Deficiency of Complement 1r subcomponent in early-onset SLE: Role for disease-modifying alleles in a monogenic disease

Objective: To identify a genetic cause of early-onset systemic lupus erythematosus (SLE) in a large consanguineous family from Turkey and to study the mechanisms of disease. Methods: We performed whole exome sequencing (WES) and SNP array genotyping in affected and unaffected family members. Protein studies, gene expression, cytokine profiling, neutrophil extracellular trap formation, and presence of low-density granulocytes were evaluated in patient primary cells and serum samples. Results: We identified a novel homozygous loss-of-function mutation (p.Pro445Leufs*11) in the C1R gene. Sanger sequencing of 14 family members confirmed the homozygous mutation in four affected patients, and in an asymptomatic 9-year old female. Sera from patients with truncated C1r protein had low complement levels. Two affected siblings available for detailed evaluation exibited strong type I interferon inflammatory signatures despite being clinically inactive at the time of sampling. The type-I IFN transcriptional signature in patients' blood correlated with disease expressivity, whereas the neutrophil signature in patients' PBMCs was likely associated with disease severity. The affected female with the most severe phenotype, showed a stronger neutrophil signature, defined by enhanced neutrophil extracellular trap formation and the presence of low-density granulocytes. Analysis of exome data for modifying alleles suggested enrichment of common SLE-associated variants in the more severely affected patients. Lupus-associated HLA alleles or HLA haplotypes were not shared among the 4 affected subjects. Conclusion: We report a novel high-penetrance mutation in C1R as the cause of monogenic SLE. Disease expressivity in this family appears to be influenced by additional common and rare genetic variants. This article is protected by copyright. All rights reserved.