Telomere dysfunction and mucociliary impairment drive idiopathic pulmonary fibrosis susceptibility: insights from a Sardinian whole-exome study

Background Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which both environmental exposures and genetic predisposition contribute to disease susceptibility. Studying the burden of rare variants in a genetically homogeneous founder population may help identify disease-associated alleles that are difficult to detect in more heterogeneous populations. Methods Whole exome sequencing was performed on 123 patients with IPF and 1110 unrelated controls from Sardinia (Italy). Variant prioritisations were conducted according to the American College of Medical Genetics (ACMG) guidelines. In parallel, gene burden of rare predicted loss-of-function variants was assessed using the Cohort Allelic Sums Test (CAST) algorithm to identify genes significantly enriched in IPF cases compared with controls. Results Pathogenic or likely pathogenic variants in known telomere-related genes were identified in 11.4% of patients. These variants were associated with younger age at diagnosis and a higher prevalence among never-smokers. CAST analysis identified a significant enrichment of loss-of-function variants in 82 genes, including MUC5B (OR=443.1, false discovery rate=3.7E−05), functionally related to cilium organisation and motility, with a significant overrepresentation of dynein-related genes. Conclusions This study supports the contribution of telomere-related variants to IPF susceptibility and suggests a possible role for rare variants affecting mucociliary pathways. Together, these findings broaden the current understanding of IPF biology in this cohort. The distinctive genetic background of the Sardinian population may have facilitated the identification of rare or population-specific variants, underscoring the potential value of founder populations in complex disease genetics.