Expanding the spectrum of genetic causes of DNA-specific exonuclease TREX1 variants in thrombotic microangiopathy.

Introduction: Thrombotic microangiopathy (TMA) is a complex condition involving endothelial damage and microvascular thrombi. The International Society of Nephrology's aHUS International Forum identified genetic variants as crucial for tailored therapies like plasma exchange and anti-complement therapy. Recent studies suggested that new pathogenic genes beyond complement and coagulation pathways contribute to TMA including TREX1 variants. The protein TREX1, a DNA-specific exonuclease, maintains genome integrity and regulates immune responses by degrading damaged cytosolic DNA. Variants disrupting TREX1's endoplasmic reticulum anchoring can lead to vasculopathy.

Methods: We conducted retrospective in silico studies involving 53 patients with TMA, 94 with IgA nephropathy with microangiopathic lesions, 25 with C3G glomerulopathy and 20 with ANCA-associated vasculitis.

Results: Pathogenic variants of TREX1 were found in 5.7% of patients with TMA and 3.2% of patients with IgA nephropathy with microangiopathic lesions, but none in C3 glomerulopathy or ANCA-associated vasculitis.

Conclusions: Our study highlights the importance of TREX1 variants in microvascular diseases, particularly in thrombotic microangiopathy and IgA nephropathy. TREX1's critical role in genome integrity and immune regulation may offer new therapeutic avenues for treatment.