Clinical utility of the ERS recommendations for genetic evaluation in interstitial lung disease: a prospective cohort study

The European Respiratory Society (ERS) recommends genetic evaluation in selected patients with interstitial lung disease (ILD), particularly those with familial disease, early disease onset, or clinical features suggestive of telomere biology disorders. However, prospective data evaluating the diagnostic yield and clinical utility of these recommendations remain limited. We aimed to assess the diagnostic performance of combined whole-exome sequencing (WES) and telomere length assessment in ILD patients selected according to the ERS recommendations. In this prospective observational cohort study, 52 consecutive ILD patients fulfilling at least one ERS indication for genetic evaluation underwent WES and quantitative PCR-based telomere length measurement. Diagnostic yield was assessed according to the clinical indication for testing, and the complementary value of genetic testing and telomere length assessment was evaluated. Pathogenic or likely pathogenic variants were identified in 4 of 52 patients (7.7%). The highest diagnostic yield was observed among patients with clinical suspicion of telomere biology disorders, whereas no pathogenic variants were identified in patients with isolated early-onset ILD without any patient with a relative carrying a pathogenic/likely pathogenic variant known to cause ILD. Short telomeres (< 10th percentile) were detected in 21.2% of patients, including individuals without identifiable pathogenic variants, indicating that telomere length assessment provided additional clinically relevant information beyond genetic testing alone. Our findings support the clinical usefulness of the current ERS recommendations for selecting ILD patients for genetic evaluation. Patients with suspected telomere biology disorders and familial ILD appear to derive the greatest diagnostic benefit. Combined assessment using WES and telomere length measurement provides complementary information and may improve the identification and clinical management of patients with inherited forms of ILD. Not applicable.