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

M J Geerlings1, E B Volokhina2,3, E K de Jong1

  • 1Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

Clinical Genetics
|June 12, 2018
PubMed

Insights

Genetic variants in complement genes CFH, C3, and CFI are linked to atypical hemolytic uremic syndrome (aHUS)/C3 glomerulopathy (C3G) and age-related macular degeneration (AMD). Distinct domain clustering of these variants was observed between the disease groups.

Area of Science:

  • Immunogenetics
  • Complement System Biology
  • Ophthalmology

Background:

  • Genetic variations in complement genes, including complement factor H (CFH), complement factor I (CFI), and complement C3 (C3), are implicated in diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and age-related macular degeneration (AMD).
  • Understanding the spectrum and distribution of low-frequency alleles within these genes is crucial for elucidating disease mechanisms.

Purpose of the Study:

  • To identify and characterize low-frequency genetic variants in CFH, CFI, and C3 in patients with aHUS/C3G and AMD.
  • To investigate genotype-phenotype correlations and domain-specific variant clustering between these distinct disease groups.

Main Methods:

  • Sequence analysis of CFH, CFI, and C3 genes was performed in a cohort of 866 patients with aHUS/C3G and 697 patients with AMD.
  • Identification and classification of low-frequency alleles and novel variants.
  • Comparative analysis of variant distribution and genotype-phenotype correlations across disease groups.

Main Results:

  • A total of 121 unique low-frequency variants (51 novel) were identified across the three genes.
  • CFH harbored the highest number of unique variants (53%), followed by C3 (26%) and CFI (21%).
  • Significant overlap (40%) in variants was observed between aHUS/C3G and AMD patient groups, with distinct variant clustering noted within specific functional domains (e.g., SCR20 in CFH for aHUS/C3G; MG3 in C3 for AMD).

Conclusions:

  • There is a substantial overlap of low-frequency genetic variants in complement genes between aHUS/C3G and AMD.
  • Distinct patterns of variant clustering within specific functional domains of CFH, CFI, and C3 correlate with these different disease phenotypes.
  • These findings highlight the complex role of the complement system in both renal and ocular diseases and suggest potential shared and distinct pathogenic mechanisms.

Keywords:
C3 glomerulopathyage-related macular degenerationalternative pathwayatypical hemolytic uremic syndromecomplement system

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