Background There are reports showing Three Prime Repair Exonuclease 1 (TREX1) mutations in atypical Systemic Lupus Erythematosus (SLE) patients.
Objectives Here we report a family with SLE and Antiphospholipid Syndrome (aPL) who are positive for TREX1 mutation and complicated with AA amyloidosis
Methods DNA samples were extracted from peripheral blood samples of two affected (mother and daughter) and two unaffected individuals of the same family. Exome sequencing was performed for the daughter and data was processed according to GATK Best Practices recommendations. Exome variants were used to search for a rare candidate variant causing the disease. Identified variant was screened in four family members using Sanger sequencing.
Results The index case (mother) was a 63 year-old woman who had developed polyarthritis and recurrent cerebrovascular accident (CVA) at the age of 44. She was positive for ANA, anti-ds-DNA and IgG anti-cardiolipin antibodies. On anticoagulant therapy she still experiences frequent CVAs. The daughter who is 43 years old had experienced depression, non-erosive arthritis and alopecia at the age of 13. She was positive for ANA, dsDNA and ACA and was treated with hydroxychloroquine, prednisolone, and rituximab. She had attacks of deep vein thrombosis despite anticoagulant therapy. A renal biopsy was performed because of an increase in her creatinine level, with no proteinuria and normal urinary sediment, which revealed AA amyloidosis. She was heterozygous for p.R202Q variant in MEFV gene. Further genetic testing was performed for the mother and the daughter as well as two other non-affected members of the family.
Candidate variant search in exome data resulted a novel c.2T>A (p.M1?) variant in TREX1 gene. The variant was in heterozygous state for both affected members. Since the variant disrupts translation initiation codon (ATG/AAG), it is predicted to cause loss of complete protein production.
Conclusions There is evidence that TREX1 is involved in the pathogenesis of SLE, especially with neuropsychiatric disease. Here we report a familial SLE and aPL syndrome complicated with AA amyloidosis, with a novel TREX1 variant. Such cases will increase our ability to understand the genetic spectrum of SLE and may allow the development of more effective therapies.
Disclosure of Interest None declared