Figure - available from: Frontiers in Genetics
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Ultrasound findings: (A) Cystic hygroma measuring 18 × 6 × 14 mm (CRL:60.9 mm) at the mid-sagittal plane. (B) Cystic hygroma in a transverse view. (C) Short and bowed femurs (<first centile). (D) Sagittal anterior angulated tibiae (fifth centile). (E) Sagittal anterior angulated fibula (fifth centile). (F) Unilateral equinovarus clubfoot. (G) Micrognathia.
Source publication
Introduction: Campomelic dysplasia (CD) is a rare autosomal dominant skeletal malformation syndrome characterized by shortness and bowing of the lower extremities with or without XY sex reversal. Diagnosis using ultrasonography is most often made in the latter half of pregnancy. Intragenic heterozygous mutations in SOX9 are responsible for most cas...
Citations
... CH has been reported in about 1 in 800 pregnancies and 1 in 8000 live births. Although with the development of nextgeneration sequencing technology, genetic variants such as SOX9, KDR, and BRCA1 are involved in the pathogenesis of cystic hygroma, the specific pathogenesis of cystic hygroma remains unclear [3][4][5][6]. There are currently no studies that explain the pathogenesis of CH from the perspective of single cell subpopulations. ...
Background
The molecular mechanism of fetal cystic hygroma (CH) is still unclear, and no study has previously reported the transcriptome changes of single cells in CH. In this study, single-cell transcriptome sequencing (scRNA-seq) was used to investigate the characteristics of cell subsets in the lesion tissues of CH patients.
Methods
Lymphoid tissue collected from CH patients and control donors for scRNA-seq analysis. Differentially expressed gene enrichment in major cell subpopulations as well as cell-cell communication were analyzed. At the same time, the expression and interactions of important VEGF signaling pathway molecules were analyzed, and potential transcription factors that could bind to KDR (VEGFR2) were predicted.
Results
The results of scRNA-seq showed that fibroblasts accounted for the largest proportion in the lymphatic lesions of CH patients. There was a significant increase in the proportion of lymphatic endothelial cell subsets between the cases and controls. The VEGF signaling pathway is enriched in lymphatic endothelial cells and participates in the regulation of cell-cell communication between lymphatic endothelial cells and other cells. The key regulatory gene KDR in the VEGF signaling pathway is highly expressed in CH patients and interacts with other differentially expressed EDN1, TAGLN, and CLDN5 Finally, we found that STAT1 could bind to the KDR promoter region, which may play an important role in promoting KDR up-regulation.
Conclusion
Our comprehensive delineation of the cellular composition in tumor tissues of CH patients using single-cell RNA-sequencing identified the enrichment of lymphatic endothelial cells in CH and highlighted the activation of the VEGF signaling pathway in lymphoid endothelial cells as a potential modulator.
Simple summary
The molecular and cellular pathogenesis of fetal cystic hygroma (CH) remains largely unknown. This study examined the distribution and gene expression signature of each cell subpopulation and the possible role of VEGF signaling in lymphatic endothelial cells in regulating the progression of CH by single-cell transcriptome sequencing. The enrichment of lymphatic endothelial cells in CH and the activation of the VEGF signaling pathway in lymphatic endothelial cells provide some clues to the pathogenesis of CH from the perspective of cell subpopulations.
... Frontiers in Pediatrics also led to CD (15). The reported cases of CD that SOX9 being completely deletion over the past few decades were thought to represent evidence for the dosage-dependent action of SOX9 protein in normal chondrogenesis (8,16). However, Csukasi et al. (14) revealed dominant-negative mutations of SOX9 in CD-affected individuals, and the reported deletion of SOX9 also overlapped the Frontiers in Pediatrics upstream enhancer region (7,17,18). ...
Background
Campomelic dysplasia (CD) is an autosomal dominant skeletal dysplasia syndrome characterized by shortness and bowing of lower extremities, and often accompanied by XY sex reversal. Heterozygous pathogenic variants of SOX9 or rearrangement involving the long arm of chromosome 17 are the causes of disease. However, evidence for pathogenesis of SOX9 haploinsufficiency is insufficient.
Methods
We enrolled a Chinese family where the fetus was diagnosed with CD. The affected fetus was selected for whole-exome sequencing to identify the pathogenic mutations in this family.
Results
After data filtering, a novel non-sense SOX9 variant (NM_000346.3; c.1249C > T; p.Q417*) was identified as the pathogenic lesion in the fetus. Further co-segregation analysis using Sanger sequencing confirmed that this novel SOX9 mutation (c.1249C > T; p.Q417*) was a de novo mutation in the affected fetus. This terminated codon mutation identified by bioinformatics was located at an evolutionarily conserved site of SOX9 . The bioinformatics-based analysis predicted this variant was pathogenic and affected SOX9 transactivation activity.
Conclusion
CD is a rare condition, which connected with SOX9 tightly. We identified a novel heterozygous SOX9 variant (p.Q417*) in a Chinese CD family. Our study supports the putative reduced transactivation of SOX9 variants in the pathogenicity of CD.
