Background and aims Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Twin studies indicate a strong genetic contribution to lupus, yet often the pathogenic variant remains unknown. A better understanding of the individual genetic causes of SLE will enable personalised therapies. Using next generation sequencing technologies (WES/WGS) it is now possible to identify rare/novel gene variants that cause disease.

Methods We have used WES/WGS to identify rare genetic variants with strong effects that contribute to SLE and complex autoimmunity. The effect of variants on protein function were evaluated using in vitro biochemical and over-expression assays. Immunophenotyping of patient PBMCs and the use of bespoke mouse models engineered by CRISPR/Cas9 to harbour patient-specific variants were used to dissect disease mechanisms.

Results We identified a genetic variant in TREX1 as a cause of cerebral SLE, providing proof of principle that rare genetic variants do contribute to complex autoimmunity. The patient was revealed to be a prime candidate for tailored therapies targeting type-I interferons. Using our validated bioinformatics pipeline and methodology, we have now identified two other cohorts of patients with genetic variants that impair thymic tolerance and T1-IFN signalling, respectively. Biochemical assays confirmed the variants impair protein function. Furthermore, flow cytometry identified immunophenotypes in the patients’ PBMCs that may explain disease pathogenesis. The mechanisms by which they drive SLE pathogenesis are being evaluated in patient-specific mice mouse models.

Conclusions By understanding the precise genetic mechanisms that contribute to SLE pathogenesis, our data is able to stratify patients and, through a personalised approach, identify tailored therapeutic options.