CFH-CFHR1 hybrid genes in two cases of atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated disease that manifests as the triad of thrombotic microangiopathy. We identified two aHUS patients with neither anti-complement factor H (CFH) antibodies nor causative variants of seven aHUS-related genes (CFH, CFI, CFB, C3, MCP, THBD, and DGKE); however, their plasma showed increased levels of hemolysis by hemolytic assay, which strongly suggests CFH-related abnormalities. Using a copy number variation (CNV) analysis of the CFH/CFHR gene cluster, we identified CFH-CFHR1 hybrid genes in these patients. We verified the absence of aHUS-related abnormal CNVs of the CFH gene in control genomes of 2036 individuals in the general population, which suggests that pathogenicity is related to these hybrid genes. Our study emphasizes that, for patients suspected of having aHUS, it is important to perform an integrated analysis based on a clinical examination, functional analysis, and detailed genetic investigation.

Automated summary

We identified two aHUS patients with no CFH antibodies or causative variants of aHUS-related genes, but their plasma showed increased hemolysis levels, suggesting CFH-related abnormalities. CNV analysis revealed CFH-CFHR1 hybrid genes in these patients. Our study highlights the importance of integrated analysis based on clinical examination, functional analysis, and detailed genetic investigation for suspected aHUS patients.