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

• Published in: Clinical genetics Vol. 94; no. 3-4; pp. 330 - 338
• Main Authors: Geerlings, M.J., Volokhina, E.B., de Jong, E.K., van de Kar, N., Pauper, M., Hoyng, C.B., van den Heuvel, L.P., den Hollander, A.I.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-10-2018
• Subjects: age‐related macular degeneration; Alleles; alternative pathway; atypical hemolytic uremic syndrome; Atypical Hemolytic Uremic Syndrome - genetics; Atypical Hemolytic Uremic Syndrome - metabolism; Atypical Hemolytic Uremic Syndrome - physiopathology; C3 glomerulopathy; Cohort Studies; Complement C3 - genetics; Complement C3 - metabolism; Complement component C3; Complement factor H; Complement Factor H - genetics; Complement Factor H - metabolism; Complement factor I; Complement Factor I - genetics; Complement Factor I - metabolism; Complement system; Gene frequency; Genetic Predisposition to Disease; Genotype; Genotypes; Glomerulonephritis, Membranous - genetics; Glomerulonephritis, Membranous - metabolism; Glomerulonephritis, Membranous - physiopathology; Hemolytic uremic syndrome; Humans; Macular degeneration; Macular Degeneration - genetics; Macular Degeneration - metabolism; Macular Degeneration - physiopathology; Original; Phenotype; Phenotypes; Serine; Serine proteinase; atypical hemolytic uremic syndrome; alternative pathway; age-related macular degeneration; C3 glomerulopathy; complement system
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.13392

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.