TREX1 Mutation Causing Autosomal Dominant Thrombotic Microangiopathy and CKD-A Novel Presentation.

ABSTRACT

Renal thrombotic microangiopathy (TMA) involves diverse causes and clinical presentations. Genetic determinants causing alternate pathway complement dysregulation underlie a substantial proportion of cases. In a significant proportion of TMAs, no defect in complement regulation is identified. Mutations in the major mammalian 3' DNA repair exonuclease 1 (TREX1) have been associated with autoimmune and cerebroretinal vasculopathy syndromes. Carboxy-terminal TREX1 mutations that result in only altered localization of the exonuclease protein with preserved catalytic function cause microangiopathy of the brain and retina, termed retinal vasculopathy and cerebral leukodystrophy (RVCL). Kidney involvement reported with RVCL usually accompanies significant brain and retinal microangiopathy. We present a pedigree with autosomal dominant renal TMA and chronic kidney disease found to have a carboxy-terminal frameshift TREX1 variant. Although symptomatic brain and retinal microangiopathy is known to associate with carboxy-terminal TREX1 mutations, this report describes a carboxy-terminal TREX1 frameshift variant causing predominant renal TMA. These findings underscore the clinical importance of recognizing TREX1 mutations as a cause of renal TMA. This case demonstrates the value of whole-exome sequencing in unsolved TMA.