Abstract: PO1644
Extremely Rare Variants in Four Complement Genes Contribute to Genetic Susceptibility to Atypical Hemolytic and Uremic Syndrome
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Marchal, Armance, Assistance Publique - Hopitaux de Paris, Paris, Île-de-France, France
- Zuber, Julien, Assistance Publique - Hopitaux de Paris, Paris, Île-de-France, France
- Limou, Sophie, Centre Hospitalier Universitaire de Nantes, Nantes, Pays de la Loire, France
- Vieira-Martins, Paula, Assistance Publique - Hopitaux de Paris, Paris, Île-de-France, France
- Le Clech, Alice, Centre Hospitalier Universitaire de Nantes, Nantes, Pays de la Loire, France
- Leman, Claire, Centre Hospitalier Universitaire de Nantes, Nantes, Pays de la Loire, France
- Rondeau, Eric, Assistance Publique - Hopitaux de Paris, Paris, Île-de-France, France
- Fakhouri, Fadi, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Fremeaux-Bacchi, Veronique, Assistance Publique - Hopitaux de Paris, Paris, Île-de-France, France
Background
The study of complement genetics has dramatically changed the landscape of atypical hemolytic uremic syndrome (aHUS) and has paved the way for highly tailored therapy. However, the assessment of the contribution of each identified variant to aHUS pathogenesis still remains a challenge. In this study we aimed to analyze the enrichment of rare variants in 6 aHUS-associated genes, including C3, CFH, CFI, CD46/MCP, CFB and THBD, in comparison with a reference population.
Methods
We analyzed the distribution of rare variants in 433 adult patients with a clinical diagnosis of aHUS, without coexisting disease. As a control group, we used European individuals from the 1000 Genomes project (N=503), focusing on the 6 genes of interest. We analyzed the enrichment of genetic variants in the aHUS cohort compared to the reference population.
Results
A total of 168 variants in complement genes, with a minor allele frequency (MAF) <1%, involving 247 alleles, were identified in 224 patients (51.7%). 115 of the identified variants were not reported in the population database gnomAD, including 75 variants detected in CFH gene (65%). Variants with a MAF of <0.01% in the C3 and MCP genes and variants with a MAF <0.1% in the CFH and CFI genes were enriched in the aHUS population as compared to controls. In contrast, rare variants in CFB and THBD genes were not significantly enriched in the aHUS population. We identified 18 variants overrepresented in patients, including the CFH/CFHR1 hybrid genes. Among these variants resulting with functional deficiency in the encoded protein the C3 variant p.Lys155Gln associated with risk of advanced age-related macular degeneration was not significantly increased in the aHUS population. Finally, multiple rare variants in a single individual were more frequently present in aHUS patients compared to controls.
Conclusion
We showed the enrichment of extremely rare variants limited to CFH, CFI, CD46/MCP and C3, genes. The study confirms that a variant with a MAF>0.1% should not be considered at risk for developing aHUS. Our study indicates that targeting the MAF provide reasonable diagnostic tools as a guide to variant classification.