Genetic and phenotypic landscape of monogenic lupus: insights from an international cohort.
PMID 41850754 | PMCID PMC13007097 | DOI 10.1136/lupus-2025-001918 · Lupus science & medicine · 2026
OBJECTIVE: To characterise the clinical, immunologic and molecular genetic features of monogenic lupus in a large, ethnically diverse paediatric cohort and to evaluate genotype-phenotype correlations. METHODS: We conducted a retrospective multicentre study of 100 children with genetically confirmed monogenic lupus diagnosed before the age of 14 years. Patients were enrolled between 2000 and 2025 from centres in Saudi Arabia, Iran, Russia, Italy, Palestine and Oman. Demographic data, clinical manifestations, immunological findings, genetic results, treatments and outcomes were systematically analysed. Multivariable logistic regression was used to evaluate associations between specific genotypes and clinical phenotypes. RESULTS: The median age at onset was 24 months, with 69% of patients carrying homozygous pathogenic mutations. The most frequently implicated genes were C1Q (26%) and DNASE1L3 (25%), representing complement and type I interferon pathways, respectively. Mucocutaneous (84%), musculoskeletal (74%) and neurological (42%) were the most common clinical features. Disease burden was substantial, reflected by a median Paediatric Systemic Disease Index score of 3 and a mortality rate of 16%. Distinct ethnic clustering of specific gene mutations was observed. Genotype-phenotype analysis revealed that C1Q pathway defects were significantly associated with neurologic involvement, recurrent infections and anti-Sjögren's syndrome antibody A (SSA)/SSB positivity, defining a characteristic clinical profile. In contrast, DNASE1L3-related disease showed inverse associations with several clinical features, including recurrent infections, suggesting a different pathogenic and clinical trajectory. CONCLUSION: This large international cohort highlights the clinical and genetic heterogeneity of monogenic lupus. C1Q and DNASE1L3 mutations account for most cases and display distinct phenotypic profiles. These findings underscore the need for genotype-guided diagnostic and therapeutic approaches in monogenic lupus.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | DNASE1L3 | “The most frequently implicated genes were C1Q (26%) and DNASE1L3 (25%), representing complement and type I interferon pathways, respectively.” | 0.98 | hgnc_dict_v1 |
| gene | SSB | “Genotype-phenotype analysis revealed that C1Q pathway defects were significantly associated with neurologic involvement, recurrent infections and anti-Sjögren's syndrome antibody A (SSA)/SSB positivity, defining a characteristic clinical profile.” | 0.98 | hgnc_dict_v1 |
| phenotype | systemic lupus erythematosus | “Genetic and phenotypic landscape of monogenic lupus: insights from an international cohort.” | 0.93 | phenotype_alias_lexicon_v2 |
| population | Saudi Arabia | “METHODS: We conducted a retrospective multicentre study of 100 children with genetically confirmed monogenic lupus diagnosed before the age of 14 years. Patients were enrolled between 2000 and 2025 from centres in Saudi Arabia, Iran, Russia, Italy, Palestine and Oman.” | 0.95 | saudi_context_rules_v1 |