Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

Abstract

Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and overactivation of the complement alternative pathway. Typically, gene analysis for aHUS and C3G is undertaken in small patient numbers, yet it is unclear which genes most frequently predispose to aHUS or C3G. Accordingly, we performed a six-center analysis of 610 rare genetic variants in 13 mostly complement genes (, ,, ,, ,, ,, ,, , and) from >3500 patients with aHUS and C3G. We report 371 novel rare variants (RVs) for aHUS and 82 for C3G. Our new interactive Database of Complement Gene Variants was used to extract allele frequency data for these 13 genes using the Exome Aggregation Consortium server as the reference genome. For aHUS, significantly more protein-altering rare variation was found in five genes ,, ,, and than in the Exome Aggregation Consortium (allele frequency< 0.01%), thus correlating these with aHUS. For C3G, an association was only found for RVs in and the N-terminal C3b-binding or C-terminal nonsurface-associated regions of In conclusion, the RV analyses showed nonrandom distributions over the affected proteins, and different distributions were observed between aHUS and C3G that clarify their phenotypes.

Genetic Analysis of 400 Patients Refines Understanding and Implicates a New Gene in Atypical Hemolytic Uremic Syndrome

“…These results are consistent with the recently reported collaborative study looking at 3128 patients with aHUS from six centers. 18 In that study, CFB, THBD, CFHR5, and PLG showed insignificant burden for ultrarare variants compared with Exome Aggregation Consortium controls, suggesting that if these genes make any contribution to aHUS, it is small. In the absence of segregation and functional data, pathogenic mutations in CFB, THBD, CFHR5, and PLG should be reported with caution.…”

“…In a study by Osborne et al, 39% of patients with aHUS harbored variants with an MAF,1.0%. 18 Applying this MAF to our cohort increases the rare variant carrier rate to 36% (144 patients), suggesting that lowering the MAF had a major impact. We recommend reviewing archived data and applying an MAF of 0.1% to refine the genetic diagnosis of aHUS.…”

“…Rare variants in CFH, C3, CD46, CFI, and CFB were identified in 105 patients (26.3%), which is lower than the anticipated rate based on other reports. 6,7,18 This difference reflects the inclusion of "secondary" aHUS, the implementation of relatedness analysis, and the use of a lower MAF (,0.1%). In a study by Osborne et al, 39% of patients with aHUS harbored variants with an MAF,1.0%.…”

“…A recent collaborative, multi-institution study failed to find enrichment for rare genetic variants in the CFB, THBD, and PLG genes in patients with aHUS compared with controls from the Exome Aggregation Consortium database. 18 That study, however, did not control for population stratification, which affects rare variant burden (Supplemental Figure 1). In addition, only a few genes were considered.…”

A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease

“…Second, the actual pathogenetic and functional meaning of many mutations is still not defined. Finally, most genetic variants have a low penetrance, and combined variants may coexist, which also involves other genes, such as thrombomodulin (THBD) and diacylglycerol kinase-epsilon (DGKE) [55]. Thus, it is necessary to cautiously analyze the detected gene alterations to determine if they are specifically disease associated.…”