Exome sequencing identifi es mutant TINF2 in a family with pulmonary fibrosis

BACKGROUND: Short telomeres are a common defect in idiopathic pulmonary fi brosis, yet mutations in the telomerase genes account for only a subset of these cases. METHODS: We identifi ed a family with pulmonary fi brosis, idiopathic infertility, and short telomeres. RESULTS: Exome sequencing of blood-derived DNA revealed two mutations in the telomerebinding protein TINF2 . Th e fi rst was a 15-base-pair deletion encompassing the exon 6 splice acceptor site, and the second was a missense mutation, Th r284Arg. Haplotype analysis indicated both variants fell on the same allele. However, lung-derived DNA showed predominantly the Th r284Arg allele, indicating that the deletion seen in the blood was acquired and may have a protective advantage because it diminished expression of the missense mutation. Th is mosaicism may represent functional reversion in telomere syndromes similar to that described for Fanconi anemia. No mutations were identifi ed in over 40 uncharacterized pulmonary fi brosis probands suggesting that mutant TINF2 accounts for a small subset of familial cases. However, similar to affected individuals in this family, we identified a history of male and female infertility preceding the onset of pulmonary fi brosis in 11% of TERT and TR mutation carriers (fi ve of 45). CONCLUSIONS: Our fi ndings identify TINF2 as a mutant telomere gene in familial pulmonary fi brosis and suggest that infertility may precede the presentation of pulmonary fi brosis in a small subset of adults with telomere syndromes.