Genetic abnormalities in biopsy-proven, adult-onset hemolytic uremic syndrome and C3 glomerulopathy View Full Text


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Article Info

DATE

2021-10-29

AUTHORS

Ludwig Haydock, Alexandre P. Garneau, Laurence Tremblay, Hai-Yun Yen, Hanlin Gao, Raphaël Harrisson, Paul Isenring

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. More... »

PAGES

269-284

References to SciGraph publications

  • 2013-07-11. Current evidence for the role of complement in the pathogenesis of Shiga toxin haemolytic uraemic syndrome in PEDIATRIC NEPHROLOGY
  • 2020-06-26. Detection of copy-number variations from NGS data using read depth information: a diagnostic performance evaluation in EUROPEAN JOURNAL OF HUMAN GENETICS
  • 2015-03-05. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology in GENETICS IN MEDICINE
  • 2012-09-18. STEC-HUS, atypical HUS and TTP are all diseases of complement activation in NATURE REVIEWS NEPHROLOGY
  • 2021-05-05. Thrombotic microangiopathy in aHUS and beyond: clinical clues from complement genetics in NATURE REVIEWS NEPHROLOGY
  • 2018-12-21. The genetics of atypical hemolytic uremic syndrome in MEDIZINISCHE GENETIK
  • 2020-09-11. Resolving misalignment interference for NGS-based clinical diagnostics in HUMAN GENETICS
  • 2017-11-17. Genetic testing of complement and coagulation pathways in patients with severe hypertension and renal microangiopathy in MODERN PATHOLOGY
  • 2011-09-08. Atypical hemolytic uremic syndrome in ORPHANET JOURNAL OF RARE DISEASES
  • 2018-06-09. Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy in PEDIATRIC NEPHROLOGY
  • 2013-09-13. Computational tools for copy number variation (CNV) detection using next-generation sequencing data: features and perspectives in BMC BIOINFORMATICS
  • 2019-01-28. C3 glomerulopathy — understanding a rare complement-driven renal disease in NATURE REVIEWS NEPHROLOGY
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    32 schema:description 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.
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