Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype

Abstract

Several abnormalities in complement genes reportedly contribute to atypical hemolytic uremic syndrome (aHUS), but incomplete penetrance suggests that additional factors are necessary for the disease to manifest. Here, we sought to describe genotype-phenotype correlations among patients with combined mutations, defined as mutations in more than one complement gene. We screened 795 patients with aHUS and identified single mutations in 41% and combined mutations in 3%. Only 8%-10% of patients with mutations in CFH, C3, or CFB had combined mutations, whereas approximately 25% of patients with mutations in MCP or CFI had combined mutations. The concomitant presence of CFH and MCP risk haplotypes significantly increased disease penetrance in combined mutated carriers, with 73% penetrance among carriers with two risk haplotypes compared with 36% penetrance among carriers with zero or one risk haplotype. Among patients with CFH or CFI mutations, the presence of mutations in other genes did not modify prognosis; in contrast, 50% of patients with combined MCP mutation developed end stage renal failure within 3 years from onset compared with 19% of patients with an isolated MCP mutation. Patients with combined mutations achieved remission with plasma treatment similar to patients with single mutations. Kidney transplant outcomes were worse, however, for patients with combined MCP mutation compared with an isolated MCP mutation. In summary, these data suggest that genotyping for the risk haplotypes in CFH and MCP may help predict the risk of developing aHUS in unaffected carriers of mutations. Furthermore, screening patients with aHUS for all known disease-associated genes may inform decisions about kidney transplantation.

Figure 1.

Localization of the mutations in CFH, MCP, CFI, C3, and CFB that were found in 27 patients with combined gene mutations and patients with single mutations from the four cohorts. Gene variations found in patients as the sole mutation are in gray, changes found only combined with other mutations are in yellow, and changes found both as single or combined mutations are in light blue.

Figure 2.

Impact of the number of risk haplotypes in CFH (CFH-H3 targeted by rs3753394, c.1-332C>T and rs1065489, c.2808G>T p.E936D) and MCP (MCPggaac targeted by rs7144, c.*897T>C) on aHUS penetrance in single- (carrying mutations in one complement gene), double- (carrying mutations in two different genes), or triple-mutated subjects (carrying mutations in three different genes). Penetrance in each subgroup was calculated by the ratio between the number of carriers affected and the total number of carriers. We considered only pedigrees for which at least one relative other than the proband was genotyped for the mutations and haplotypes (marked with an asterisk in Supplemental Figure 1). In the table below the graph, we reported the number of affected subjects (bold)/the number of carriers for each group. The chi-squared or Fisher exact test was used for statistical analysis as appropriate.