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Genetic Abnormalities in Complement Regulating Proteins in C3 Glomerulopathy
Abstract   Open access   Peer reviewed

Genetic Abnormalities in Complement Regulating Proteins in C3 Glomerulopathy

Aishwarya Ravindran, Richard J H Smith, Fernando Fervenza, Fengxiao Bu, Nicolo Borsa, Yuzhou Zhang, Michael Jones, Amanda Bierer, Nicole Meyer, Kathy Frees, …
American journal of clinical pathology, Vol.150(suppl_1), pp.S131-S131
09/21/2018
DOI: 10.1093/ajcp/aqy102.313
url
https://doi.org/10.1093/ajcp/aqy102.313View
Published (Version of record) Open Access

Abstract

Abstract Objectives C3 glomerulopathy (C3G) is a rare disease entity characterized by accumulation of complement factors in the glomeruli due to overactivation of the alternative pathway of complement due to acquired or genetic abnormalities of the complement regulatory proteins. C3G includes C3 glomerulonephritis and dense deposit disease. In this study, we analyzed genetic variants of complement genes in C3G patients. Methods We identified 114 patients evaluated at our institution from 2007 to 2016 with a diagnosis of C3 glomerulopathy. Patients (n = 70) that were evaluated for complement abnormalities were included. Genetic testing was based on next-generation sequencing using a HiSeq 2500 or a MiSeq Sequencer. The analysis was performed on dedicated computing resources maintained by the Iowa Institute of Human Genetics. Results Twenty-six (37.1%, n = 70) patients were positive for rare or novel genetic variants in complement genes, of which 6 were pathogenic variants (5 CFH, 1 CFHR2), 3 likely pathogenic variants (2 C3, 1 CFH), and the remaining 17 had variants of unknown significance involving complement genes, including CFH (5), C8G (1), CFI (2), C8A (1), C3 (4), C9 (1), CFHR2 (1), CFHR5 (3), C5 (2), and C8B (2). Forty-seven (97.9%, n = 48) carried known C3G-associated genetic polymorphisms in the CFH and/or C3 genes. C3 nephritic factor (C3Nef) was present in 30 patients (43.5%, n = 69), and 9 (13.4%, n = 67) had other autoantibodies (C4Nef, C5Nef, factor B autoantibodies, factor H autoantibodies). Of 26 patients with genetic variants, 23 patients had a genetic variant(s) in a single gene, 2 patients had genetic variant(s) in two genes, and 1 patient had genetic variant(s) in three genes. Conclusion Our results confirmed the presence of genetic variants in complement regulatory proteins in a significant proportion of patients. CFH genetic variants were the most common genetic variants detected. C3G-associated risk polymorphisms were present in almost all the patients.

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