Trisomy 8-associated Autoinflammatory Disease (TRIAD) is Characterized by Dysregulated Myeloid Cells

Abstract Trisomy 8 mosaicism (T8M) has been associated with a Behçet’s-like inflammatory disease, but immunologic features and treatment responses are not well-characterized. Here, we characterize 20 individuals with constitutional T8M and inflammatory disease. Most participants had congenital dysmorphologies and developmental delay. Two developed hematologic malignancies, two had bleeding diathesis due to platelet dense granule deficiency, and most had macrocytosis. The majority had recurrent fever and severe oral ulcerations, while nearly half had genital ulcers or rash. Colchicine, apremilast, and IL-1 and TNFa inhibitors were effective therapies. With ddPCR on sorted cell populations, we found that cells from the myeloid lineage (monocytes, neutrophils, megakaryocytes, erythroid progenitors) had a significantly higher percentage of trisomy 8 mosaicism compared to those from the lymphoid lineage (T and B cells) in both the peripheral blood and bone marrow, suggesting that trisomy 8 is tolerated to a greater degree by myeloid cells. Furthermore, we found that participants with T8M had more classical monocytes and had upregulation of genes associated with activated neutrophils and monocytes in their whole blood compared to healthy controls. With single cell RNAseq, we identifed which cells were trisomy 8 and disomy based on chromosome 8 gene expression and found that trisomy 8 monocytes had distinct transcriptional signatures and alteration of innate immune genes. Our findings suggest that patients with T8M are prone to a distinct autoinflammatory disease which we propose calling trisomy 8 associated autoinflammatory disease (TRIAD) and have complications due to dysregulation of cells arising from the myeloid lineage. This work was supported by the Intramural Research Program of NIAID, NHGRI, and NHLBI, NIH.