A progranulin variant causing childhood interstitial lung disease responsive to anti-TNF-α biologic therapy Journal Article
| Authors: | Kennedy, J. C.; Vargas, S. O.; Fishman, M. P.; Alesi, N.; Baek, S. H.; Khabibillin, D.; Platt, C. D.; Garcia-de-Alba, C.; Agrawal, P. B.; Carmichael, N. E.; Henderson, L. A.; Wehrman, A.; Boland, S.; Walther, T.; Farese, R. V.; Casey, A. M. H.; Manis, J. P.; Collen, L. V.; Lvova, M.; Barbieri, A.; Sullivan, B.; Raby, B. A. |
| Article Title: | A progranulin variant causing childhood interstitial lung disease responsive to anti-TNF-α biologic therapy |
| Abstract: | Background: Childhood interstitial and diffuse lung diseases are a collection of rare disorders with significant associated morbidity. Only a small subset of these diseases have precise diagnostic or therapeutic options identified to date. Methods: Whole-exome sequencing in a family identified a candidate pathogenic variant predicted to be causing fibrotic lung and liver disease in a child. Digital spatial mRNA profiling of clinical lung biopsies was done to identify aberrant signaling pathways. ELISA confirmed low circulating protein levels in the patient. Findings: We identified homozygosity of the p.Cys139Arg loss-of-function progranulin (GRN) variant and an alveolar macrophage transcriptomic signature consistent with tumor necrosis factor alpha (TNF-α) pathway activation. This motivated treatment with anti-TNF monoclonal antibodies, resulting in dramatic improvement of the patient's lung and liver disease. Conclusions: These findings demonstrate the clinical utility of convergent multiomics in the evaluation and implementation of precision therapeutics in rare diseases. Funding: This work was supported by a grant from the Chan Zuckerberg Initiative Patient-Partnered Collaboration for single-cell analysis of rare inflammatory pediatric disease, the Corkin Family Fund for Research, and in part by cooperative agreement U01TR002623 from the National Center for Advancing Translational Sciences/NIH and the PrecisionLink Project at Boston Children's Hospital. © 2025 Elsevier Inc. |
| Keywords: | immunohistochemistry; child; clinical article; protein expression; school child; gene mutation; human cell; genetics; case report; liver function; phenotype; quality of life; computer assisted tomography; gene expression; protein protein interaction; immunofluorescence; transcriptomics; enzyme linked immunosorbent assay; genetic transfection; tumor necrosis factor-alpha; glucocorticoid; interstitial lung disease; upregulation; monocyte; biological therapy; drug therapy; macrophage; bioinformatics; genetic screening; lung biopsy; dna extraction; tumor necrosis factor; rna sequence; dna isolation; spirometry; principal component analysis; bronchiectasis; infliximab; gene ontology; lung diseases, interstitial; mycophenolic acid; tnf-α; transient elastography; humans; human; male; female; article; exome sequencing; precision medicine; progranulin; whole exome sequencing; multiomics; spatial transcriptomics; obstructive pneumonia; translation to patients; tnf signaling; childhood interstitial lung disease; fibrotic lung disease; rare lung disease; progranulins; grn protein, human |
| Journal Title: | Med |
| Volume: | 6 |
| Issue: | 6 |
| ISSN: | 2666-6359 |
| Publisher: | Cell Press |
| Date Published: | 2025-01-01 |
| Start Page: | 100607 |
| Language: | English |
| DOI: | 10.1016/j.medj.2025.100607 |
| PUBMED: | 40020677 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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