DNASE1L3 deficiency, new phenotypes, and evidence for a transient type I IFN signaling.

BACKGROUND: Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans. OBJECTIVES: To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human. METHODS: We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24th 2022. RESULTS: We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients. CONCLUSIONS: DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI).

PIK3AP1 and SPON2 Genes Are Differentially Methylated in Patients With Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) Syndrome.

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is the most common autoinflammatory disease in children and is often grouped together with hereditary periodic fever syndromes, although its cause and hereditary nature remain unexplained. We investigated whether differential DNA methylation was present in DNA from peripheral blood mononuclear cells (PBMC) in patients with PFAPA vs. healthy controls. A whole-epigenome analysis (MeDIP and MBD) was performed using pooled DNA libraries enriched for methylated genomic regions and identified candidate genes, two of which were further evaluated with methylation-specific restriction enzymes coupled with qPCR (MSRE-qPCR). The analysis showed that the PIK3AP1 and SPON2 gene regions are differentially methylated in patients with PFAPA. MSRE-qPCR proved to be a quick, reliable, and cost-effective method of confirming results from MeDIP and MBD. Our findings indicate that a B-cell adapter protein (PIK3AP1), as the PI3K binding inhibitor of inflammation, and spondin-2 (SPON2), as a pattern recognition molecule and integrin ligand, could play a role in the etiology of PFAPA. Their role and the impact of changed DNA methylation in PFAPA etiology and autoinflammation need further investigation.