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

DNASE1L3

Biallelic DNASE1L3 variants — impaired extracellular DNA clearance and sustained immune activation

DNASE1L3 deficiency is a rare monogenic cause of lupus and lupus-like autoimmunity resulting from impaired extracellular DNA clearance. This work combines a series of four genetically confirmed children followed at a tertiary paediatric rheumatology centre with a systematic review (PubMed/MEDLINE, Scopus, Web of Science), totalling 49 individuals. Among the 45 previously reported patients, the dominant phenotype was systemic lupus (27, 60%), ahead of hypocomplementaemic urticarial vasculitis (10, 22.2%) and overlap phenotypes (8, 17.8%); renal involvement was reported in 30 (66.7%) and onset occurred before age 3 in 20 (44.4%). Identical recurrent variants such as p.Asn191Ser and p.Thr97IlefsTer2 were found across organ-limited vasculitic disease and severe multisystem lupus alike, arguing against a simple genotype-phenotype model.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The useful information here is negative: for the same variant, severity ranges from organ-limited vasculitis to destructive renal disease, which rules out any genotype-based prognosis. In very early-onset lupus with persistent C3 and C4 hypocomplementaemia, sequencing remains justified, but the report should stay cautious about expected course. The proposed G1–G3 grading is descriptive and retrospective; it needs prospective validation before use in clinic.

Analysis by Dr Thibaut Benquey