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Abstract: PO1320

The Complex Landscape of Factor H and Factor I Rare Variants in Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Fremeaux-Bacchi, Veronique, Assistance Publique-Hôpitaux de Paris, Paris, France
  • Meuleman, Marie-Sophie, INSERM U1138, Paris, France
  • Vieira-Martins, Paula, Assistance Publique-Hôpitaux de Paris, Paris, France
  • Chauvet, Sophie, Assistance Publique-Hôpitaux de Paris, Paris, France
  • Fakhouri, Fadi, Lausanne University Hospital, Lausanne, Switzerland
Background

Complement genetics has been extensively studied to dissect the pathophysiology of atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) paving the way for highly tailored therapy. However, the assessment of each identified variant’s contribution to disease pathogenesis remains a challenge in particular for rare variants detected in patients as well as in healthy individuals in the genome Aggregation Database (gnomAD). In this study we aimed to describe the rare variants in Factor H (CFH) and Factor I (CFI) genes identified in the French cohort of patients with aHUS and C3G.

Methods

We analyzed the distribution of the allele frequency (AF) of rare variants identified in 397 and 398 adult patients with a diagnosis of aHUS without coexisting disease and with C3G/Ig-mediated membranoproliferative glomerulonephritis (Ig-MPGN), respectively. We selected for this study variants with minor AF (MAF) below 0.1% in European healthy individuals.

Results

The frequency of patients with rare variants in CFH (108/398 vs 54/398) and CFI (33/397 vs 17/397) genes was higher in aHUS compared to C3G. A total of 148 variants were identified in CFH (n=98) and in CFI (n=50) genes. Among them, 9 were present in both diseases. We identified 43 (67%) and 20 (66%) novel variants in CFH in aHUS and C3G, respectively. Among them, 98% are pathogenic compared to 44% of the variants reported in gnomAD. The frequency of variants causing FH and FI deficiency is similar in both diseases (70% of the variants). The frequency of CFH variants identified in more than 1 patient is increased in aHUS compared to C3G (11/64 vs 2/30). We identified 12 (12/38; 31%) and 2 (2/12; 16%) novel variants in CFI in aHUS and C3G, respectively. Reported variants in CFI are more frequent in C3G than in aHUS (10/12 vs 26/38). The frequency of variants reported in gnomAD is higher in CFI (80%) compared to CFH (14% ).

Conclusion

Our study indicates that novel pathogenic rare variants in complement genes is more frequent in aHUS than in C3G. However, half of the variants reported in gnamAD have a potential impact on gene function. Our results suggest that CFH variants are more damaging than CFI variants, and may contribute more significantly to the pathogenesis of both diseases, as compared to CFI.