Submission Details

CFI was first reported in relation to autosomal dominant atypical hemolytic uremic syndrome (aHUS) in 2004 (Fremeaux-Bacchi et al., PMID: 15173250). 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: 612923) and C3 glomerulopathy (C3G) (OMIM: 610984). The split curation for autosomal dominant C3G will be conducted separately. Thirteen variants (missense, nonsense, and frameshift) that have been reported in thirteen probands in four publications (PMIDs: 15173250, 15917334, 17597211, 20016463) 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, causing dysregulation of the complement mediated immune pathway. This gene-disease relationship is also supported by biochemical functions indicating the role of CFI in the complement pathway and protein interaction with CFH (PMID: 28671664). Of note, enrichment of CFI rare genetic variants has been demonstrated in aHUS in two studies using burden type testing (PMIDs: 29500241, 30377230). It should also be noted that a recent analysis of the genotyping data from UK biobank aimed to identify CFI variants that are known to result in low levels of factor I and identified no cases of aHUS with any of the 1,671 type 1 variants, demonstrating very low penetrance for CFI. In summary, there is definitive evidence supporting the relationship between CFI and autosomal dominant aHUS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Complement Mediated Kidney Diseases GCEP on the meeting date June 1, 2023 (SOP Version 9).