Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening

Bridget D. Stuart, Jungmin Choi, Samir Zaidi, Chao Xing, Brody Holohan, Rui Chen, Mihwa Choi, Pooja Dharwadkar, Fernando Torres, Carlos E. Girod, Jonathan Weissler, John Fitzgerald, Corey Kershaw, Julia Klesney-Tait, Yolanda Mageto, Jerry W. Shay, Weizhen Ji, Kaya Bilguvar, Shrikant Mane, Richard P. LiftonChristine Kim Garcia

Research output: Contribution to journalArticlepeer-review

301 Citations (Scopus)


Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 × 10 -8); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 × 10 -6). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain â 1/47% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.

Original languageEnglish
Pages (from-to)512-517
Number of pages6
JournalNature Genetics
Issue number5
Publication statusPublished - 2015 May 30
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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