Genetic sequencing in Saudi patients with systemic lupus erythematosus

Objective: To perform Whole Exome Sequencing on a cohort of Saudi SLE patients to Identify rare pathogenic variants and investigated their distribution against 550 common variant loci from the NHGRI-EBI GWAS Catalogue. Methods: Whole Exome Sequencing was performed on the extracted genomic DNA for 29 patients with confirmed systemic lupus erythematosus. Descriptive analyses were used to summarize the patients’ characteristics. The genomic analysis was conducted using R software R version 4.4.2 and several specialised packages. Results: Our analysis revealed a "multi-hit" genetic landscape, with significant co-occurrence clusters involving the DNA damage response (ATM, BRCA1, RECQL4), membrane integrity (DYSF, USH2A), and signal transduction (GRK2, GRK4). Notably, NPFFR2 emerged as a major recurrently mutated gene, identified in 24% of the cohort. Phenotypic partitioning analysis demonstrated that NPFFR2 variants define a distinct neuro-musculoskeletal endotype, where 85.7% (6/7) of mutated patients exhibited musculoskeletal involvement alongside a marginal trend toward oral ulcers (P=0.093). Conversely, NPFFR2 mutation showed a strong trend toward mutual exclusivity with haematological involvement (P=0.066), suggesting a disease trajectory that bypasses traditional systemic complications. Furthermore, complex mutational profiles involving NPFFR2 and the spindle assembly checkpoint kinase BUB1 were associated with clinical drug resistance. These findings establish a novel neuro-immune hypothesis for SLE, where rare variants in the NPFFR2–HPA axis pathway act as phenotypic determinants, guiding disease expression toward specific organ systems. Conclusion: This study shifts the paradigm of SLE from a monolithic autoimmune condition to a collection of genetically defined endotypes, providing a roadmap for precision medicine and the early identification of treatment-refractory patients.