Oral Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

Whole exome sequencing in early-onset cerebral SLE identifies a pathogenic variant in TREX1. (#108)

Julia I Ellyard 1 , Rebekka Jerjen 1 , Jaime L Martin 1 , Adrian Lee 1 , Matthew A Field 2 , Simon H Jiang 1 3 , Jean Capello 1 , Svenja K Neumann 1 , Daniel Andrews 4 , Hamish S Scott 5 , Marco G Casarotto 6 , Christopher C Goodnow 4 , Jeffrey Chaitow 7 , Virginia Pascual 8 , Paul Hertzog 9 , Stephen I Alexander 10 , Matthew C Cook 4 11 , Carola G Vinuesa 1
  1. Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University, ACTON, ACT, Australia
  2. Department of Immunology, John Curtin School of Medical Research, Australian National University, ACTON, ACT, Australia
  3. Department of Renal Medicine, The Canberra Hospital, Canberra, ACT, Australia
  4. Department of Immunology, John Curtin School of Medical Research, Australian National University, ACTON, ACT, Australia
  5. Division of Molecular Pathology, , Institute of Medical and Veterinary Science, University of Adelaide, Adelaide, SA, Australia
  6. Department of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, ACTON, ACT, Australia
  7. Department of Rheumatology, Sydney Children's Hospitals Network, Sydney, NSW, Australia
  8. Baylor Institute for Immunology Research, Dallas, Texas, USA
  9. Monash Institute of Medical Research (MIMR), Clayton, VIC, Australia
  10. Centre for Kidney Research, Children's Hospital at Westmead, Westmead, NSW, Australia
  11. Department of Immunology, The Canberra Hospital, Canberra, ACT, Australia
Systemic lupus erythematosus (SLE) is a chronic and heterogeneous autoimmune disease. Twin studies indicate a strong genetic contribution to lupus, but in the majority of cases the pathogenic variant remains unknown. The genetic contribution to disease is likely to be greatest in cases with early-onset and severe phenotypes. Whole exome sequencing (WES) now offers the possibility of identifying rare alleles responsible for disease in such cases. We performed WES in a 4-year-old female with early-onset cerebral SLE and conducted biochemical analysis of the putative defect. WES identified a rare, homozygous mutation in the Three Prime Repair Exonuclease 1 (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 IFN-a signature in the patient. The discovery and characterization of a pathogenic TREX1 in our proband has therapeutic implications: the patient is now a candidate for neutralizing anti-IFN-a therapy. Our study is the first to demonstrate that WES can be used to identify rare or novel deleterious variants as genetic causes of SLE and, through a personalized approach, improve therapeutic options.