Sept. 03, 2026
Advances in genomics have substantially expanded understanding of the inherited basis of pulmonary fibrosis. Pathogenic variants involving telomere biology and surfactant protein pathways are increasingly recognized in patients with fibrotic interstitial lung disease (F-ILD). Yet genetic testing remains underutilized in routine pulmonary practice, in part because of uncertainty about who to test, how to interpret results and whether those findings meaningfully affect clinical management.
"These diseases are often difficult to diagnose, and patients may be treated based on incomplete or unclear underlying causes," says Kathryn T. del Valle, M.D., lead author of the study and a pulmonologist at Mayo Clinic in Rochester, Minnesota.
To address this gap, Mayo Clinic investigators established an integrated genetic testing and counseling (GTAC) model in collaboration with the ILD pulmonary practice. In a study published in Mayo Clinic Proceedings, investigators evaluated the clinical utility of combining genetic testing with telomere length assessment in patients with F-ILD.
From 2019 through 2023, 66 patients with F-ILD were referred for genetic evaluation. Referral was considered for patients with a family history of pulmonary fibrosis, progressive fibrotic disease, clinical features suggesting a telomere biology disorder (TBD), or pulmonary fibrosis beginning at age 60 or younger. Importantly, the model was designed to reflect real-world pulmonary practice rather than restrict testing to patients meeting narrowly defined familial pulmonary fibrosis criteria. Ultimately, the decision to refer was at the discretion of the treating pulmonary clinician.
Patients referred to the GTAC unit received pretest counseling from certified genetic counselors and were offered multigene panels that included key telomere biology and surfactant-related genes. Genetic results were interpreted in the context of the patient's phenotype, radiographic findings and laboratory data through multidisciplinary collaboration between pulmonary clinicians and genetics professionals. Telomere length was assessed independently using flow cytometry with fluorescence in situ hybridization and reported relative to age-matched controls.
Of the 66 referred patients, 54 (82%) completed genetic testing. The cohort included a broad range of ILD diagnoses, not only classic idiopathic pulmonary fibrosis (IPF). The most common diagnoses were unclassifiable fibrotic lung disease and IPF, and the most frequent radiographic pattern was indeterminate for usual interstitial pneumonia.
Genetic testing identified pathogenic or likely pathogenic variants in nearly 1 in 5 tested patients (10 of 54 patients, 19% of the cohort). Nine of these 10 patients had variants affecting telomere biology genes. RTEL1 was most frequently implicated, followed by TERT, with additional pathogenic variants involving TERC, PARN and the surfactant-associated gene SFTPA2.
Short telomere length also was common among testing patients. Among 47 patients who underwent telomere testing, 37 (79%) had telomere length at or below the 10th percentile in lymphocytes, granulocytes or both. Shorter lymphocyte telomere length was associated with substantially greater odds of identifying a genetic cause of disease, with an adjusted odds ratio of 6.26. However, shortened telomeres also were found in patients without an identifiable pathogenic variant, underscoring that telomere testing and genetic sequencing provide complementary rather than interchangeable information.
Family history alone was an imperfect discriminator. More than half of patients with negative genetic testing met criteria for familial pulmonary fibrosis, while half of those with solved or potentially solved cases did not. Limiting evaluation to patients with a known family history may therefore miss some patients with clinically relevant genetic disease.
Perhaps most importantly, testing influenced care. Clinical management changed in 54% of patients who had genetic testing. Changes included referral to a specialized TBD clinic or additional testing, medication modifications — for example, caution regarding immune suppression — expedited lung or liver transplant evaluation, and testing of family members. Management changes were particularly frequent among patients with pathogenic or likely pathogenic variants.
The integrated approach also helps identify extrapulmonary manifestations of telomere disorders, including liver disease, bone marrow dysfunction and malignancy, and provides opportunities to identify at-risk relatives. Embedding genetics expertise within ILD care can thus move genomic testing beyond diagnostic classification and translate results directly into treatment and surveillance decisions.
Although the cohort was relatively small and enriched by referral for suspected genetic disease, the findings demonstrate the substantial clinical value of incorporating telomere length assessment and genetic testing into the evaluation of selected patients with progressive pulmonary fibrosis.
"This work demonstrates a practical, scalable way to incorporate genetic and telomere assessment into clinical care for patients with fibrotic interstitial lung disease," says Eva M. Carmona Porquera, M.D., Ph.D., a senior author and a pulmonologist at Mayo Clinic in Rochester, Minnesota. "Genetic and telomere testing may help elucidate why disease is occurring, guide management decisions and identify family members who may be at risk."
For more information
del Valle KT, et al. Advancing pulmonary fibrosis care: Integrating genomic insights into clinical practice. Mayo Clinic Proceedings. In press.
Refer a patient to Mayo Clinic.