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Project description:RATIONALE:Disruption of normal pulmonary development is a leading cause of morbidity and mortality in infants. Congenital lung malformations are a unique model to study the molecular pathogenesis of isolated structural birth defects, as they are often surgically resected. OBJECTIVES:To provide insight into the molecular pathogenesis of congenital lung malformations through analysis of cell-type and gene expression changes in these lesions. METHODS:Clinical data, and lung tissue for DNA, RNA, and histology, were obtained from 58 infants undergoing surgical resection of a congenital lung lesion. Transcriptome-wide gene expression analysis was performed on paired affected and unaffected samples from a subset of infants (n = 14). A three-dimensional organoid culture model was used to assess isolated congenital lung malformation epithelium (n = 3). MEASUREMENTS AND MAIN RESULTS:Congenital lung lesions express higher levels of airway epithelial related genes, and dysregulated expression of genes related to the Ras and PI3K-AKT-mTOR (phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) signaling pathways. Immunofluorescence confirmed differentiated airway epithelial cell types throughout all major subtypes of congenital lung lesions, and three-dimensional cell culture demonstrated a cell-autonomous defect in the epithelium of these lesions. CONCLUSIONS:This study provides the first comprehensive analysis of the congenital lung malformation transcriptome and suggests that disruptions in Ras or PI3K-AKT-mTOR signaling may contribute to the pathology through an epithelial cell-autonomous defect.
| S-EPMC5955056 | biostudies-literature
Project description:To explore the long non-coding RNA (lncRNA) expression pattern of congenital lung malformations on a genome-wide scale and investigate their potential biological function in four types of congenital lung malformations.
2021-12-07 | GSE179404 | GEO
Project description:The treatment of asymptomatic patients with congenital pulmonary malformations (CPMs) remains controversial, partially because the relationship between congenital lung malformations and malignancy is still undefined. Change in methylation pattern is a crucial event in human cancer, including lung cancer. We therefore studied all differentially methylated regions (DMRs) in a series of CPMs in an attempt to find methylation anomalies in genes already described in association with malignancy. The DNA extracted from resected congenital lung malformations and control lung tissue was screened using Illumina MethylationEPIC arrays. Comparison between the group of malformed samples or the malformed samples of same histology or each malformed sample and the controls, and between a pleuropulmonary blastoma (PPB) and controls were performed. All differentially methylated regions (DMRs) with an adjusted p value < 0,05 were studied. Every comparison highlighted a number of DMRs closed to genes involved either in cell proliferation or in embryonic development or included in the Cancer Gene Census. Their abnormal methylation had been already described in lung tumors. The presence of methylation abnormalities is suggestive of a correlation between congenital lung malformations and some step of malignant transformation.
2021-05-19 | GSE174625 | GEO
Project description:Whole-genome methylation study of congenital lung malformations in children
| PRJNA730816 | ENA
Project description:Global interpretation of novel alternative splicing events in human congenital pulmonary airway malformations
| PRJNA743568 | ENA
Project description:The application of second-generation sequencing in congenital pulmonary airway malformations
| PRJNA787785 | ENA
Project description:<p>We report a study of large rare, copy number variants (CNVs) in 192 patients with renal hypodysplasia (RHD). Congenital malformations of the kidney and urinary tract are present in 3 to 7 per 1,000 births, accounting for 16% of birth defects. These malformations account for 40-50% of pediatric and 7% of adult end-stage renal disease worldwide. Among these malformations, RHD represents a severe forms of disease with profound impact on long-term renal survival. We found that a significant fraction of RHD patients have a molecular diagnosis attributable to a genomic disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances.</p>
| phs000565.v1.p1 | EGA
Project description:Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations
| PRJNA480261 | ENA
Project description:Congenital heart disease (CHD) is the most common type of birth defect, affecting ~1% of all live births. Malformations of the cardiac outflow tract (OFT) account for ~30% of all CHD and include a range of CHDs from bicuspid aortic valve (BAV) to tetralogy of Fallot (TOF). We hypothesized that transcriptomic profiling of a mouse model of CHD would highlight disease-contributing genes implicated in congenital cardiac malformations in humans. To test this hypothesis, we utilized global transcriptional profiling differences from a mouse model of OFT malformations to prioritize damaging, de novo variants identified from exome sequencing datasets from published cohorts of CHD patients. Notch1+/-;Nos3-/- mice display a spectrum of cardiac OFT malformations ranging from BAV, semilunar valve (SLV) stenosis to TOF. Global transcriptional profiling of the E13.5 Notch1+/-;Nos3-/- mutant mouse OFTs and wildtype controls was performed by RNA sequencing (RNA-Seq). Analysis of the RNA-Seq dataset demonstrated genes belonging to the Hif1α, Tgf-β, Hippo, and Wnt signaling pathways were differentially expressed in the mutant OFT. Mouse to human comparative analysis was then performed to determine if patients with TOF and SLV stenosis display an increased burden of damaging, genetic variants in gene homologs that were dysregulated in Notch1+/-; Nos3-/- OFT. We found an enrichment of de novo variants in the TOF population among the 1,352 significantly differentially expressed genes in Notch1+/-;Nos3-/- mouse OFT but not the SLV population. This association was not significant when compared to only highly expressed genes in the murine OFT and of de novo variants in the TOF population. These results suggest that transcriptomic datasets generated from the appropriate temporal, anatomic and cellular tissues from murine models of CHD may provide a novel approach for the prioritization of disease-contributing genes in patients with CHD.
2021-06-28 | GSE171238 | GEO
Project description:Congenital heart disease (CHD) is the most common type of birth defect, affecting ~1% of all live births. Malformations of the cardiac outflow tract (OFT) account for ~30% of all CHD and include a range of CHDs from bicuspid aortic valve (BAV) to tetralogy of Fallot (TOF). We hypothesized that transcriptomic profiling of a mouse model of CHD would highlight disease-contributing genes implicated in congenital cardiac malformations in humans. To test this hypothesis, we utilized global transcriptional profiling differences from a mouse model of OFT malformations to prioritize damaging, de novo variants identified from exome sequencing datasets from published cohorts of CHD patients. Notch1+/-;Nos3-/- mice display a spectrum of cardiac OFT malformations ranging from BAV, semilunar valve (SLV) stenosis to TOF. Global transcriptional profiling of the E13.5 Notch1+/-;Nos3-/- mutant mouse OFTs and wildtype controls was performed by RNA sequencing (RNA-Seq). Analysis of the RNA-Seq dataset demonstrated genes belonging to the Hif1α, Tgf-β, Hippo, and Wnt signaling pathways were differentially expressed in the mutant OFT. Mouse to human comparative analysis was then performed to determine if patients with TOF and SLV stenosis display an increased burden of damaging, genetic variants in gene homologs that were dysregulated in Notch1+/-; Nos3-/- OFT. We found an enrichment of de novo variants in the TOF population among the 1,352 significantly differentially expressed genes in Notch1+/-;Nos3-/- mouse OFT but not the SLV population. This association was not significant when compared to only highly expressed genes in the murine OFT and of de novo variants in the TOF population. These results suggest that transcriptomic datasets generated from the appropriate temporal, anatomic and cellular tissues from murine models of CHD may provide a novel approach for the prioritization of disease-contributing genes in patients with CHD.
2021-06-28 | GSE171237 | GEO