Single cell RNA-seq analysis of hematopoietic cell types in 22q11.2 deletion syndrome reveals significant changes to...

22q11.2 Deletion syndrome is one of the most common inborn errors of immunity. There is a large body of literature supporting alterations to T cells as a result of thymic hypoplasia. Additional studies have supported changes to B cell behavior which have been presumed to be secondary to impaired T cell help. Yet, there remains a significant gap in our understanding of the impact of this syndrome on non-T cells.

This study utilized a cohort of 46 participants with 22q11.2 deletion syndrome and 18 age and sex-matched controls. 5' single-cell RNAseq was performed to characterize cell populations and altered gene expression.

All cell types exhibited RNA expression differences between patients and controls. Across T cells, B cells, NK cells and monocytes, there were no conserved modules either up or down regulated; however, all cell types exhibited differences between controls and patients. Among naïve, memory, and terminal effector CD4 T cells, we observed a number of signatures related to proliferation as manifested by translation initiation and ribosomal component gene expression that were increased in patients. Patients who had had cardiac surgery had altered CD8 T cells with lower naïve CD8 T cells compared to patients who did not have cardiac surgery and increased gene expression in modules defined by oxidative phosphorylation and interferon exposure.

Surprisingly, all cell types examined exhibited differences between patients and controls. Monocytes and NK cells, the cell types least likely to be directly impacted by thymic effects, had unique patterns of gene expression, although both were highly altered in patients. This suggests a widespread impact of the deletion that may be related to direct and indirect effects of reduced gene dosage.