CFH was first reported in relation to semidominant atypical hemolytic uremic syndrome (aHUS) in 1998 (Warwicker et al., PMID: 9551389). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following diseases have been split into separate entities, aHUS (OMIM: 235400) and C3 glomerulopathy (C3G) (OMIM: 609814). The split curation for semidominant C3G will be conducted separately. Fourteen variants (missense, nonsense, frameshift) that have been reported in eleven probands in three publications (PMIDs: 12424708, 14978182, 28941939) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by experimental evidence (animal models, in vitro functional assays, and biochemical function) (PMIDs: 83964, 16338962, 17517971, 28057640).
One mouse model (PMID 17517971 lacking the terminal five SCR cell surface recognition domains of factor H (FHΔ16-20) controlled C3 turnover in plasma but defective control of complement activation on renal endothelium resulted in aHUS. A subsequent mouse (PMID: 28057640) carried a homozygous W1206R missense change in mouse FH that corresponded to the W1183R missense variant in human FH found in multiple aHUS families. This again led to impaired FH activity on cell surface and an aHUS phenotype in the mouse model.
Generally, CFH is known to inhibit C3 function (PMID: 83964) and the C-terminal region of CFH is known to be responsible for cell surface binding and complement regulation via glycosaminoglycan and C3b/C3d (PMID: 18684951). Multiple variants in this region of CFH were shown to reduce heparin affinity as well as binding with C3b/C3d (PMID: 16338962) resulting in aHUS.
Of note, some variants in CFH can cause aHUS and/or C3G in separate patients, although the mechanism of disease leading to different clinical presentations is not fully understood. In summary, there is definitive evidence supporting the relationship between CFH and semidominant aHUS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over. This classification was approved by the ClinGen Complement Mediated Kidney Diseases GCEP on the meeting date April 19, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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