A Granulin Variant Causing Childhood Interstitial Lung Disease Responsive to anti-TNF-a Biologic Therapy

We combined whole exome sequencing with digital spatial mRNA profiling of clinical lung biopsies in the diagnostic evaluation ofapre-teen with progressive idiopathic fibrotic lung and liver disease refractory to standard therapies. The combined findings of homozygosity for the p.Cys139Arg loss-of-function progranulin (GRN) variant and an alveolar macrophage transcriptomic signature consistent with TNF-alpha pathway activation motivated treatment with anti-TNF monoclonal antibodies, resulting in dramatic improvement of her lung and liver disease. These findings demonstrate the clinical utility of convergent multiomics in the evaluation and treatment of rare disease Eight FFPE lung biopsy samples were assembled into an array FFPE block. Immunoflorescence staining was completed for epithelium (PanCK), Macrophages (CD68), Type-2 pneumocytes (ABCA3) and nuclei per GeoMX DSP protocol. Three Regions of interest (ROI) of macrophages within alveoli, were selected for each sample and whole transcriptome data was retrieved and analysed with Next Generation Sequencing (NGS) readout per GeoMx DSP NGS readout protocol. The study was designed to compare intra-alveolar macrophages from pediatric Interstitial lung disease samples from children with known monogenic lung disease and histocopies.