Prevalence and characteristics ofTERTandTERCmutations in suspected genetic pulmonary fibrosis

Abstract

Telomerase reverse transcriptase (TERT) or telomerase RNA (TERC) gene mutation is a major monogenic cause of pulmonary fibrosis. Sequencing of TERT/TERC genes is proposed to patients with familial pulmonary fibrosis. Little is known about the possible predictors of this mutation and its impact on prognosis.We retrospectively analysed all the genetic diagnoses made between 2007-2014 in patients with pulmonary fibrosis. We evaluated the prevalence of TERT/TERC disease-associated variant (DAV), factors associated with a DAV, and the impact of the DAV on survival.237 patients with pulmonary fibrosis (153 with familial pulmonary fibrosis, 84 with telomere syndrome features without familial pulmonary fibrosis) were tested for TERT/TERC DAV. DAV was diagnosed in 40 patients (16.8%), including five with non-idiopathic interstitial pneumonia. Prevalence of TERT/TERC DAV did not significantly differ between patients with familial pulmonary fibrosis or with only telomere syndrome features (18.2% versus 16.4%). Young age, red blood cell macrocytosis, and low platelet count were associated with the presence of DAV; the probability of DAV was increased for patients 40-60 years. Transplant-free survival was lower with than without TERT/TERC DAV (4.2 versus 7.2 years; p=0.046).TERT/TERC DAV were associated with specific clinical and biological features and reduced transplant-free survival.

Management of suspected monogenic lung fibrosis in a specialised centre

“…A typical UIP pattern on chest CT was initially reported in up to 74% of cases, but was recently found in only 46-55% of cases (figure 3) [9,28,36]. Unusual features found in 13-20% of cases included upper-lung predominance of fibrosis, centrolobular fibrosis, or a pleuro-parenchymal fibroelastosis pattern [9,28,36].…”

“…Unusual features found in 13-20% of cases included upper-lung predominance of fibrosis, centrolobular fibrosis, or a pleuro-parenchymal fibroelastosis pattern [9,28,36]. In all, 14-40% of cases show a combined pulmonary fibrosis and emphysema pattern [45].…”

“…Patients with TERC mutations may be relatively younger at ILD diagnosis than cases of mutations in other genes [9]. In a recent series of 114 patients with ILD associated with telomerase complex mutation, ILD was diagnosed at a mean age of 51 years (n=7) for TERC mutation carriers, 58 years (n=75) for TERT mutation carriers, 60 years (n=14) for RTEL1 mutation carriers and 65 years (n=19) for PARN mutation carriers ( p=0.03) [9,36]. The male/female ratio of patients with ILD varies from 0.5 to 0.7.…”

“…IPF is the most frequent diagnosis (86% in one cohort, 45-47% in recent cohorts) [9,28,36]. Pleuroparenchymal fibroelastosis (up to 10%), chronic HP (7-11%) and unclassifiable fibrosis (19-30%) are also frequent [9,36]. )…”

“…as reported in the Telomerase Database, http://telomerase.asu.edu/diseases.html). The penetrance (risk of pulmonary fibrosis developing in a carrier of TERT and TERC mutations) depends on several factors, including environmental exposure [28,36]. The gene-environment interaction reported for carriers of TERT or TERC mutations may also be implicated for carriers of RTEL1 mutations [9].…”