LAUSR

Background C3 glomerulopathy often presents with a membranoproliferative glomerulonephritis (MPGN) pattern, and is principally caused by unrestricted activation of the complement alternative pathway. Genetic abnormalities of the complement system critically implicate in the pathogenesis of C3 glomerulopathy, but a systemic profile remains open, especially in Asia. Methods In this study, we completed a comprehensive screen of 11 candidate alternative pathway genes by using targeted genomic enrichment and massively parallel sequencing on 43 patients with sporadic C3 glomerulopathy, which were classified as dense deposit disease (DDD; n = 10) and C3 glomerulonephritis (C3GN; n = 33) cases. An additional 24 patients with immune complex-mediated MPGN were also enrolled. Results In total, 4 novel and 16 rare variants were identified: one was classified as likely pathogenic, and the remaining 19 were of uncertain significance. Three variants reportedly led to functional deficiency with supporting evidences. Variants in the CFH, CFI, CD46 and C3 genes were most frequently detected. A defective control of the complement alternative pathway due to hereditary abnormalities was found at frequencies of 50%, 27% and 17% in DDD, C3GN and immune complex-mediated MPGN, respectively. Irrespective of histological type, the patients with likely pathogenic and uncertain significant variants were clinically similar to those without. Conclusions Accurate genetic screening can give rise to progress in understanding the pathogenesis of C3 glomerulopathy, and the correct assignment of pathogenicity classification is of great importance for better patient care and prognostic or therapeutic advice.