Abstract
Studies of complement genetics have changed the landscape of thrombotic microangiopathies (TMAs), particularly atypical haemolytic uraemic syndrome (aHUS). Knowledge of complement genetics paved the way for the design of the first specific treatment for aHUS, eculizumab, and is increasingly being used to aid decisions regarding discontinuation of anti-complement treatment in this setting. Complement genetic studies have also been used to investigate the pathogenic mechanisms that underlie other forms of HUS and provided evidence that contributed to the reclassification of pregnancy- and postpartum-associated HUS within the spectrum of complement-mediated aHUS. By contrast, complement genetics has not provided definite evidence of a link between constitutional complement dysregulation and secondary forms of HUS. Therefore, the available data do not support systematic testing of complement genes in patients with typical HUS or secondary HUS. The potential relevance of complement genetics for distinguishing the underlying mechanisms of malignant hypertension-associated TMA should be assessed with caution owing to the overlap between aHUS and other causes of malignant hypertension. In all cases, the interpretation of complement genetics results remains complex, as even complement-mediated aHUS is not a classical monogenic disease. Such interpretation requires the input of trained geneticists and experts who have a comprehensive view of complement biology.
Key points
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Knowledge of complement genetics has transformed the landscape of atypical haemolytic uraemic syndrome (aHUS) and other forms of HUS.
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To date, aHUS is the only form of HUS that has been clearly associated with genetic susceptibility factors related to complement regulation.
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Pregnancy- and postpartum-associated HUS is part of the spectrum of complement-mediated HUS.
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Secondary forms of HUS do not share genetic risk factors with aHUS.
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Malignant hypertension is highly prevalent in patients with aHUS; however, aHUS is a rare cause of malignant hypertension.
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Interpretation of complement genetics results requires comprehensive expertise in complement biology.
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F.F. has received consultancy and/or speaker honoraria from Roche, Alexion, Apellis, Achillion, Novartis and Alnylam. V.F.-B has received fees from Alexion Pharmaceuticals, Roche, Apellis, Novartis and Baxter for invited lectures and/or board membership and is the recipient of a research grant from Alexion Pharmaceuticals and Apellis.
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Glossary
- Next-generation sequencing
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A high-throughput methodology that enables rapid sequencing of the base pairs in DNA samples.
- Sanger sequencing
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This ‘first-generation’ DNA sequencing method is considered to be the gold standard for validating DNA sequences, including those that have been obtained using next-generation sequencing.
- Multiplex ligation-dependent probe amplification
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A multiplex assay to detect copy number variations of genomic DNA sequences.
- Non-allelic homologous recombination
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A molecular mechanism of exchange between two long segments of DNA (~300 bp or longer) that have very high sequence homology.
- Combined annotation dependent depletion
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(CADD). An in silico tool that is designed to predict the pathogenicity of variants. CADD scores are based on diverse genomic features derived from the surrounding sequence context, gene model annotations, evolutionary constraint, epigenetic measurements and functional predictions. In silico predictive scores should be used, at most, as supporting evidence of pathogenicity.
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Fakhouri, F., Frémeaux-Bacchi, V. Thrombotic microangiopathy in aHUS and beyond: clinical clues from complement genetics. Nat Rev Nephrol 17, 543–553 (2021). https://doi.org/10.1038/s41581-021-00424-4
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DOI: https://doi.org/10.1038/s41581-021-00424-4
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