A multimorphic variant in ThPOK causes an inborn error of immunity with T cell defects and fibrosis

ThPOK is a transcription factor that acts as a master regulator of CD4+ T cell lineage commitment. We report the first human disease caused by a genetic alteration in ThPOK, specifically, a damaging heterozygous de novo variant in ThPOK (NM_001256455.2:c.1080A>C, p.K360N). This patient exhibited the unusual constellation of persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The ThPOKK360N variant displayed abnormal multimorphic activity, interfering with ThPOKWT (antimorph), failing to bind wild-type ThPOK consensus sequences (amorph), and showing novel DNA-binding specificity (neomorph). Single-cell RNA sequencing revealed defects in CD4+ and CD8+ T cell maturation and activation (hypomorph). Recapitulated in lentivirally transduced healthy control T cells and fibroblasts, the transcriptomic analysis showed ThPOKK360N-transduced T cells had impaired TCR activation and ThPOKK360N-transduced fibroblasts with increased profibrotic gene expression. This novel human disease confirms ThPOK’s role in CD4+ T cell development but also uncovers novel roles in TCR activation and regulation of fibrotic pathways in fibroblasts.