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International Journal of Molecular... Apr 2024Hemifacial microsomia (HFM) is a rare congenital genetic syndrome primarily affecting the first and second pharyngeal arches, leading to defects in the mandible,...
Hemifacial microsomia (HFM) is a rare congenital genetic syndrome primarily affecting the first and second pharyngeal arches, leading to defects in the mandible, external ear, and middle ear. The pathogenic genes remain largely unidentified. Whole-exome sequencing (WES) was conducted on 12 HFM probands and their unaffected biological parents. Predictive structural analysis of the target gene was conducted using PSIPRED (v3.3) and SWISS-MODEL, while STRING facilitated protein-to-protein interaction predictions. CRISPR/Cas9 was applied for gene knockout in zebrafish. In situ hybridization (ISH) was employed to examine the spatiotemporal expression of the target gene and neural crest cell (NCC) markers. Immunofluorescence with PH3 and TUNEL assays were used to assess cell proliferation and apoptosis. RNA sequencing was performed on mutant and control embryos, with rescue experiments involving target mRNA injections and specific gene knockouts. was identified as a novel candidate gene for HFM, with four nonsynonymous de novo variants detected in three unrelated probands. Structural predictions indicated significant alterations in the secondary and tertiary structures of . knockout in zebrafish resulted in craniofacial malformation, spine deformity, and cardiac edema, mirroring typical HFM phenotypes. Abnormalities in somatic cell apoptosis, reduced NCC proliferation in pharyngeal arches, and chondrocyte differentiation issues were observed in mutants. mRNA injections and or knockout significantly rescued pharyngeal arch cartilage dysplasia, while mRNA administration partially restored the defective phenotypes. Our findings suggest a functional link between and HFM, primarily through the inhibition of proliferation and disruption of pharyngeal chondrocyte differentiation.
Topics: Animals; Zebrafish; Humans; Male; Female; Goldenhar Syndrome; Apoptosis; Neural Crest; Exome Sequencing; Cell Proliferation; Phenotype; Mutation; Gene Knockout Techniques
PubMed: 38731925
DOI: 10.3390/ijms25094707 -
Science Progress 2024Treacher Collins syndrome (TCS) is a rare congenital craniofacial disorder, typically inherited as an autosomal dominant condition. Here, we report on a family in which... (Review)
Review
Treacher Collins syndrome (TCS) is a rare congenital craniofacial disorder, typically inherited as an autosomal dominant condition. Here, we report on a family in which germline mosaicism for TCS was likely present. The proband was diagnosed with TCS based on the typical clinical features and a pathogenic variant (c.4369_4373delAAGAA, p.K1457Efs*12). The mutation was not detected in his parents' peripheral blood DNA samples, suggesting a mutation had occurred in the proband. However, a year later, the proband's mother became pregnant, and the amniotic fluid puncture revealed that the fetus carried the same mutation as the proband. Prenatal ultrasound also indicated a maxillofacial dysplasia with unilateral microtia. The mother then disclosed a previous birth history in which a baby had died of respiratory distress shortly after birth, displaying a TCS-like phenotype. Around the same time, the proband's father was diagnosed with mild bilateral conductive hearing loss. Based on array data, we concluded that the father may have had germline mosaicism for mutation. Our findings highlight the importance of considering germline mosaicism in sporadic mutations when providing genetic consulting, and prenatal diagnosis is important when the proband's parents become pregnant again.
Topics: Humans; Pedigree; Mosaicism; Mandibulofacial Dysostosis; Mutation; Germ Cells
PubMed: 38629201
DOI: 10.1177/00368504241242278 -
Clinical Medicine & Research Mar 2024Goldenhar syndrome, a rare congenital anomaly, manifests as craniofacial malformations often necessitating intricate surgical interventions. These procedures, though...
