofacial birth defects.
Topics: Child; Forecasting; Humans; Infant; Mandibulofacial Dysostosis; Neural Crest; Neural Tube Defects
PubMed: 20734335
DOI: 10.1002/ajmg.a.33454 -
The Journal of Clinical Pediatric... Sep 2022To systematically review literature on therapeutic options for treating hemifacial microsomia (HFM), in young patients with growth potential, classifying and comparing...
OBJECTIVE
To systematically review literature on therapeutic options for treating hemifacial microsomia (HFM), in young patients with growth potential, classifying and comparing the different dentofacial treatment methods.
STUDY DESIGN
An independent review of databases (Scopus, Embase, Ovid, Cochrane Library and PubMed) following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA), conducted by four evaluators. The protocol of this study was registered in International prospective register of systematic reviews (PROSPERO), under the number CRD42021293076.
RESULTS
Between 1970-2021, a total number of 1137 articles were published of which 27 were included in this study according to the selection criteria: one randomized multicentric trial, two case-control studies, three case series and 21 case reports.
CONCLUSIONS
The most common orthopedic treatments provide vertical stimulation of the maxillary process in the affected side. Orthodontic approaches are mainly applied for vertical correction and stabilization of the occlusal plane. Other treatment options include orthognathic surgery, osteogenic distraction, temporomandibular reconstruction and grafting. It is recommended that prospective clinical randomized controlled studies be conducted using homogeneous pediatric groups with long-term follow-up, to establish recommended evidence-based methods for treating each set of hemifacial microsomia symptoms.
Topics: Humans; Child; Goldenhar Syndrome; Facial Asymmetry; Treatment Outcome; Retrospective Studies; Prospective Studies; Mandible; Randomized Controlled Trials as Topic
PubMed: 36624910
DOI: 10.22514/jocpd.2022.003 -
Human Molecular Genetics Nov 2019The craniofacial disorder mandibulofacial dysostosis Guion-Almeida type is caused by haploinsufficiency of the U5 snRNP gene EFTUD2/SNU114. However, it is unclear how...
The craniofacial disorder mandibulofacial dysostosis Guion-Almeida type is caused by haploinsufficiency of the U5 snRNP gene EFTUD2/SNU114. However, it is unclear how reduced expression of this core pre-mRNA splicing factor leads to craniofacial defects. Here we use a CRISPR-Cas9 nickase strategy to generate a human EFTUD2-knockdown cell line and show that reduced expression of EFTUD2 leads to diminished proliferative ability of these cells, increased sensitivity to endoplasmic reticulum (ER) stress and the mis-expression of several genes involved in the ER stress response. RNA-Seq analysis of the EFTUD2-knockdown cell line revealed transcriptome-wide changes in gene expression, with an enrichment for genes associated with processes involved in craniofacial development. Additionally, our RNA-Seq data identified widespread mis-splicing in EFTUD2-knockdown cells. Analysis of the functional and physical characteristics of mis-spliced pre-mRNAs highlighted conserved properties, including length and splice site strengths, of retained introns and skipped exons in our disease model. We also identified enriched processes associated with the affected genes, including cell death, cell and organ morphology and embryonic development. Together, these data support a model in which EFTUD2 haploinsufficiency leads to the mis-splicing of a distinct subset of pre-mRNAs with a widespread effect on gene expression, including altering the expression of ER stress response genes and genes involved in the development of the craniofacial region. The increased burden of unfolded proteins in the ER resulting from mis-splicing would exceed the capacity of the defective ER stress response, inducing apoptosis in cranial neural crest cells that would result in craniofacial abnormalities during development.
Topics: CRISPR-Cas Systems; Cell Proliferation; Craniofacial Abnormalities; Endoplasmic Reticulum Stress; Exons; Gene Expression; Gene Expression Regulation, Developmental; HEK293 Cells; Haploinsufficiency; Humans; Introns; Mandibulofacial Dysostosis; Mutation; Peptide Elongation Factors; Phenotype; RNA Precursors; RNA Splicing; Ribonucleoprotein, U5 Small Nuclear; Sequence Analysis, RNA; Spliceosomes
PubMed: 31304552
DOI: 10.1093/hmg/ddz169 -
AJNR. American Journal of Neuroradiology Jul 2015Cranial nerve abnormalities might be observed in hemifacial microsomia and microtia (oculo-auriculo-vertebral spectrum), but the rate, features, and relationship with...
