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Original Research: Diffuse Lung Disease |

Exome Sequencing Identifies Mutant TINF2 in a Family With Pulmonary FibrosisMutant TINF2 in Familial Pulmonary Fibrosis

Jonathan K. Alder, PhD; Susan E. Stanley, BS; Christa L. Wagner, BA; Makenzie Hamilton, BS; Vidya Sagar Hanumanthu, MBBS; Mary Armanios, MD
Author and Funding Information

From the Department of Oncology and Sidney Kimmel Comprehensive Cancer Center (Drs Alder, Hanumanthu, and Armanios and Mss Stanley and Wagner) and the McKusick-Nathans Institute of Genetic Medicine (Mss Stanley and Wagner and Drs Hanumanthu and Armanios), Johns Hopkins University School of Medicine, Baltimore, MD; and the Department of Physiology and Developmental Biology (Dr Alder and Ms Hamilton), Brigham Young University, Provo, UT.

CORRESPONDENCE TO: Mary Armanios, MD, 1650 Orleans St, CRB 1, Room 186, Baltimore, MD 21287; e-mail: marmani1@jhmi.edu


Dr Alder and Ms Stanley contributed equally to this work.

FUNDING/SUPPORT: This work was supported by the National Institutes of Health (NIH) [Grant RO1 CA160433] and by the Commonwealth Foundation (to Dr Armanios). Dr Alder received support from the NIH [Grant R00 HL113105], and Ms Stanley received support from the NIH [Grant T32 GM007309].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(5):1361-1368. doi:10.1378/chest.14-1947
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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.

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