A progranulin variant causing childhood interstitial lung disease responsive to anti-TNF-α biologic therapy.

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.