Genotype‐phenotype correlations of low‐frequency variants in the complement system in renal disease and age‐related macular degeneration

Abstract

Genetic alterations in the complement system have been linked to a variety of diseases, including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and age‐related macular degeneration (AMD). We performed sequence analysis of the complement genes complement factor H (CFH), complement factor I (CFI), and complement C3 (C3) in 866 aHUS/C3G and 697 AMD patients. In total, we identified 505 low‐frequency alleles, representing 121 unique variants, of which 51 are novel. CFH contained the largest number of unique low‐frequency variants (n = 64; 53%), followed by C3 (n = 32; 26%) and CFI (n = 25; 21%). A substantial number of variants were found in both patients groups (n = 48; 40%), while 41 (34%) variants were found only in aHUS/C3G and 32 (26%) variants were AMD specific. Genotype‐phenotype correlations between the disease groups identified a higher frequency of protein altering alleles in short consensus repeat 20 (SCR20) of factor H (FH), and in the serine protease domain of factor I (FI) in aHUS/C3G patients. In AMD, a higher frequency of protein‐altering alleles was observed in SCR3, SCR5, and SCR7 of FH, the SRCR domain of FI, and in the MG3 domain of C3. In conclusion, we observed a substantial overlap of variants between aHUS/C3G and AMD; however, there is a distinct clustering of variants within specific domains.

Effect of rare coding variants in the CFI gene on Factor I expression levels

“…In light of the natural variation in plasma FI levels in vivo , and since plasma samples were not available for carriers of all rare variants reported in literature ( 14 , 16 ), 126 rare coding variants were selected for recombinant expression analysis in vitro . Expression levels of mutant and wild-type (WT) recombinant FI proteins were determined with ELISA in supernatants and lysates of transfected HEK293T cells ( Fig.…”

“…In C3G the association with CFI is less striking, but pathogenic variants are found at a low frequency ( 13 ). Interestingly, 26% of rare variants reported in CFI have been detected in both AMD and aHUS (( 14 , 15 ) and https://www.complement-db.org/home.php , 09.01.2020), including the p.Gly119Arg (rs141853578) variant, which confers a high risk for AMD ( 16 , 17 ).…”

“…FI consists of five domains, FI membrane attack complex (FIMAC) domain, CD5 domain, two low-density lipoprotein receptor type A (LDLRA) domains and a serine proteinase (SP) domain, containing the catalytic site of FI. A recent study noted clustering of CFI variants in the SP domain of FI in aHUS and in the CD5 domain in AMD, but a substantial proportion of variants identified in both AMD and aHUS patients are spread across the whole protein ( 14 ).…”

“…The listed variants were found in AMD (green), aHUS/C3G (yellow) or both in AMD and aHUS/C3G (red). Variant selection was based on ( 14 , 16 ). Details of the shown variants are summarized in Supplementary Material, Table S1 .…”

IgA Nephropathy with Thrombotic microangiopathy: Is this secondary thrombotic microangiopathy or IgA nephropathy-triggered atypical Hemolytic Uremic Syndrome?IgA Nephropathy with Thrombotic microangiopathy: Is this secondary thrombotic microangiopathy or IgA nephropathy-triggered atypical Hemolytic Uremic Syndrome?

“…Patients with CFH mutations have the worst outcome of all the patients with C-TMA, usually progressing to end-stage renal disease (ESRD) or death within one year of presentation 14 . The C3 variant is usually benign but can have a cumulative effect on the patient's phenotype when co-inherited with pathologic mutations 15 .…”