Familial Pulmonary Fibrosis: Clinical, genetic and radiological characterization

<bold>Background:</bold> Familial Pulmonary Fibrosis (FPF) is defined as interstitial lung disease (ILD) affecting ≥2 members of the same primary biological family, and it is commonly progressive and associated with poor outcome. <bold>Methods:</bold> We analyzed retrospectively patients with FPF criteria followed in our unit. All patients underwent NGS based 32-gene panel from exome sequencing. Additionally, Sanger sequencing was used for regulatory region of <italic>TERC</italic> gene and real-time PCR for <italic>MUC5B rs35705950</italic>. <bold>Results:</bold> 96 patients from 91 families were included (62% female, mean age 56±16.6y). Most frequent genetic variant was <italic>rs35705950.</italic> Causal variants in telomerase related genes were found in 20% cases and surfactant related genes in 4% cases. Other genetic variants were found in 18% of patients. Patients also had relevant environmental exposures, including smoking (52%), birds (49%) or mold (26%), gastroesophageal reflux disease (27%), and established connective-tissue diseases (16%). Dyspnea (70%) and cough (58%) were the most common symptoms. Mean baseline FVC and DLCO were 89%±19 and 60%±18, respectively. Radiological findings were diverse, including cases with UIP pattern (23%), probable UIP (13%) and indeterminate for UIP (7%). Most common provisional diagnosis following MDT discussion were the following: 40% pleuroparenchymal fibroelastosis, 20% idiopathic pulmonary fibrosis, 10% fibrotic hypersensitivity pneumonitis, 10% fibrotic unclassifiable ILD. Combined emphysem was present in 28% of cases. <bold>Conclusion:</bold> Our findings suggest that <italic>MUC5B</italic> variant is associated with the occurrence of FPF. The majority of patients had additional risk factors for ILD and are associated with a range of clinical and radiological presentations.