Clinical Impact of Telomere Length Testing for Interstitial Lung Disease

Abstract

Background: Shortened telomere length (TL) is a genomic risk factor for fibrotic interstitial lung disease (ILD), but its role in clinical management is unknown.

Research question: What is the clinical impact of TL testing on the management of ILD?

Study design and methods: Patients were evaluated in the Columbia University ILD clinic and underwent Clinical Laboratory Improvement Amendments-certified TL testing by flow cytometry and fluorescence in situ hybridization (FlowFISH) as part of clinical treatment. Short TL was defined as below the 10th age-adjusted percentile for either granulocytes or lymphocytes by FlowFISH. Patients were offered genetic counseling and testing if they had short TL or a family history of ILD. FlowFISH TL was compared with research quantitative polymerase chain reaction (qPCR) TL measurement.

Results: A total of 108 patients underwent TL testing, including those with clinical features of short telomere syndrome such as familial pulmonary fibrosis (50%) or extrapulmonary manifestations in the patient (25%) or a relative (41%). The overall prevalence of short TL was 46% and was similar across clinical ILD diagnoses. The number of short telomere clinical features was independently associated with detecting short TL (OR, 2.00; 95% CI, 1.27-3.32). TL testing led to clinical treatment changes for 35 patients (32%), most commonly resulting in reduction or avoidance of immunosuppression. Of the patients who underwent genetic testing (n = 34), a positive or candidate diagnostic finding in telomere-related genes was identified in 10 patients (29%). Inclusion of TL testing below the 1st percentile helped reclassify eight of nine variants of uncertain significance into actionable findings. The quantitative polymerase chain reaction test correlated with FlowFISH, but age-adjusted percentile cutoffs may not be equivalent between the two assays.

Interpretation: Incorporating TL testing in ILD impacted clinical management and led to the discovery of new actionable genetic variants.

Keywords: genetic counseling; genomics; idiopathic pulmonary fibrosis; precision medicine; pulmonary fibrosis; telomere.