Unraveling the Clinical Spectrum of DNASE1L3 Deficiency: Insights from Case Series and Systematic Literature Review.

DNASE1L3 deficiency is a rare monogenic cause of lupus and lupus-like autoimmunity resulting from impaired extracellular DNA clearance and sustained immune activation. Although most reported patients present with early-onset systemic lupus erythematosus (SLE), emerging evidence suggests broader phenotypic variability, including vasculitic and overlap manifestations. Whether these presentations represent distinct clinical entities or a continuum of DNASE1L3-associated immune dysregulation remains unclear. We aimed to define the clinical spectrum of DNASE1L3 deficiency and examine the relationship between recurrent pathogenic variants and disease severity. We conducted a combined pediatric case series and systematic literature review. Four children with genetically confirmed biallelic DNASE1L3 variants followed at a tertiary pediatric rheumatology centre were retrospectively analysed for clinical, immunological, genetic, treatment, and outcome data. In parallel, a systematic search of PubMed/MEDLINE, Scopus, and Web of Science identified previously reported patients with confirmed biallelic pathogenic or likely pathogenic DNASE1L3 variants and extractable patient-level clinical data. To facilitate cross-case comparison, we applied an exploratory three-tier descriptive framework reflecting increasing disease severity: vasculitic or organ-limited disease (G1), systemic lupus or overlap phenotypes without irreversible organ damage (G2), and severe systemic organ-damaging disease (G3). The assigned grades were descriptive rather than permanent categories, as some patients may meet the criteria for a higher grade if broader systemic manifestations or irreversible organ damage develop during follow-up. Fifteen reports provided extractable patient-level data, corresponding to 45 unique previously reported patients after accounting for known or probable overlapping reports. Combined with four patients from our centre, the analysis included 49 genetically confirmed individuals. SLE-dominant disease was the most frequent phenotype (27 [60%] of 45), followed by hypocomplementaemic urticarial vasculitis/HUVS-dominant disease (10 [22.2%]) and overlap phenotypes (8 [17.8%]). Renal involvement was reported in 30 (66.7%) of 45 patients, and disease onset occurred by age 3 years in 20 (44.4%). Persistent hypocomplementemia affecting C3 and C4 was frequently reported across the spectrum. Recurrent DNASE1L3 variants were observed across multiple phenotypic and severity grades. Variants such as p.Asn191Ser and p.Thr97Ilefs*2 occurred in patients spanning organ-limited vasculitic disease, lupus overlap phenotypes, and severe multisystem lupus with major organ involvement. DNASE1L3 deficiency was associated with a broad clinical spectrum of immune-mediated disease rather than a single clinicopathological entity. The occurrence of identical pathogenic variants across distinct phenotypic and severity states argues against a simple genotype-phenotype model and suggests that additional modifiers influence disease expression.