Abstract: TH-PO713
Additional Genes Associated with Atypical Hemolytic Uremic Syndrome
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - I
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidney
- 1002 Genetic Diseases of the Kidney: Non-Cystic
Authors
- Kain, James, Machaon Diagnostics, Oakland, California, United States
- Venkataramani, Sujatha, Machaon Diagnostics, Oakland, California, United States
- Lim, Joo E., Machaon Diagnostics Inc., Oakland, California, United States
- Raghuraman, Gayatri, Machaon Diagnostics, Oakland, California, United States
- Lewis, Brad, Machaon Diagnostics, Inc, Oakland, California, United States
- Ero, Michael, Machaon Diagnostics, Oakland, California, United States
Background
Atypical hemolytic uremic syndrome (aHUS) is a life-threatening, ultra-rare thrombotic microangiopathy. This partially penetrant genetic disease, featuring a characteristic triad of hemolytic anemia, thrombocytopenia and renal failure, is caused by complement overactivation. 50 to 80% of aHUS patients have a detectable genetic mutation in one of several genes that may lead to overactivation of complement. All aHUS sequencing assays cover a core group of complement genes: CFH, CFI, CFB, C3, MCP/CD46. Additionally, sequencing of CFHR5, THBD, DGKE, as well as copy number to detect the homozygous deletion of CFHR1-CFHR3 or CFHR1-CFHR4 (but not single nucleotide variants within CFHR1, CFHR3 or CFHR4 alone), are often included. More rarely, PLG is sequenced; its inclusion is based on findings from a single publication (Bu (2014) J Am Soc Nephrol 25, 1) where they found several aHUS patients harboring known, rare pathogenic PLG variants.
Methods
Genomic DNA was extracted from patient whole blood and sequenced using an aHUS genetic panel. This panel comprised twelve genes (CFH, CFI, CFB, C3, MCP/CD46, CFHR1, CFHR3, CFHR4, CFHR5, THBD, DGKE and PLG) and was sequenced using targeted next generation sequencing. Variants were confirmed by Sanger sequencing as needed.
Results
Here we describe multiple instances where we detected suspicious variants within PLG and CFHR3 in patients where the aHUS Genetic Panel was ordered by their physician. Some of the suspicious variants we found in PLG (eight cases with p.Lys38Glu and one case with p.Arg253His) were the same variants seen previously by Bu et al; both variants are also associated with plasminogen deficiency. The suspicious CFHR3 variants we observed were severe (splice site, nonsense, frameshift) and either exceedingly rare or novel.
Conclusion
These results 1) replicate the finding by Bu et al of PLG having a role in aHUS, and 2) suggest a potential novel contribution from CFHR3. CFHR3 has previously only been implicated in aHUS as part of a large homozygous deletion that also removes the neighboring gene CFHR1. Furthermore, it is thought that in the case of this large homozygous deletion, it is the absence of CFHR1 that is causitive while CFHR3 is incidental. These results hint at the possibility that rare, dominant negative variants in CFHR3 may also lead to aHUS.