Goldenhar syndrome, a rare congenital anomaly, manifests as craniofacial malformations often necessitating intricate surgical interventions. These procedures, though crucial, can expose patients to diverse postoperative complications, including hemorrhage or infection. A noteworthy complication is stroke, potentially linked to air embolism or local surgical trauma. We highlight a case of a male patient, aged 20 years, who experienced a significant postoperative complication of an ischemic stroke, theorized to be due to an air embolism, after undergoing orthognathic procedures for Goldenhar syndrome. The patient was subjected to LeFort I maxillary osteotomy, bilateral sagittal split ramus osteotomy of the mandible, and anterior iliac crest bone grafting to the right maxilla. He suffered an acute ischemic stroke in the left thalamus post-surgery, theorized to stem from an air embolism. Advanced imaging demonstrated air pockets within the cavernous sinus, a rare and concerning finding suggestive of potential air embolism. This case underscores the intricate challenges in treating Goldenhar syndrome patients and the rare but significant risk of stroke due to air embolism or surgical trauma. Limited literature on managing air embolism complications specific to Goldenhar syndrome surgeries exists. Generally, management includes immediate recognition, positional adjustments, air aspiration via central venous catheters, hyperbaric oxygen therapy, hemodynamic support, and high-flow oxygen administration to expedite air resorption. Our patient was conservatively managed post-surgery, and at a 3-month neurology follow-up, he showed significant improvement with only residual right arm weakness. It emphasizes the imperative of a comprehensive, multidisciplinary approach.
Topics: Humans; Male; Goldenhar Syndrome; Ischemic Stroke; Orthognathic Surgery; Embolism, Air; Stroke; Intraoperative Complications
PubMed: 38609140
DOI: 10.3121/cmr.2024.1882 -
Molecular Genetics & Genomic Medicine Apr 2024Mandibulofacial dysostosis with microcephaly (MFDM, OMIM# 610536) is a rare monogenic disease that is caused by a mutation in the elongation factor Tu GTP binding domain...
BACKGROUND
Mandibulofacial dysostosis with microcephaly (MFDM, OMIM# 610536) is a rare monogenic disease that is caused by a mutation in the elongation factor Tu GTP binding domain containing 2 gene (EFTUD2, OMIM* 603892). It is characterized by mandibulofacial dysplasia, microcephaly, malformed ears, cleft palate, growth and intellectual disability. MFDM can be easily misdiagnosed due to its phenotypic overlap with other craniofacial dysostosis syndromes. The clinical presentation of MFDM is highly variable among patients.
METHODS
A patient with craniofacial anomalies was enrolled and evaluated by a multidisciplinary team. To make a definitive diagnosis, whole-exome sequencing was performed, followed by validation by Sanger sequencing.
RESULTS
The patient presented with extensive facial bone dysostosis, upward slanting palpebral fissures, outer and middle ear malformation, a previously unreported orbit anomaly, and spina bifida occulta. A novel, pathogenic insertion mutation (c.215_216insT: p.Tyr73Valfs*4) in EFTUD2 was identified as the likely cause of the disease.
CONCLUSIONS
We diagnosed this atypical case of MFDM by the detection of a novel pathogenetic mutation in EFTUD2. We also observed previously unreported features. These findings enrich both the genotypic and phenotypic spectrum of MFDM.
Topics: Humans; Microcephaly; Mandibulofacial Dysostosis; Phenotype; Mutation; Intellectual Disability; Peptide Elongation Factors; Ribonucleoprotein, U5 Small Nuclear
PubMed: 38562046
DOI: 10.1002/mgg3.2426 -
Scientific Reports Mar 2024Treacle ribosome biogenesis factor 1 (TCOF1) is responsible for about 80% of mandibular dysostosis (MD) cases. We have formerly identified a correlation between TCOF1...
Treacle ribosome biogenesis factor 1 (TCOF1) is responsible for about 80% of mandibular dysostosis (MD) cases. We have formerly identified a correlation between TCOF1 and CNBP (CCHC-type zinc finger nucleic acid binding protein) expression in human mesenchymal cells. Given the established role of CNBP in gene regulation during rostral development, we explored the potential for CNBP to modulate TCOF1 transcription. Computational analysis for CNBP binding sites (CNBP-BSs) in the TCOF1 promoter revealed several putative binding sites, two of which (Hs791 and Hs2160) overlap with putative G-quadruplex (G4) sequences (PQSs). We validated the folding of these PQSs measuring circular dichroism and fluorescence of appropriate synthetic oligonucleotides. In vitro studies confirmed binding of purified CNBP to the target PQSs (both folded as G4 and unfolded) with K values in the nM range. ChIP assays conducted in HeLa cells chromatin detected the CNBP binding to TCOF1 promoter. Transient transfections of HEK293 cells revealed that Hs2160 cloned upstream SV40 promoter increased transcription of downstream firefly luciferase reporter gene. We also detected a CNBP-BS and PQS (Dr2393) in the zebrafish TCOF1 orthologue promoter (nolc1). Disrupting this G4 in zebrafish embryos by microinjecting DNA antisense oligonucleotides complementary to Dr2393 reduced the transcription of nolc1 and recapitulated the craniofacial anomalies characteristic of Treacher Collins Syndrome. Both cnbp overexpression and Morpholino-mediated knockdown in zebrafish induced nolc1 transcription. These results suggest that CNBP modulates the transcriptional expression of TCOF1 through a mechanism involving G-quadruplex folding/unfolding, and that this regulation is active in vertebrates as distantly related as bony fish and humans. These findings may have implications for understanding and treating MD.
