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American Journal of Human Genetics May 2023Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis,...
Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.
Topics: Humans; Mice; Animals; Mandibulofacial Dysostosis; Apoptosis; Mutagenesis; Ribosomes; Phenotype; Neural Crest; Craniofacial Abnormalities
PubMed: 37075751
DOI: 10.1016/j.ajhg.2023.03.014 -
Frontiers in Pediatrics 2023Mandibulo-Facial Dysostosis with Microcephaly (MFDM) is a rare disease with a broad spectrum of symptoms, characterized by zygomatic and mandibular hypoplasia,...
INTRODUCTION
Mandibulo-Facial Dysostosis with Microcephaly (MFDM) is a rare disease with a broad spectrum of symptoms, characterized by zygomatic and mandibular hypoplasia, microcephaly, and ear abnormalities. Here, we aimed at describing the external ear phenotype of MFDM patients, and train an Artificial Intelligence (AI)-based model to differentiate MFDM ears from non-syndromic control ears (binary classification), and from ears of the main differential diagnoses of this condition (multi-class classification): Treacher Collins (TC), Nager (NAFD) and CHARGE syndromes.
METHODS
The training set contained 1,592 ear photographs, corresponding to 550 patients. We extracted 48 patients completely independent of the training set, with only one photograph per ear per patient. After a CNN-(Convolutional Neural Network) based ear detection, the images were automatically landmarked. Generalized Procrustes Analysis was then performed, along with a dimension reduction using PCA (Principal Component Analysis). The principal components were used as inputs in an eXtreme Gradient Boosting (XGBoost) model, optimized using a 5-fold cross-validation. Finally, the model was tested on an independent validation set.
RESULTS
We trained the model on 1,592 ear photographs, corresponding to 1,296 control ears, 105 MFDM, 33 NAFD, 70 TC and 88 CHARGE syndrome ears. The model detected MFDM with an accuracy of 0.969 [0.838-0.999] ( < 0.001) and an AUC (Area Under the Curve) of 0.975 within controls (binary classification). Balanced accuracies were 0.811 [0.648-0.920] ( = 0.002) in a first multiclass design (MFDM vs. controls and differential diagnoses) and 0.813 [0.544-0.960] ( = 0.003) in a second multiclass design (MFDM vs. differential diagnoses).
CONCLUSION
This is the first AI-based syndrome detection model in dysmorphology based on the external ear, opening promising clinical applications both for local care and referral, and for expert centers.
PubMed: 37664547
DOI: 10.3389/fped.2023.1171277 -
Frontiers in Genetics 2021Pre-mRNA splicing is performed by the spliceosome, a dynamic macromolecular complex consisting of five small uridine-rich ribonucleoprotein complexes (the U1, U2, U4,... (Review)
Review
Pre-mRNA splicing is performed by the spliceosome, a dynamic macromolecular complex consisting of five small uridine-rich ribonucleoprotein complexes (the U1, U2, U4, U5, and U6 snRNPs) and numerous auxiliary splicing factors. A plethora of human disorders are caused by genetic variants affecting the function and/or expression of splicing factors, including the core snRNP proteins. Variants in the genes encoding proteins of the U5 snRNP cause two distinct and tissue-specific human disease phenotypes - variants in , , and are associated with retinitis pigmentosa (RP), while variants in and cause the craniofacial disorders mandibulofacial dysostosis Guion-Almeida type (MFDGA) and Burn-McKeown syndrome (BMKS), respectively. Furthermore, recurrent somatic mutations or changes in the expression levels of a number of U5 snRNP proteins (, , , , and ) have been associated with human cancers. How and why variants in ubiquitously expressed spliceosome proteins required for pre-mRNA splicing in all human cells result in tissue-restricted disease phenotypes is not clear. Additionally, why variants in different, yet interacting, proteins making up the same core spliceosome snRNP result in completely distinct disease outcomes - RP, craniofacial defects or cancer - is unclear. In this review, we define the roles of different U5 snRNP proteins in RP, craniofacial disorders and cancer, including how disease-associated genetic variants affect pre-mRNA splicing and the proposed disease mechanisms. We then propose potential hypotheses for how U5 snRNP variants cause tissue specificity resulting in the restricted and distinct human disorders.
PubMed: 33584830
DOI: 10.3389/fgene.2021.636620 -
Genetics in Medicine : Official Journal... Jan 2023Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of...
PURPOSE
Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown.
METHODS
We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro.
RESULTS
We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3.
CONCLUSION
Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.
Topics: Humans; Goldenhar Syndrome; Congenital Microtia; Ear; Face; Micrognathism
PubMed: 36260083
DOI: 10.1016/j.gim.2022.09.005 -
Texas Heart Institute Journal 2009Andersen-Tawil syndrome is an autosomal dominant condition characterized by dysmorphic features, periodic paralysis, and ventricular arrhythmias. Twiddler syndrome is...
Andersen-Tawil syndrome is an autosomal dominant condition characterized by dysmorphic features, periodic paralysis, and ventricular arrhythmias. Twiddler syndrome is characterized by intentional or inadvertent manipulation of implanted devices in the pacemaker pocket. We describe an unusual case of an 8-year-old girl who had both syndromes.
Topics: Andersen Syndrome; Child; Defibrillators, Implantable; Electric Countershock; Electrocardiography, Ambulatory; Equipment Failure; Female; Foreign-Body Migration; Humans; Radiography; Treatment Outcome
PubMed: 19693314
DOI: No ID Found -
Nature Communications Aug 2021Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing...
Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.
