A truncating ELF4 variant in a pediatric patient with autoinflammatory disease and cell type-specific immune alterations

Introduction ELF4 is an ETS family transcription factor involved in immune regulation, including antiviral responses and inflammatory signaling. Germline loss-of-function variants in ELF4 cause deficiency in ELF4, X-linked (DEX), a disorder characterized by recurrent mucocutaneous inflammation and variable immune abnormalities. To date, ELF4-related disease has been reported only in association with germline mutations. Here, we report a pediatric patient with autoinflammatory disease harboring a truncating ELF4 variant (c.239T>A, p.L80*). Methods Clinical and genetic evaluations were performed in the patient and his family. The ELF4 c.239T>A variant was assessed by Sanger sequencing in peripheral blood and buccal mucosa samples. ELF4 protein expression was examined in patient-derived cells and ectopic expression of wild-type and mutant ELF4 constructs in HEK293T cells by immunoblotting. Full-length single-cell RNA sequencing was performed on whole-blood leukocytes to compare mutant-assigned and wild-type-assigned immune cells within the same individual. Results An ELF4 truncating variant (c.239T>A, p.L80*) was detected in peripheral blood but was not detected in parental blood samples or the patient’s buccal mucosa by Sanger sequencing. Given the limited sensitivity of Sanger sequencing, the developmental origin and tissue distribution of the variant could not be definitively determined. A reduced full-length ELF4 signal was observed in patient-derived PBMCs and in the p.L80* HEK293T overexpression system, together with impaired transcriptional activity in an IFN-β promoter reporter assay. Single-cell transcriptomic analysis identified cells with p.L80*-supporting transcripts across multiple immune lineages and suggested cell type-specific transcriptional alterations. Pathway analyses indicated reduced antiviral and interferon-related programs in mutant-assigned NK cells. Exploratory analysis of mutant-assigned CD16 + monocytes also suggested inflammation-related pathway alterations, although the limited number of allele-informative cells warrants cautious interpretation. Conclusions ELF4 is an ETS family transcription factor that plays an important role in immune regulation. Our study identifies a functionally impaired ELF4 p.L80* variant in a pediatric patient with autoinflammatory disease and provides preliminary evidence of cell type-specific transcriptional alterations associated with this variant.