Topics: Animals; Humans; DNA; G-Quadruplexes; HEK293 Cells; HeLa Cells; Mandibulofacial Dysostosis; Nuclear Proteins; Phosphoproteins; RNA-Binding Proteins; Transcription Factors; Zebrafish
PubMed: 38553547
DOI: 10.1038/s41598-024-58255-9 -
BMC Medical Genomics Mar 2024Treacher Collins syndrome (TCS; OMIM 154500) is a craniofacial developmental disorder.
BACKGROUND
Treacher Collins syndrome (TCS; OMIM 154500) is a craniofacial developmental disorder.
METHODS
To investigate the genetic features of a four-generation Chinese family with TCS, clinical examinations, hearing tests, computed tomography, whole-exome sequencing (WES), Sanger sequencing, reverse transcription (RT)-PCR, and the Minigene assay were performed.
RESULTS
The probands, an 11-year-old male and his cousin exhibited typical clinical manifestations of TCS including conductive hearing loss, downward slanting palpebral fissures, and mandibular hypoplasia. Computed tomography revealed bilateral fusion of the anterior and posterior stapedial crura and malformation of the long crura of the incus. WES of both patients revealed a novel heterozygous intronic variant, i.e., c.4342 + 5_4342 + 8delGTGA (NM_001371623.1) in TCOF1. Minigene expression analysis revealed that the c.4342 + 5_4342 + 8delGTGA variant in TCOF1 caused a partial deletion of exon 24 (c.4115_4342del: p.Gly1373_Arg1448del), which was predicted to yield a truncated protein. The deletion was further confirmed via RT-PCR and sequencing of DNA from proband blood cells. A heterozygous variant in the POLR1C gene (NM_203290; exon6; c.525delG) was found almost co-segregated with the TCOF1 pathogenic variant.
CONCLUSIONS
In conclusion, we identified a heterozygous TCOF1 splicing variant c.4342 + 5_4342 + 8delGTGA (splicing) in a Chinese TSC family with ossicular chain malformations and facial anomalies. Our findings broadened the spectrum of TCS variants and will facilitate diagnostics and prognostic predictions.
Topics: Male; Humans; Child; Mandibulofacial Dysostosis; Mutation; Exons; Introns; China; Nuclear Proteins; Phosphoproteins
PubMed: 38500116
DOI: 10.1186/s12920-024-01828-4 -
Molecular Genetics & Genomic Medicine Mar 2024Treacher Collins Ι syndrome (TCS1, OMIM:154500) is an autosomal dominant disease with a series of clinical manifestations such as craniofacial dysplasia including eye...
BACKGROUND
Treacher Collins Ι syndrome (TCS1, OMIM:154500) is an autosomal dominant disease with a series of clinical manifestations such as craniofacial dysplasia including eye and ear abnormalities, small jaw deformity, cleft lip, as well as repeated respiratory tract infection and conductive hearing loss. Two cases of Treacher Collins syndrome with TCOF1(OMIM:606847) gene variations were reported in the article, with clinical characteristics, gene variants and the etiology.
METHODS
The clinical data of two patients with Treacher Collins syndrome caused by TCOF1 gene variation were retrospectively analyzed. The whole exome sequencing (WES) was performed to detect the pathogenic variants of TCOF1 gene in the patients, and the verification of variants were confirmed by Sanger sequencing.
