Background Monogenic lupus is a rare, inherited entity, and the precise prevalence is unknown. It demonstrates great heterogeneity in etiopathogenesis and phenotypes. To date, there is no standardized definition or criteria for identifying monogenic lupus.

To report the phenotypic characteristics, and identify the spectrum of genetic variants related to monogenic lupus from a single tertiary lupus clinic.

Methods A descriptive, observational, cross-sectional study was conducted. Data was retrospectively collected on patients with lupus manifestations and genetic variants seen between 1997 and 2022. Data comprised the clinical findings, including family history and consanguinity, and laboratory findings. Genetic testing, including Whole exome sequencing (WES), was performed on all monogenic lupus patients.

Results Among the 256 patients with childhood systemic lupus erythematosus (cSLE) seen in our lupus clinic at King Faisal Specialist Hospital & Research Center (KFSHRC)-Riyadh, 30 patients (11.7%) (16 females) were identified as having monogenic lupus. All patients included in the study were of Arab origin, with 70% having early-onset disease. The most frequent features were fever (100%), musculoskeletal (93.3%), and mucocutaneous lesions (86.7%). Renal, cardiac, and pulmonary involvement were seen at 33.3%, 30%, and 26.7%, respectively. Thirteen patients (43.3%) experienced recurrent infections. Complement deficiency was the most frequent genetic variant (40%), followed by DNase variants (23.3%). Interestingly, genetic analysis revealed 12 novel gene variants. All patients were treated aggressively with corticosteroids and sequential conventional immunosuppressive drugs. Twenty-eight patients received biologic agents (14 belimumab, 12 rituximab, and 2 JAK inhibitors), while 23 received IVIG. Most of them showed a poor response to treatment. There were five deaths related to serious infections.

Conclusions This report expands the pathogenic variants and the clinical spectrum of monogenic lupus. Patients with various variants share clinical characteristics. The outcome is guarded by a high mortality rate. Unfortunately, to date, there is no effective standard treatment.