Integrating genetics in the clinical care of patients with fibrotic interstitial lung diseases helps in diagnosis and predicting progression

Growing evidence suggests genetic basis in familial and other types of fibrotic interstitial lung disease (ILD). Genetics may improve diagnostic accuracy and risk stratification. The objective was to evaluate the utility of integrating genetic data into ILD clinical practice. A retrospective observational study was conducted in 194 newly diagnosed patients with fibrotic ILD and family aggregation or other clinical suspicion of a genetic etiology. A 12-month follow-up was performed to assess disease progression. Clinical and genetic variables were analysed using bivariate and multiple logistic regression models to identify predictors of progression. The diagnostic efficiency of the developed predictive model was evaluated and validated in 57 patients from the PRECISION-ILD prospective cohort. A potentially fibrotic-causing genetic variant was identified in 17% of patients, with RTEL1 and TERT as the most frequent pathogenic genes. Fibrotic progression at 12 months was observed in 54% of cases. Variant carriers had a significantly higher proportion of disease progression compared with non-carriers (79% vs. 48%, p = 0.002). Additionally, carrying the T allele in the MUC5B promoter region associated higher risk of progression compared to GG genotype ( p = 0.002). Carriers of both variant-positive and MUC5B T-allele associated the highest risk of progression (OR[95%CI]: 7.00[1.82–46.39]; p = 0.003). A predictive model of fibrotic progression including age at diagnosis and the genetic profile showed a sensitivity of 82.7% and an area under the curve of 0.707[0.634–0.780]. Integrating genetic analysis with clinical variables enhances diagnostic yield and risk prediction of fibrotic progression, enhancing precision management strategies in fibrotic ILDs. Schematic representation of the study