BACKGROUND AND PURPOSE
Cranial nerve abnormalities might be observed in hemifacial microsomia and microtia (oculo-auriculo-vertebral spectrum), but the rate, features, and relationship with functional impairment or phenotype severity have not yet been defined. This study aimed at investigating absence/asymmetry, abnormal origin, morphology and course of cranial nerves, and presence/asymmetry of the foramen ovale and inferior alveolar nerve canal in a cohort of oculo-auriculo-vertebral spectrum patients.
MATERIALS AND METHODS
Twenty-nine patients with oculo-auriculo-vertebral spectrum (mean age, 7 years; age range, 0.2-31 years; 12 females) underwent brain MR imaging, CT, and neurologic evaluation; 19 patients had a more severe phenotype (Goldenhar syndrome).
RESULTS
Cranial nerve abnormalities were detected only in patients with Goldenhar syndrome (17/19, bilaterally in 8) and were involved the second (4/19), third (1/18), fifth (11/19), sixth (8/16), seventh (11/18), and eighth (8/18) cranial nerves. Multiple cranial nerve abnormalities were common (11/17). Eleven patients showed bone foramina abnormalities. Trigeminal and facial nerve dysfunctions were common (44% and 58%, respectively), especially in patients with Goldenhar syndrome. Trigeminal abnormalities showed a good correlation with ipsilateral dysfunction (P = .018), which further increased when bone foramina abnormalities were included. The facial nerve showed a trend toward correlation with ipsilateral dysfunction (P = .081). Diplopia was found only in patients with Goldenhar syndrome and was associated with third and sixth cranial nerve abnormalities (P = .006).
CONCLUSIONS
Among patients with oculo-auriculo-vertebral spectrum, cranial nerve morphologic abnormalities are common, correlate with phenotype severity, and often entail a functional impairment. The spectrum of cranial nerve abnormalities appears wider than simple hypo-/aplasia and includes an anomalous cisternal course and partial/complete fusion of diverse cranial nerves.
Topics: Adolescent; Adult; Child; Child, Preschool; Cranial Nerves; Female; Goldenhar Syndrome; Humans; Infant; Infant, Newborn; Magnetic Resonance Imaging; Male; Phenotype; Tomography, X-Ray Computed; Young Adult
PubMed: 25814660
DOI: 10.3174/ajnr.A4273 -
Journal of Oral Biology and... 2011Treacher Collins syndrome (TCS) is the most common of the human mandibulofacial dysostosis disorders. It is an autosomal-dominant disorder of the craniofacial...
Treacher Collins syndrome (TCS) is the most common of the human mandibulofacial dysostosis disorders. It is an autosomal-dominant disorder of the craniofacial development occurring between the fifth and the eighth weeks of embryonic development with an incidence of 1/50,000 live births, range between 1-40,000 and 1-70,000. We present here the various clinical, radiographical and other diagnostic findings of the TCS to correlate the clinical assessment with the diagnostic imaging and review the various investigations and management options being carried out to improve their facial deformity.
PubMed: 25756016
DOI: 10.1016/S2212-4268(11)60009-2 -
Journal of Medical Genetics Jul 2002Treacher Collins syndrome (TCS), the most common type of mandibulofacial dysostosis (MFD), is genetically homogeneous. Other types of MFD are less common and, of these,...
BACKGROUND
Treacher Collins syndrome (TCS), the most common type of mandibulofacial dysostosis (MFD), is genetically homogeneous. Other types of MFD are less common and, of these, only the Bauru type of MFD has an autosomal dominant (AD) mode of inheritance established. Here we report clinical features of a kindred with a unique AD MFD with the exclusion of linkage to the TCS locus (TCOF1) on chromosome 5q31-q32.
METHODS
Six affected family members underwent a complete medical genetics physical examination and two affected subjects had skeletal survey. All available medical records were reviewed. Linkage analysis using the markers spanning the TCOF1 locus was performed. One typically affected family member had a high resolution karyotype.
RESULTS
Affected subjects had significant craniofacial abnormalities without any significant acral changes and thus had a phenotype consistent with a MFD variant. Distinctive features included hypoplasia of the zygomatic complex, micrognathia with malocclusion, auricular abnormalities with conductive hearing loss, and ptosis. Significantly negative two point lod scores were obtained for markers spanning the TCOF1 locus, excluding the possibility that the disease in our kindred is allelic with TCS. High resolution karyotype was normal.
CONCLUSIONS
We report a kindred with a novel type of MFD that is not linked to the TCOF1 locus and is also clinically distinct from other types of AD MFD. Identification of additional families will facilitate identification of the gene causing this type of AD MFD and further characterisation of the clinical phenotype.
