Type I interferon-mediated autoinflammation in two unrelated patients due to a proximal intronic splice site variant...

Type I interferonopathies are Mendelian inborn errors of immunity caused by defective clearance or recognition of nucleic acids, resulting in chronic type I interferon (IFN) activation. DNase II is a lysosomal endonuclease critical for degrading DNA during erythropoiesis and apoptosis. Biallelic loss-of-function variants in DNASE2 cause a rare autoinflammatory disorder. We aimed to characterize the clinical, genetic, and functional impact of a novel DNASE2 splice site variant in two unrelated patients.

We performed exome and RNA sequencing to identify and validate variants. A minigene assay assessed splicing effects. DNase II activity was tested in cell lysates. Structural modeling, cytokine profiling, and immune stimulation assays were conducted to evaluate pathway activation and therapeutic response.

Both patients carried a homozygous DNASE2 splice site variant (c.511+5G>A), resulting in exon 4 skipping and impaired DNase II activity. They presented at birth with rash, thrombocytopenia, and anemia, later developing neutropenia, arthritis, failure to thrive, and systemic inflammation. One patient also harbored a homozygous USP43 variant that reduced USP43 expression and enhanced IFN signaling. Both patients showed increased JAK-STAT activation and responded clinically to JAK1/2 inhibition with ruxolitinib.

We report a novel proximal intronic splice variant in DNASE2 associated with DNase II deficiency and type I interferon-mediated autoinflammation. Our findings expand the genotypic and phenotypic spectrum of this disorder, highlight the role of intronic variants in rare immune diseases, and support JAK inhibition as a targeted treatment approach.