RESULTS
Proband 1 presented with bilateral craniofacial deformities, conductive hearing loss and recurrent respiratory tract infection. Proband 2 showed bilateral craniofacial malformations with cleft palate, which harbored similar manifestations in her family. She died soon after birth due to dyspnea and feeding difficulties. WES identified two novel pathogenic variants of TCOF1 gene in two probands, each with one variant. According to the American College of Medical Genetics and Genomics, the heterozygous variation NM_001371623.1: c.877del (p. Ala293Profs*34) of TCOF1 gene was detected in Proband 1, which was evaluated as a likely pathogenic (LP) and de novo variant. Another variant found in Proband 2 was NM_001135243.1: c.1660_1661del (p. D554Qfs*3) heterozygous variation, which was evaluated as a pathogenic variation and the variant inherited from the mother. To date, the two variants have not been reported before.
CONCLUSION
Our study found two novel pathogenic variants of TCOF1 gene and clarified the etiology of Treacher Collins syndrome. We also enriched the phenotypic spectrum of Treacher Collins syndrome and TCOF1 gene variation spectrum in the Chinese population, and provided the basis for clinical diagnosis, treatment and genetic counseling.
Topics: Female; Humans; China; Hearing Loss, Conductive; Mandibulofacial Dysostosis; Nuclear Proteins; Phosphoproteins; Respiratory Tract Infections; Retrospective Studies
PubMed: 38444283
DOI: 10.1002/mgg3.2405 -
Scientific Reports Feb 2024This study aimed to probe into the anatomic course of inferior alveolar nerve canal (IANC) in hemifacial microsomia (HFM) on a large scale, morphological observations...
This study aimed to probe into the anatomic course of inferior alveolar nerve canal (IANC) in hemifacial microsomia (HFM) on a large scale, morphological observations and further quantitative study were performed. Patients were classified by Pruzansky-Kaban classification. The anatomic course of IANC was analyzed morphologically with three-dimensional (3D) imaging software among 248 patients. Seven distances between fixed landmarks on both sides were measured for 236 patients. The differences between affected and unaffected sides were compared. Significant differences were found in the entrance (P < 0.001), route (P < 0.001), and exit (P < 0.05) of IANC in type IIb and III HFM. The higher the degree of mandibular deformity was, the higher the incidence of IANC variation was (P < 0.05). The distances in the horizontal aspect of IANC including from mandibular foramen to mental foramen (P < 0.05) and from mental foramen to gonion (P < 0.05) were significantly shorter on the affected side. Abnormalities of the anatomical course of IANC exist in patients with Pruzansky-Kaban type IIb and type III HFM. The reduction of IANC on the affected side in the horizontal distance is more obvious. Three-dimensional imaging assessment is recommended before surgery.
Topics: Humans; Goldenhar Syndrome; Tomography, X-Ray Computed; Mandible; Imaging, Three-Dimensional; Mandibular Nerve
PubMed: 38413665
DOI: 10.1038/s41598-024-54318-z -
BMC Ophthalmology Feb 2024To report a case of a 4-year-old patient with Goldenhar syndrome. (Review)
Review
BACKGROUND
To report a case of a 4-year-old patient with Goldenhar syndrome.
CASE PRESENTATION
The author presents a rare case report involving a 4-year-old boy with multiple malformations. A comprehensive examination showed that the patient primarily had a limbal dermoid. He also has bilateral microtia and ear canal deformities. The skull CT scan and spine X-ray showed Maxillofacial Abnormalities and scoliosis. Whole Exome Sequencing revealed potential gene variations related to microtia. Although certain circumstances prevented us from initiating follow-up treatment for the patient, we have provided a detailed account of the diagnostic methodologies used for this condition.
CONCLUSIONS
Goldenhar syndrome is a congenital condition, predominantly presenting as sporadic cases. Its diagnosis and management typically necessitate the involvement of multiple disciplines, including otolaryngology and craniofacial surgery. The syndrome encompasses a variety of craniofacial features, which can facilitate early diagnosis and guide subsequent therapeutic interventions.
Topics: Male; Humans; Child, Preschool; Goldenhar Syndrome; Congenital Microtia; Abnormalities, Multiple; Tomography, X-Ray Computed; Eye Neoplasms
PubMed: 38388885
DOI: 10.1186/s12886-024-03317-9