Abstract
Regulator of telomere length 1 (RTEL1) mutations have been evidenced in 5–9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.
Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase (TERT) mutation carriers.
We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1 years (range 28.0–80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2 months and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.
Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.
Abstract
RTEL1 mutations are associated with heterogeneous lung phenotypes with limited and heterogeneous extra-respiratory manifestations http://ow.ly/1Ssr30mCZjx
Footnotes
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Collaborators: Isabelle Callebaut (UPMC UMR CNRS 7590 Paris); Smail Amar, Eline Magois (CHU d'Amiens Amiens); Aurélie Plessier (Hôpital Beaujon Clichy); Pierre-Yves Brillet, Marianne Kambouchner, Dominique Valeyre, Yurdagul Uzunhan (Hôpital Avicenne Bobigny); Evguenia Dobrinskikh (University of Colorado Denver USA); Sophie Park (CHU Grenoble Alpes Grenoble); Anas Mehdaoui (Hôpital Eure Seine Evreux); Reza Azarian (Hôpital André Mignot Le Chesnay); Nicolas Pottier, Benoit Wallaert (CHRU de Lille Lille); Chantal-Michele Bertocchi (Centre hospitalier Annecy Genevois Metz-Tessy); Kaïs Ahmad (Hôpital Louis Pradel Lyon); Jacques Piquet (Centre hospitalier Intercommunal Le Raincy-Montfermeil Montfermeil); Arnaud Bourdin (CHRU de Montpellier Montpellier); Farida Skander (CHU Oran Oran); Claire Danel, Gaelle Dauriat, Aurelien Justet, Camille Taillé (Hôpital Bichat Paris); Isabelle Honoré (Hôpital Cochin Paris); Flore Sicre de Fontbrune (Hôpital Saint Louis Paris); Sandrine Hirschi, Armelle Schuller (Hôpitaux Universitaires de Strasbourg Strasbourg); Serge Amselem, Nadia Nathan, Annick Clement (Hôpital Trousseau Paris).
Conflict of interest: R. Borie reports grants and personal fees from Roche, personal fees from Boerhinger Ingelheim and Savapharma, outside the submitted work.
Conflict of interest: D. Bouvry has nothing to disclose.
Conflict of interest: V. Cottin reports personal fees for consultancy, lecturing and travel to medical meetings from Actelion and Roche, personal fees for development of educational presentations, consultancy, lecturing and travel to medical meetings from Boehringer Ingelheim, personal fees for consultancy from Bayer and GSK, personal fees for adjudication committee work from Gilead, personal fees for consultancy and travel to medical meetings from MSD, personal fees for consultancy and lecturing from Novartis and Sanofi, institutional grants from Boehringer Ingelheim and Roche, personal fees for data and safety monitoring board work from Promedior and Celgene, personal fees for consultancy and data and safety monitoring board work from Galapagos, outside the submitted work.
Conflict of interest: C. Gauvain has nothing to disclose.
Conflict of interest: A. Cazes has nothing to disclose.
Conflict of interest: M-P. Debray reports personal fees from Boehringer-Ingelheim, and reimbursement for travel and accommodation for medical meeting for Guerbet and Roche, outside the submitted work.
Conflict of interest: J. Cadranel has nothing to disclose.
Conflict of interest: P. Dieude has nothing to disclose.
Conflict of interest: T. Degot reports personal fees for expert testimony in ILD and travel reimbursement for the Congress CPLF 2018 in Lyon from Boerhinger Ingelheim France, and personal fees for expert testimony in ILD from Roche France, outside the submitted work.
Conflict of interest: S. Dominique reports personal fees from Roche and Boehringer Ingelheim, outside the submitted work.
Conflict of interest: A.S. Gamez has nothing to disclose.
Conflict of interest: M. Jaillet has nothing to disclose.
Conflict of interest: P-A. Juge has nothing to disclose.
Conflict of interest: A. Londono-Vallejo has nothing to disclose.
Conflict of interest: A. Mailleux has nothing to disclose.
Conflict of interest: H. Mal has nothing to disclose.
Conflict of interest: C. Boileau has nothing to disclose.
Conflict of interest: C. Menard has nothing to disclose.
Conflict of interest: H. Nunes has nothing to disclose.
Conflict of interest: G. Prevot has nothing to disclose.
Conflict of interest: S. Quetant has nothing to disclose.
Conflict of interest: P. Revy has nothing to disclose.
Conflict of interest: J. Traclet has nothing to disclose.
Conflict of interest: L. Wemeau-Stervinou reports personal fees and non-financial support from Boehringer-Ingelheim and Roche, personal fees from Bristol-Myers-Squibb and Jansen-Cilag, outside the submitted work.
Conflict of interest: M. Wislez has nothing to disclose.
Conflict of interest: C. Kannengiesser has nothing to disclose.
Conflict of interest: B. Crestani reports grants for research and personal fees for development of educational presentations, consultancy, lecturing and travel to medical meetings from Boehringer Ingelheim, grants for research and personal fees for consultancy, lecturing and travel to medical meetings from Roche, personal fees for consultancy and lecturing from Sanofi and Apellis, personal fees for consultancy, lecturing and travel to medical meetings from AstraZeneca, and research grants from MedImmune, outside the submitted work.
Support statement: This work was supported by le Fonds de Recherche en Santé Respiratoire et de la Fondation du Souffle, la Chancellerie des Universités de Paris (legs Poix), and a grant from Roche. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received March 13, 2018.
- Accepted November 6, 2018.
- Copyright ©ERS 2019
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