#956 Exome sequencing in adults with secondary thrombotic microangiopathy with kidney involvement

Abstract Background and Aims Currently, genetic testing is recommended in patients with thrombotic microangiopathy (TMA) and renal involvement when a complement-dependent TMA is clinically suspected. Due to a possibly poor phenotype-genotype correlation, this strategy may be suboptimal. We aimed to assess the impact of a strategy using Exome Sequencing (ES) regardless of initial suspicion. Method We conducted a prospective observational study. Data was collected in all consecutive adult patients who received a primary diagnostic ES test as part of routine care for unexplained chronic kidney disease between October 10, 2017, and December 31, 2022, at the Nephrology Department of Assistance Publique-Hôpitaux de Paris/Sorbonne University, Paris, France (Tenon and Pitié-Salpêtrière hospitals). Patients with thrombotic thrombocytopenic purpura or typical hemolytic and uremic syndrome were not included. The association between patients’ phenotypes and genotypes was explored using a validated method relying on Term Frequency-Inverse Document Frequency (TF-IDF). Results 1 413 patients underwent ES, of whom 153 (11%) had biological and/or histological indicators of TMA. ES identified a variant consistent with the renal phenotype in 20/153 (13%) cases. In 13/20 cases (65%), a genetic disorder which was not complement TMA was diagnosed: five patients had nephronophthisis (TTC21B, n = 4, NPHP3, n = 1); two had Alport's disease (COL4A4 and COL4A3, n = 1); one had Cobalamin-C deficiency (MMACHC); five had other distinct conditions (variants in SOX18, IFT140, WT1, TREX1 and UMOD). Direct clinical implications of performing ES were observed in 35/153 (23%) cases. An interactive web-app was developed to enable in-depth exploration of phenotype-genotype association, and no association between patients’ phenotypes and genotypes were observed. Conclusion First-tier ES in patients with TMA and renal involvement, irrespective of clinical suspicion, revealed diagnoses that would not have been initially obtained according to the currently recommended strategy. In patients with TMA and renal involvement, we did not find an association between patients’ phenotypes and genotypes.