Topics: Adolescent; Adult; Animals; Child; Exome; Female; Genetic Association Studies; Goldenhar Syndrome; Haploinsufficiency; Humans; Infant; Male; Mutation; Neural Crest; Pedigree; RNA Splicing Factors; Spliceosomes; Xenopus laevis
PubMed: 34344887
DOI: 10.1038/s41467-021-24852-9 -
Disability and Rehabilitation Jan 2022To examine differences in community participation and environmental support for youth with and without craniofacial microsomia.
PURPOSE
To examine differences in community participation and environmental support for youth with and without craniofacial microsomia.
METHODS
This study involved secondary analyses of a subset of data ( = 396) from a longitudinal cohort study. Multiple linear and Poisson regression analyses and Wilcoxon Mann-Whitney tests were used to estimate differences in community participation and environmental support between youth with craniofacial microsomia and youth without craniofacial microsomia, stratified based on their history of education and health-related service use. Chi-square analyses were used to explore item-level group differences in change desired across community activities.
RESULTS
Statistically significant differences were found in community participation frequency ( = -0.52; < 0.001), level of involvement ( = -0.16; = 0.010), and desire for change in participation when comparing youth with craniofacial microsomia and non-affected peers not receiving services ( < 0.001). There were no statistically significant differences between youth with craniofacial microsomia and non-affected peers receiving services.
CONCLUSIONS
Results suggest lower community participation in youth with craniofacial microsomia as compared to non-affected peers not receiving services. This may suggest opportunities for designing and testing interventions to promote community participation among youth with craniofacial microsomia, so as to support their transition to adulthood.Implications for rehabilitationYouth with craniofacial microsomia may have unmet rehabilitation needs related to their community participation.Rehabilitation professionals should pay attention to participation of youth with craniofacial microsomia in activities that place a higher demand on involvement with others.Rehabilitation professionals should appraise participation frequency and involvement of youths with craniofacial microsomia to gain accurate insight into their current community participation.
Topics: Adolescent; Adult; Cohort Studies; Community Participation; Goldenhar Syndrome; Humans; Longitudinal Studies
PubMed: 32478589
DOI: 10.1080/09638288.2020.1765031 -
Anaesthesia Jul 1990
Topics: Atropine; Goldenhar Syndrome; Heart Rate; Humans; Infant; Intubation, Intratracheal; Mandibulofacial Dysostosis
PubMed: 2386290
DOI: 10.1111/j.1365-2044.1990.tb14846.x -
Proceedings of the Royal Society of... May 1974
Topics: Animals; Antimetabolites; Cell Differentiation; Cleft Lip; Cleft Palate; Dermoid Cyst; Eye Neoplasms; Face; Female; Glucocorticoids; Humans; Male; Mandibulofacial Dysostosis; Mice; Mice, Inbred A; Micrognathism; Morphogenesis; Phenobarbital; Pregnancy; Rats; Salicylates; Sex Factors; Stress, Mechanical; Thalidomide; Uvula
PubMed: 4835278
DOI: No ID Found -
Nature Feb 2018Many craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as transcription or ribosome biogenesis....
Many craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as transcription or ribosome biogenesis. Although it is understood that many of these malformations are a consequence of defects in cranial neural crest cells, a cell type that gives rise to most of the facial structures during embryogenesis, the mechanism underlying cell-type selectivity of these defects remains largely unknown. By exploring molecular functions of DDX21, a DEAD-box RNA helicase involved in control of both RNA polymerase (Pol) I- and II-dependent transcriptional arms of ribosome biogenesis, we uncovered a previously unappreciated mechanism linking nucleolar dysfunction, ribosomal DNA (rDNA) damage, and craniofacial malformations. Here we demonstrate that genetic perturbations associated with Treacher Collins syndrome, a craniofacial disorder caused by heterozygous mutations in components of the Pol I transcriptional machinery or its cofactor TCOF1 (ref. 1), lead to relocalization of DDX21 from the nucleolus to the nucleoplasm, its loss from the chromatin targets, as well as inhibition of rRNA processing and downregulation of ribosomal protein gene transcription. These effects are cell-type-selective, cell-autonomous, and involve activation of p53 tumour-suppressor protein. We further show that cranial neural crest cells are sensitized to p53-mediated apoptosis, but blocking DDX21 loss from the nucleolus and chromatin rescues both the susceptibility to apoptosis and the craniofacial phenotypes associated with Treacher Collins syndrome. This mechanism is not restricted to cranial neural crest cells, as blood formation is also hypersensitive to loss of DDX21 functions. Accordingly, ribosomal gene perturbations associated with Diamond-Blackfan anaemia disrupt DDX21 localization. At the molecular level, we demonstrate that impaired rRNA synthesis elicits a DNA damage response, and that rDNA damage results in tissue-selective and dosage-dependent effects on craniofacial development. Taken together, our findings illustrate how disruption in general regulators that compromise nucleolar homeostasis can result in tissue-selective malformations.
Topics: Animals; Apoptosis; Benzothiazoles; Cell Nucleolus; Cell Nucleus; Chromatin; DEAD-box RNA Helicases; DNA Damage; DNA, Ribosomal; DNA-Directed RNA Polymerases; Embryonic Stem Cells; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins; Mandibulofacial Dysostosis; Mice; Naphthyridines; Neural Crest; Nuclear Proteins; Organ Specificity; Phenotype; Phosphoproteins; Protein Transport; RNA Helicases; RNA Polymerase I; RNA, Ribosomal; Ribosomal Proteins; Ribosomes; Skull; Stress, Physiological; Tumor Suppressor Protein p53; Xenopus; Zebrafish; Zebrafish Proteins
PubMed: 29364875
DOI: 10.1038/nature25449