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. The 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: 17 patients (46%) harbored copy number variations (CNVs), 10 (27%) did non harbor any CNVs , 5 (13.5%) showed a mosaic deletion of Y chromosome, and 5 (13.5%) a run of homozygosity (ROH). NGS identified causative variants (included a novel one) in 5 patients (5/37, 13.5%) and confirmed the high prevalence of MUC5B promoter polymorphism rs35705950, including the detection of a previously unreported 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 set-up of these patients.