Genetic Sequencing in Saudi Patients with Systemic Lupus Erythematosus

To identify novel candidate gene variants and investigate their role in a cohort of Saudi patients with Systemic Lupus Erythematosus (SLE). In addition, evaluate their distribution relative to common risk loci identified in the NHGRI-EBI GWAS Catalog.

Whole Exome Sequencing (WES) was performed on the extracted genomic DNA for 29 patients with confirmed SLE. Descriptive analyses were used to summarize the patients' characteristics. Variant prioritization was initiated through a manual clinical interpretation according to ACMG guidelines, followed by a multi-step filtering pipeline to identify rare, high-impact candidates (gnomAD MAF < 1%, CADD > 20). The statistical analysis was conducted using R software R version 4.4.2 and several specialised packages.

The analysis revealed an exploratory "multi-hit" genetic landscape. Notable candidate variants were identified in genes related to DNA damage response (ATM, BRCA1) and membrane integrity (DYSF, USH2A). NPFFR2 emerged as a recurrently variant candidate gene (24% of the cohort). Phenotypic partitioning suggested that NPFFR2 variant may be associated with a distinct neuro-musculoskeletal profile; 85.7% of carriers exhibited musculoskeletal involvement. Conversely, carriers showed a marginal inverse trend with oral ulcers (P = 0.093), and NPFFR2 variant showed a potential trend toward mutual exclusivity with haematological involvement (P = 0.066), suggesting carriers may be less likely to present with either mucocutaneous or haematological manifestations. These findings suggest a hypothesis-generating neuro-immune model for SLE, where rare variants may influence disease expression toward specific organ systems.

This study highlights the presence of rare, candidate variants in a Saudi SLE cohort that are distinct from common GWAS-identified loci. These findings suggest that SLE clinical heterogeneity may be influenced by specific genetic endotypes. Our observations open the door for a preliminary roadmap for precision medicine and the identification of potentially treatment-refractory patients.