A deep dive into monogenic lupus: insights on DNASE1L3 mutation

Abstract Objective In this study, we aim to describe the largest cohort of monogenic lupus caused by DNASE1L3 yet reported, describing its phenotypic characteristics and outcomes. Methods We performed a multicentre retrospective chart review for enrolled patients with childhood-onset systemic lupus erythematosus (cSLE) followed in pediatric rheumatology tertiary centers in the Sultanate of Oman. We included cSLE patients with genetically confirmed DNASE1L3 mutation. The demographic, clinical and laboratory data of the monogenic lupus cohort was compared with sporadic cSLE cohort. Results We recruited 33 patients from 15 families with confirmed homozygous DNASE1L3 mutation. The median age of disease onset was 4 years, with 18 (55%) of cohort presenting before the age of 5 years. There were higher proportion of boys 20(61%) affected. Significant proportion of cohort had hypocomplementemic urticarial vasculitis (HUV) symptoms including arthritis (82%), urticarial vasculitis (79%), fever (49%), abdominal pain (36%) and conjunctivitis (25%). Compared with sporadic cohort, there was higher frequency of nephritis (60%) and pulmonary hemorrhage (15%). SLE disease activity index score on presentation was 13.3 ± 3.64 (SD), while disease damage was identified in n = 14 (42%) of patients with mean damage index score of 2.14 ± 1.12 (SD). Despite treatment, significant proportion continued to display HUV symptoms that were refractory to standard treatment. Conclusion Given the early onset, aggressive nature and refractory natures of cSLE caused by DNASE1L3 mutation, further research aimed at targeted therapies that could restore the function of DNASE1L3 or compensate for its deficiency is warranted.