DNASE1L3 Deficiency With Novel Missense Variant: Enzymatic and Plasma Fragmentomic Evidence of Pathogenicity and Partial Response to JAK Blockade.

objectiveBiallelic loss-of-function variants in DNASE1L3 cause inherited systemic lupus erythematosus and hypocomplementemic urticarial vasculitis. These disorders arise from defective clearance of extracellular chromatin, leading to autoantibody formation, immune complex deposition, and complement consumption. The full clinical and therapeutic spectrum of DNASE1L3 deficiency remains incompletely defined.

methodsWe evaluated a 24-year-old woman with lifelong systemic inflammation characterized by polyarthritis, urticarial vasculitis, episcleritis, recurrent abdominal pain with intestinal angioedema, and persistent hypocomplementemia. Testing included autoantibody profiling, whole-exome sequencing, DNASE1L3 enzymatic assays in cell lysates and supernatants, and plasma analysis of cell-free DNA fragmentation.

resultsThe patient lacked antinuclear, anti-double-stranded DNA, and anti-Smith antibodies, though antiphospholipid antibodies were intermittently positive. The disease was refractory to multiple immunosuppressive agents but showed partial improvement with JAK inhibition. Genetic analysis revealed compound heterozygous DNASE1L3 variants: a pathogenic frameshift (c.290_291delCA) and a novel missense change (c.179T>G, p.Ile60Ser). Functional testing showed markedly impaired DNA degradation for both variants, with residual activity in the missense mutant. Plasma DNA analysis demonstrated reduced mononucleosomal peaks, altered fragment length distribution, and loss of cytosine-cytosine-rich end motifs, confirming reduced nuclease activity in vivo.

conclusionThis case supports the pathogenicity of the DNASE1L3 p.Ile60Ser variant broadening the genetic spectrum. Plasma DNA fragment analysis provides a sensitive biomarker of impaired nuclease function, and JAK inhibition may offer partial therapeutic benefit in DNASE1L3-related systemic inflammation.