Prenatal Histological, Cellular and Molecular Anomalies in Down Syndrome Lung

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RationaleDown Syndrome (DS), from trisomy 21 (T21), is the most common human chromosomal anomaly in the United States. Although DS can affect many organ systems, lung and heart disease are the leading causes of death. An abundance of existing data suggests lung abnormalities originate postnatally in DS. However, a single report of branching insufficiency in DS has inferred a potential prenatal origin.MethodsPrenatal DS lung histology (n=15) was assessed by H&E. Comprehensive gene expression assessment in prenatal DS lungs (n=19), and age‐matched controls (n=19), was performed using high‐throughput RNA sequencing (RNAseq) and validated by qPCR. Spatial differences in cellular phenotypes were examined using immunohistochemistry (IHC) and in situ hybridization (ISH).ResultsHistopathological abnormalities were observed in approximately half of DS (T21) prenatal lung tissue samples analyzed, and included dilated airway terminal airways/acinar tubules, dilated lymphatics and muscularized arteries. RNAseq identified 316 genes significantly dysregulated in DS lung tissue (FDR <0.05), when adjusted for age. Ontology analysis showed IFN pathway genes were significantly up‐regulated and extracellular matrix pathway genes were significantly down‐regulated. qPCR confirmed increased expression of interferon (IFN) pathway genes (MX1, IFIT27), COL6A1, and FABP4, and lower expression of SOX2 in prenatal DS lungs. ISH indicated increased IFN receptor expression in DS lung tissue. IHC for KI67 revealed significant reductions in epithelial and mesenchymal cell proliferation, predominantly in those tissues displaying pathology. Airway smooth muscle was reduced and discontinuous in the proximal airway. Reduction in SOX2 was confirmed by IHC, suggesting a reduction in prenatal airway progenitor cells.ConclusionsOur data demonstrate for the first time that specific histological, cellular and molecular abnormalities occur prenatally in the human DS lung.Support or Funding InformationFunding Source: NIH/NHLBI HL141856 and Program in Pediatric Molecular and Personalized Medicine of University of Rochester.