Topics: Adult; Aged; Blepharoptosis; Child; Chromosomes, Human, Pair 5; Deafness; Female; Genes, Dominant; Genetic Heterogeneity; Genetic Linkage; Humans; Male; Mandibulofacial Dysostosis; Nuclear Family; Nuclear Proteins; Pedigree; Phenotype; Phosphoproteins
PubMed: 12114479
DOI: 10.1136/jmg.39.7.484 -
Genes Oct 2020In spring 2020, six Hereford calves presented with congenital facial deformities attributed to a condition we termed mandibulofacial dysostosis (MD). Affected calves...
In spring 2020, six Hereford calves presented with congenital facial deformities attributed to a condition we termed mandibulofacial dysostosis (MD). Affected calves shared hallmark features of a variably shortened and/or asymmetric lower mandible and bilateral skin tags present 2-10 cm caudal to the commissure of the lips. Pedigree analysis revealed a single common ancestor shared by the sire and dam of each affected calf. Whole-genome sequencing (WGS) of 20 animals led to the discovery of a variant (Chr26 g. 14404993T>C) in Exon 3 of associated with MD. This missense mutation (p.L188P), is located in an α helix of the protein, which the identified amino acid substitution is predicted to break. The implication of this mutation was further validated through genotyping 2 additional affected calves, 760 other Herefords, and by evaluation of available WGS data from over 2500 other individuals. Only the affected individuals were homozygous for the variant and all heterozygotes had at least one pedigree tie to the suspect founder. plays a vital role in tissue-specific regulation of retinoic acid (RA) during embryonic development. Dysregulation of RA can result in teratogenesis by altering the endothelin-1 signaling pathway affecting the expression of genes, critical to mandibulofacial development. We postulate that this recessive missense mutation in impacts the catalytic activity of the encoded enzyme, leading to excess RA resulting in the observed MD phenotype.
Topics: Animals; Branchial Region; Cattle; Cattle Diseases; Cytochrome P450 Family 26; Genome; Mandibulofacial Dysostosis; Mutation, Missense; Pedigree; Tretinoin; Whole Genome Sequencing
PubMed: 33105751
DOI: 10.3390/genes11111246 -
Biomolecules Dec 2020The neural crest hypothesis states that the phenotypic features of the domestication syndrome are due to a reduced number or disruption of neural crest cells (NCCs)... (Review)
Review
The neural crest hypothesis states that the phenotypic features of the domestication syndrome are due to a reduced number or disruption of neural crest cells (NCCs) migration, as these cells differentiate at their final destinations and proliferate into different tissues whose activity is reduced by domestication. Comparing the phenotypic characteristics of modern and prehistoric man, it is clear that during their recent evolutionary past, humans also went through a process of self-domestication with a simultaneous prolongation of the period of socialization. This has led to the development of social abilities and skills, especially language, as well as neoteny. Disorders of neural crest cell development and migration lead to many different conditions such as Waardenburg syndrome, Hirschsprung disease, fetal alcohol syndrome, DiGeorge and Treacher-Collins syndrome, for which the mechanisms are already relatively well-known. However, for others, such as Williams-Beuren syndrome and schizophrenia that have the characteristics of hyperdomestication, and autism spectrum disorders, and 7dupASD syndrome that have the characteristics of hypodomestication, much less is known. Thus, deciphering the biological determinants of disordered self-domestication has great potential for elucidating the normal and disturbed ontogenesis of humans, as well as for the understanding of evolution of mammals in general.
Topics: Biological Evolution; Cell Movement; Cell Proliferation; Domestication; Fetal Alcohol Spectrum Disorders; Hirschsprung Disease; Humans; Language; Mandibulofacial Dysostosis; Neural Crest; Phenotype; Schizophrenia; Social Skills; Waardenburg Syndrome; Williams Syndrome
PubMed: 33375093
DOI: 10.3390/biom11010002 -
Indian Journal of Ophthalmology Nov 2020The ocular features of Goldenhar syndrome (GS) are typically external, like surface dermoids and lid coloboma. Retinal detachment (RD) is rare and has not been reported...
The ocular features of Goldenhar syndrome (GS) are typically external, like surface dermoids and lid coloboma. Retinal detachment (RD) is rare and has not been reported in absence of other concomitant predisposing congenital ocular disorders. We present a unique case of bilateral rhegmatogenous retinal detachment (RRD) with GS. To the best of our knowledge, this association of GS with RRD is novel and has not been reported earlier in ophthalmic and systemic literature on RRD.
Topics: Coloboma; Goldenhar Syndrome; Humans; Retinal Detachment; Retrospective Studies; Visual Acuity
PubMed: 33120701
DOI: 10.4103/ijo.IJO_401_20