Abstract
BACKGROUND: Congenital pulmonary airway malformation (CPAM) is a rare lung abnormality characterized by the formation of cystic or solid masses in lung tissues. To date, the genetic etiology of CPAM has not been well described. The objective of this study is to explore the potential genetic etiology of CPAM through trio-based whole exome sequencing (WES). METHODS: We performed WES on 13 fetuses diagnosed with CPAM and their parents. The filtered variants were further analyzed using bioinformatic prediction tools and enrichment analyses. RESULTS: A total of 23 rare variants were identified in 11 fetuses with CPAM, including 3 homozygous mutations and 19 heterozygous mutations. EYA1, FAP, THAP4 and ALDH1B1, all with extremely low population frequencies, were predicted to be deleterious. Notably, mutations in the mucin genes (MUC3A and MUC6) were identified in four cases, suggesting potential impairment of epithelial barrier function. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed significant involvement in embryonic development, epigenetic regulation, cellular morphogenesis and immunometabolism-related pathways, highlighting potential immune-metabolic crosstalk in CPAM. CONCLUSIONS: In this study, we provide novel insights into the genetic architecture of CPAM and revealed a multifactorial etiology involving developmental, metabolic, and immune-related mechanisms, which can provide a foundation for future functional studies and genetic counseling in CPAM-affected families.