Idiopathic Pulmonary Fibrosis: Analysis of Predisposing Variants in Patients with Familial Forms

Background: idiopathic pulmonary fibrosis (IPF) causes progressive and irreversible changes in the lung parenchyma, leading to respiratory failure. Its pathogenesis involves several damage/repair mechanisms leading to fibrosis, whilst alterations of genes implicated in these processes contribute to the development of the disease. At present, next-generation sequencing (NGS) analyses investigate single-nucleotide or small indel variants, and no evaluation of genomic rearrangements has been so far reported. Methods: In order to identify predisposing variants, we analyzed-both by NGS and by comparative genomic hybridization/single-nucleotide polymorphism (CGH-SNP array) array-37 patients with a diagnosis of familial pulmonary fibrosis. Results: a total of 17 patients (46%) harbored copy number variations (CNVs), 10 (27%) did not harbor any CNVs, 5 (13.5%) showed a mosaic deletion of the Y chromosome, and 5 (13.5%) showed a run of homozygosity (ROH). NGS identified causative variants (including a novel one) in five patients (5/37, 13.5%) and confirmed the high prevalence of MUC5B promoter polymorphism rs35705950, including the detection of a previously unreported form in IPF SNP (indicated as "novel" in the main text), rs141420125 (23/37; 62%). Conclusions: CGH-SNP array identified CNVs containing genes involved in mechanisms (i.e., oxidative stress, mitophagy, NF-Kb pathway) that have been shown to play a role in the pathogenesis of IPF. Therefore, the application of CGH-SNP array or other quantitative tests should be considered in the diagnostic setup of these patients.