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

Nat Genet. 2015 May;47(5):512-7. doi: 10.1038/ng.3278.

Bridget D Stuart ¹, Jungmin Choi ², Samir Zaidi ², Chao Xing ³, Brody Holohan ⁴, Rui Chen ⁵, Mihwa Choi ³, Pooja Dharwadkar ⁵, Fernando Torres ⁵, Carlos E Girod ⁵, Jonathan Weissler ⁵, John Fitzgerald ⁵, Corey Kershaw ⁵, Julia Klesney-Tait ⁶, Yolanda Mageto ⁷, Jerry W Shay ⁴, Weizhen Ji ², Kaya Bilguvar ⁸, Shrikant Mane ⁸, Richard P Lifton ⁹, Christine Kim Garcia ¹⁰

Affiliations

1 1] Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
2 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA.
3 Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
4 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
5 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
6 Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
7 Department of Internal Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA.
8 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. [2] Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut, USA.
9 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA. [3] Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut, USA. [4] Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
10 1] Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

PMID: 25848748 DOI: 10.1038/ng.3278

Abstract

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 ~7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.

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