AUTHOR=Piras Rossella , Breno Matteo , Valoti Elisabetta , Alberti Marta , Iatropoulos Paraskevas , Mele Caterina , Bresin Elena , Donadelli Roberta , Cuccarolo Paola , Smith Richard J. H. , Benigni Ariela , Remuzzi Giuseppe , Noris Marina 

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

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.670727

DOI=10.3389/fgene.2021.670727

ISSN=1664-8021

ABSTRACT=<p>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 (<italic>C3</italic>) and Factor B (<italic>CFB</italic>), or in complement Factor H (<italic>CFH</italic>) and Factor I (<italic>CFI</italic>), two genes that encode complement regulators. Copy number variations (CNVs) involving the <italic>CFH</italic>-related genes (<italic>CFHRs</italic>) 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 <italic>CFH-CFHR</italic> region and characterize CNVs in a large cohort of patients with C3G (<italic>n</italic> = 103) and IC-MPGN (<italic>n</italic> = 96) compared to healthy controls (<italic>n</italic> = 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 <italic>CFH</italic> in one patient with IC-MPGN; 2) an increased number of <italic>CFHR4</italic> copies in one IC-MPGN and three C3G patients; 3) a deletion from <italic>CFHR3</italic>-intron 3 to <italic>CFHR3-3</italic>′<italic>UTR</italic> (<italic>CFHR3<sub>4</sub><sub>–</sub><sub>6</sub></italic>Δ) that results in a FHR3-FHR1 hybrid protein in a C3G patient; and 4) a <italic>CFHR3<sub>1</sub><sub>–</sub><sub>5</sub>-CFHR4<sub>10</sub></italic> hybrid gene in a C3G patient. This work highlights the contribution of <italic>CFH-CFHR</italic> CNVs to the pathogenesis of both C3G and IC-MPGN.</p>