Identification and functional characterisation of a novel DNASE1L3 variant (c.572A>G, p.Asn191Ser) in three Emirati families with systemic lupus erythematosus and hypocomplementaemic urticarial vasculitis.

Objectives: To evaluate the functional impact of a novel variant (c.572A>G, p.Asn191Ser) in three families with SLE and hypocomplementaemic urticarial vasculitis (HUV) from the United Arab Emirates.

Methods: Whole-exome sequencing was performed on affected patients and findings were confirmed using Sanger sequencing in family members. DNASE1L3 protein expression, secretion and enzymatic activity were assessed in HEK293 cell lines. Plasma smear assay for neutrophil extracellular traps (NETs) was evaluated in patients, family members and healthy control.

Results: A total of seven patients diagnosed with both SLE and HUV were identified from three unrelated families. All affected individuals were found to carry a homozygous c.572A>G, p.Asn191Ser (191S) variant in . The variant 191S was shown to impact the secretion and activity of DNASE1L3. Patients homozygous for 191S variant had significantly higher burden (p=0.0409) of NET structure in comparison to heterozygous and healthy control.

Conclusions: We functionally evaluated the effect of a novel (c.572A>G, p.Asn191Ser) in familial SLE with a consistent pattern of HUV across seven patients. This variant resulted in impaired secretion and enzymatic activity of DNASE1L3 along with increased NETosis in patients with homozygous genotype.