Mutations in SFTPC, SFTPA2 and TERT explain 60% of familial pulmonary fibrosis and correlate to specific disease phenotypes

Idiopathic Pulmonary Fibrosis (IPF) is a fatal lung disease, histologically characterized by diffuse interstitial remodeling and patchy inflammation. A significant percentage of IPF patients have a familial form of the disease. Separate reports have identified mutations in Surfactant Protein-C (SFTPC), Surfactant Protein-A2 (SFTPA2), Telomerase Reverse Transcriptase (TERT) or Telomerase RNA component (TERC) in these families. We determined the frequency of mutations in SFTPC, SFTPA2, TERT and TERC in 20 patients with Familial Pulmonary Fibrosis (FPF). Heterozygous non-tolerated sequence changes were detected in 12 out of 20 patients, consisting of 5 SFTPC, 2 SFTPA2 and 5 TERT mutations. Mutations segregated with disease in each family and haplotype analysis showed that identical mutations had arisen independently. Families with SFTPC and SFTPA2 mutations always had evidence of parent-offspring disease transmission, while in families with TERT mutation sibs were affected. Pediatric pulmonary disease occurred only in families with SFTPC mutations. Carriers of an SFTPA2 mutation also suffered from lung cancer. Families with a TERT mutation usually presented as typical IPF and did not show clear symptons associated with other known syndromes of telomere shortening. This is the first report of a cohort of IPF families that is completely sequenced for candidate genes. We could identify a mutation in 60% of patients with FPF. These mutations correlated with a specific disease phenotype. The function of each of the mutated genes is very different, but all indicate towards a central role for the alveolar type II cell in disease pathogenesis.