CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis

C3 Glomerulopathy (C3G) and Immune Complex-Mediated Membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases characterized by glomerular deposition of C3 caused by dysregulation of the alternative pathway (AP) of complement. In approximately 20% of affected patients, dysregulation is driven by pathogenic variants in the two components of the AP C3 convertase, complement C3 (<i>C3</i>) and Factor B (<i>CFB</i>), or in complement Factor H (<i>CFH</i>) and Factor I (<i>CFI</i>), two genes that encode complement regulators. Copy number variations (CNVs) involving the <i>CFH</i>-related genes (<i>CFHRs</i>) that give rise to hybrid FHR proteins also have been described in a few C3G patients but not in IC-MPGN patients. In this study, we used multiplex ligation-dependent probe amplification (MLPA) to study the genomic architecture of the <i>CFH-CFHR</i> region and characterize CNVs in a large cohort of patients with C3G (<i>n</i> = 103) and IC-MPGN (<i>n</i> = 96) compared to healthy controls (<i>n</i> = 100). We identified new/rare CNVs resulting in structural variants (SVs) in 5 C3G and 2 IC-MPGN patients. Using long-read single molecule real-time sequencing (SMRT), we detected the breakpoints of three SVs. The identified SVs included: 1) a deletion of the entire <i>CFH</i> in one patient with IC-MPGN; 2) an increased number of <i>CFHR4</i> copies in one IC-MPGN and three C3G patients; 3) a deletion from <i>CFHR3</i>-intron 3 to <i>CFHR3-3</i>'<i>UTR</i> (<i>CFHR3₄ _- ₆</i> Δ) that results in a FHR3-FHR1 hybrid protein in a C3G patient; and 4) a <i>CFHR3₁ _- ₅-CFHR4₁₀</i> hybrid gene in a C3G patient. This work highlights the contribution of <i>CFH-CFHR</i> CNVs to the pathogenesis of both C3G and IC-MPGN.