Abstract
Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) have been linked to mutations in many of the proteins that are involved in alternative complement pathway activation. Age and etiology confounded, the prevalence of such mutations has been reported to be over 30 to 50% in these diseases. However, the cohorts studied included many children or individuals with a familial history of complement-related disorders and genetic tests were usually limited to exome sequencing of known causative or risk-associated genes. In this study, a retrospective adult cohort of 35 patients with biopsy-proven thrombotic microangiopathy (the largest in Canada) and 10 patients with C3 glomerulopathy was tested through an extended exome panel to identify causative defects in associated or candidate genes including those of the alternative and terminal complement pathways. A variant of unknown significance was also analyzed for pathogenicity through in vitro studies. To our surprise, the prevalence of known causative or risk-associated variants in either of these cohorts was found to be less than ~ 15% overall. However, the panel used and analyses carried out allowed to identify novel variants of potential clinical significance and a number of candidate genes. The prevalence of known genetic defects in adult-onset aHUS and C3G is thus probably much lower than 30 to 50%. Our results also point towards the importance of investigating diseases of the alternative complement pathway through extended exome panels and in vitro analyses.Key messagesThe alternative complement pathway plays a major role in the pathogenesis of hemolytic uremic syndrome and C3 glomerulopathy.Based on previous studies, both disorders have been commonly linked to variants in the various intermediates that sustain or regulate this pathway.The prevalence of such mutations in the adult-onset and sporadic forms of these diseases is probably much lower than expected based on larger series.The sporadic forms of complementopathies are likely to involve additional genes that are yet to be uncovered.
Highlights
The alternative complement pathway plays a major role in the pathogenesis of atypical hemolytic uremic syndrome [1, 2], and it appears to do so whether the disorder is idiopathic or due to acquired conditions [1, 3,4,5,6,7,8]
Note that among the patients who were diagnosed with primary atypical hemolytic uremic syndrome (aHUS), half presented with a non-specific infectious illness within the month that preceded admission
We have described the clinical and genetic characteristics of two adult retrospective cohorts that were each affected by a disorder of the alternative complement pathway
Summary
The alternative complement pathway plays a major role in the pathogenesis of atypical hemolytic uremic syndrome (aHUS) [1, 2], and it appears to do so whether the disorder is idiopathic or due to acquired conditions (such as those listed in Supplemental Table S1) [1, 3,4,5,6,7,8]. The pathological lesion of primary and secondary aHUS is known as thrombotic microangiopathy (TMA). It consists principally of tumefied endothelial cells and plateletbased fibrinous thrombi in the microcirculation [9]. The alternative complement pathway could play an important pathogenic role in these other TMA-causing diseases [1, 6, 7, 10,11,12,13,14,15]
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