Identification of a Pathogenic Variant in TREX1 in Early-Onset Cerebral Systemic Lupus Erythematosus by Whole-Exome Sequencing

Objective. Systemic lupus erythematosus (SLE) is a chronic and heterogeneous autoimmune disease. Both twin and sibling studies indicate a strong genetic contribution to lupus, but in the majority of cases the pathogenic variant remains to be identified. The genetic contribution to disease is likely to be greatest in cases with early onset and severe phenotypes. Whole-exome sequencing now offers the possibility of identifying rare alleles responsible for disease in such cases. This study was undertaken to identify genetic causes of SLE using whole-exome sequencing. Methods. We performed whole-exome sequencing in a 4-year-old girl with early-onset SLE and conducted biochemical analysis of the putative defect. Results. Whole-exome sequencing in a 4-year-old girl with cerebral lupus identified a rare, homozygous mutation in the three prime repair exonuclease 1 gene (TREX1) that was predicted to be highly deleterious. The TREX1 R97H mutant protein had a 20-fold reduction in exonuclease activity and was associated with an elevated interferon-alpha (IFN alpha) signature in the patient. The discovery and characterization of a pathogenic TREX1 variant in our proband has therapeutic implications. The patient is now a candidate for neutralizing anti-IFN alpha therapy. Conclusion. Our study is the first to demonstrate that whole-exome sequencing can be used to identify rare or novel deleterious variants as genetic causes of SLE and, through a personalized approach, improve therapeutic options.