Decoding the Genetic Landscape of C3 Glomerulopathy: A Tale of the common CFHR3-CFHR1 deletion

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Presentation Time: 05:45 PM - 06:00 PM
Abstract ID: 4272 - B

Presenting Author:
Amanda Slagle , Graduate Research Assistant at Univ. of Iowa Carver Col. of Med.

Abstract:

Overactivation of the alternative pathway (AP) of complement is the main driver in the pathogenesis of C3 Glomerulopathy (C3G). Normally, the AP is tightly regulated by complement Factor H (FH), while the FH-related proteins (FHRs), specifically FHR1, are thought to have an essential role in its activation. Copy number variants (CNVs) in the CFH gene cluster, in particular the deletion of two contiguous genes, CFHR3-CFHR1, are commonplace in the normal population. Therefore, we hypothesized that the CFHR3-CFHR1 CNV may provide insight to the activation state of the AP in C3G. In this study, we compared the frequency of the CFHR3-CFHR1 deletion in the normal European (Non-Finnish) population (data extracted from gnomAD) to our C3G European cohort. CNVs were identified in C3G patients by multiplex ligation-dependent probe amplification. In the C3G cohort, we detected a CFHR3-CFHR1 deletion allele frequency of 15.3%, a CFHR3-CFHR1 duplication allele frequency of 0.7% and a normal allele frequency of 83.3%. In comparison, in gnomAD, the European (Non-Finnish) reported frequency of CFHR3-CFHR1 deletions is 18.4% and duplications is 0%. These differences are significant at p<0.05 and p<0.0001, respectively (Fisher’s exact test), and suggest that fewer copies of CFHR1 are protective against C3G, while enrichment for this gene is a risk factor for disease development. In all, these data implicate the CFHR3-CFHR1 deletion CNV as a protective factor against the development of C3G.