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Abstract
Recent studies have suggested that causative variants in telomerase complex genes (TCGs) are present in around 10% of individuals with idiopathic pulmonary fibrosis (IPF) regardless of family history of the disease. However, the studies used a case-control rare variant enrichment study design which is not directly translatable to routine practice. To validate the prevalence results and to establish the individual level, routine clinical practice, and utility of those results we performed next generation sequencing of TCGs on a cohort of well-characterized consecutive individuals with IPF (diagnosis established according to ATS/ERS/JRS/ALAT guidelines). Of 27 IPF patients, three had a family history of idiopathic interstitial pneumonia (familial IPF) and 24 did not (sporadic IPF). Pathogenic/likely-pathogenic variants (according to American College of Medical Genetics criteria) in TCG were found in three individuals (11.1%) of the whole cohort; specifically, they were present in 2 out of 24 (8.3%) of the sporadic and in 1 out of 3 (33.3%) of the patients with familial IPF. Our results, which were established on an individual-patient level study design and in routine clinical practice (as opposed to the case-control study design), are roughly in line with the around 10% prevalence of causative TCG variants in patients with IPF.
Highlights
Short telomeres have long been connected to idiopathic interstitial pneumonias (IIPs); especially to the most common and most deadly of the IIPs, idiopathic pulmonary fibrosis (IPF) [1,2,3]
We have evaluated the utility of pursuing a genetic diagnosis of telomerase complex genes (TCGs) pathogenic variants in an unselected, well-characterized cohort of individuals with IPF
While the two [23,24] sought for the enrichment of rare, proteinaltering, qualifying variants on a populational level of individuals with IPF compared to controls, we explored in how many individuals with IPF a pathogenic variant according to the ACMG [31] criteria could be found
Summary
Short telomeres have long been connected to idiopathic interstitial pneumonias (IIPs); especially to the most common and most deadly of the IIPs, idiopathic pulmonary fibrosis (IPF) [1,2,3]. In familial cases but short telomeres are frequently observed in sporadic IPF patients (individuals with no family history of IIP) [1,3]. It is believed that telomere dysfunction, which results from (critically) short telomeres, triggers aberrant lung healing by fibroblasts, eventually leading to scar formation and pulmonary fibrosis [4]. Genetic [10,11] variables. Genetic variables with the highest impact on telomere length (shortness) are pathogenic-mostly ‘loss-of-function’-variants present in genes of the telomerase complex (telomerase complex genes (TCG)) [12]
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