D23-21 Genetic Testing in Interstitial Lung Disease: Identifying Patients Most Likely to Benefit

Abstract Background Genetic factors play an increasingly recognized role in the pathogenesis of interstitial lung diseases (ILDs). In 2023, the European Respiratory Society (ERS) issued a statement recommending genetic testing for patients with fibrotic ILD and a positive family history, those with relatives carrying a pathogenic variant, patients with suspected short telomere syndrome (STS), and individuals diagnosed with idiopathic fibrosing ILD before the age of 50 years. However, the diagnostic yield of these recommendations in unselected clinical cohorts remains unclear. Objective This pilot study aimed to evaluate the diagnostic yield of genetic testing in ILD patients meeting the ERS criteria and to identify patient subgroups with the highest likelihood of a positive genetic finding. Methods Fifty-one patients with fibrotic ILD fulfilling at least one ERS indication for genetic testing were enrolled. Detailed clinical phenotyping included family history, disease course, pulmonary function, therapy, and treatment-related adverse events. Whole-exome sequencing (WES) was performed using Illumina NovaSeq6000 platform. Kit for library prepartion WES by Sophia Genetics v2 using DNA Library prep kit by SG. Variant detection employed the Sophia DDM Sofware and interpretation by AI-assisted Franklin and Varsome Clinical platform. Patients were categorized by indication and genetic test result (Table 1). Subjects with no clinically relevant variants, opportunistic findings, or non-matching variants were classified as “genetically negative,” whereas those with pathogenic or possibly disease-related variants were considered “genetically positive.” Group comparisons employed Kruskal-Wallis and chi-square tests. Results Pathogenic gene variants explaining ILD were detected in 14% of cases. Opportunistic findings outnumbered pathogenic variants. Significant group differences were observed in age (p = 0.000007; group 3 patients were the oldest), sex distribution (p = 0.013; group 1 contained 100% women versus 85% men in genetically negative group 3), family history of lung disease (p = 0.0061; more frequent in genetically negative groups 3 and 4), and presence of crackles (p = 0.01; all patients in genetically positive group 3 had crackles, compared with 18% in positive group 4). The highest proportion of smokers occurred in genetically negative group 3 (92%, p = 0.017). No significant differences were found in lung function, comorbidities, bronchoalveolar lavage differential count, exposures, or use of immunosuppressive/antifibrotic therapy. Conclusion In ILD patients selected according to ERS indications, genetic testing identified pathogenic variants in a minority of cases, with a predominance of inconclusive or opportunistic findings. The lowest yield was observed in patients tested for early-onset fibrotic ILD, suggesting a need for refined selection criteria to improve diagnostic efficiency in this subgroup. This abstract is funded by: Grant of Czech Agency for Medical Research NW24-06-00050