Why some and not others? Understanding vascular phenotypes in genetic developmental lung diseases

Abstract

Purpose of review: Pulmonary vascular disease is more common in certain genetic developmental lung disorders. This review synthesizes clinical descriptions, molecular analyses, and single-cell transcriptional data to build a conceptual framework to help understand why some variants affect the vasculature while others primarily manifest with parenchymal disease.

Recent findings: Genes predominantly expressed in endothelial and mesenchymal compartments ( TBX4 , FGF10 , FOXF1 , KDR ) commonly present with both parenchymal and pulmonary vascular disease, while epithelial-restricted genes ( SFTPC , ABCA3 , NKX2.1 ) typically manifest as parenchymal disease. Single-cell analyses reveal that compartment-specific expression patterns correlate with clinical phenotypes. Phenotypic variability, even among individuals sharing identical variants, suggests complex interactions between genetic modifiers, epigenetic factors, and developmental processes that remain poorly understood.

Summary: Compartment-specific gene expression patterns fundamentally underlie the differential presence of vascular phenotypes in DEVLDs. Genetic advances and single cell technologies have revolutionized our understanding of these disorders, but we are in the early stages of translating this knowledge into meaningful clinical advances. Future efforts must bridge this gap to transform clinical care from supportive to targeted, disease-modifying treatment based on cell-specific molecular mechanisms.

Keywords: developmental lung disease; gene expression; genotype–phenotype correlation; pulmonary vascular disease; single-cell transcriptomics.