title: Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive.
abstract: Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals.115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed.Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%). Discordant interstitial lung disease diagnoses were found in affected individuals from 80% of families. Patients with TERC mutations were diagnosed at an earlier age than those with PARN mutations (51±11 years versus 64±8 years; p=0.03) and had a higher incidence of haematological comorbidities. The mean rate of forced vital capacity decline was 300 mL·year-1and the median time to death or transplant was 2.87 years. There was no significant difference in time to death or transplant for patients across gene mutation groups or for patients with a diagnosis of IPF versus a non-IPF diagnosis.Genetic mutations in telomere related genes lead to a variety of interstitial lung disease (ILD) diagnoses that are universally progressive.
authors.affiliation: Eugene McDermott Centre for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.|Dept of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Newton
authors.affiliation: Dept of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Batra
authors.affiliation: Dept of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Torrealba
authors.affiliation: Eugene McDermott Centre for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Kozlitina
authors.affiliation: Dept of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Glazer
authors.affiliation: Dept of Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Aravena
authors.affiliation: Dept of Medicine, University of Wisconsin, Madison, WI, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Meyer
authors.affiliation: Dept of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Raghu
authors.affiliation: Dept of Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Harold R
authors.initials: HR
authors.lastname: Collard
authors.affiliation: Eugene McDermott Centre for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA christine.garcia@utsouthwestern.edu.|Dept of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Christine Kim
authors.initials: CK
authors.lastname: Garcia
mesh_terms: D000368:Aged; D004265:DNA Helicases / Q000235:genetics; D005095:Exoribonucleases / Q000235:genetics; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000175:diagnosis* / Q000235:genetics* / Q000601:surgery; D016014:Linear Models; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012313:RNA / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D013781:Texas; D014057:Tomography, X-Ray Computed
chemical_list: D004265:DNA Helicases; D005095:Exoribonucleases; D012313:RNA; D019098:Telomerase; C422952:telomerase RNA; C509186:TERT protein, human; C532890:RTEL1 protein, human