Regulator of telomere length 1 (<i>RTEL1</i>) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes

Abstract

Regulator of telomere length 1 (<i>RTEL1</i>) mutations have been evidenced in 5-9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and <i>RTEL1</i> mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and <i>RTEL1</i> mutation. <i>RTEL1</i> expression was evaluated by immunochemistry in the lungs of controls, as well as in <i>RTEL1</i> and telomerase reverse transcriptase (<i>TERT</i>) 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 <i>RTEL1</i> 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 <i>RTEL1</i> was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.