title: Exome sequencing identifies mutant TINF2 in a family with pulmonary fibrosis.
abstract: BACKGROUND
  Short telomeres are a common defect in idiopathic pulmonary fibrosis, yet mutations in the telomerase genes account for only a subset of these cases.
  
  
  METHODS
  We identified a family with pulmonary fibrosis, idiopathic infertility, and short telomeres.
  
  
  RESULTS
  Exome sequencing of blood-derived DNA revealed two mutations in the telomere-binding protein TINF2. The first was a 15-base-pair deletion encompassing the exon 6 splice acceptor site, and the second was a missense mutation, Thr284Arg. Haplotype analysis indicated both variants fell on the same allele. However, lung-derived DNA showed predominantly the Thr284Arg 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. This mosaicism may represent functional reversion in telomere syndromes similar to that described for Fanconi anemia. No mutations were identified in over 40 uncharacterized pulmonary fibrosis 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 fibrosis in 11% of TERT and TR mutation carriers (five of 45).
  
  
  CONCLUSIONS
  Our findings identify TINF2 as a mutant telomere gene in familial pulmonary fibrosis and suggest that infertility may precede the presentation of pulmonary fibrosis in a small subset of adults with telomere syndromes.
authors.affiliation: Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Alder
authors.affiliation: Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Stanley
authors.affiliation: Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Christa L
authors.initials: CL
authors.lastname: Wagner
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT.
authors.forename: Makenzie
authors.initials: M
authors.lastname: Hamilton
authors.affiliation: Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Vidya Sagar
authors.initials: VS
authors.lastname: Hanumanthu
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address: marmani1@jhmi.edu.
authors.forename: Mary
authors.initials: M
authors.lastname: Armanios
mesh_terms: D059472:Exome; D005260:Female; D006801:Humans; D007246:Infertility / Q000150:complications / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D011658:Pulmonary Fibrosis / Q000150:complications / Q000235:genetics*; D012189:Retrospective Studies; D017384:Sequence Deletion; D034501:Telomere-Binding Proteins / Q000235:genetics*
chemical_list: C440868:TINF2 protein, human; D034501:Telomere-Binding Proteins