Submission Details

CD46 was first reported in relation to semidominant atypical hemolytic uremic syndrome (aHUS) in 2003 (Richards et al., PMID:14566051). Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. C3 Glomerulopathy (C3G) is characterized by hematuria, proteinuria and histopathologically by accumulation of the C3 component of complement in kidney tissue. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into separate entities, aHUS (OMIM: 612925) and C3G (OMIM: 613779). The split curation for semidominant C3G has been curated separately.

The relationship between CD46 and aHUS was evaluated using the ClinGen Clinical Validity Framework. Seven variants (two missense, three nonsense, two splice site) that have been reported in seven probands in six publications (PMIDs: 14566051, 14615110, 16762990, 23780777, 20513133, 33238263) 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 reported to be loss of function. This gene-disease relationship is also supported by experimental evidence including expression studies (PMID:14615110), functional alteration (PMID:1588280), protein interaction (PMID:16762990) and Chinese Hamster ovary (CHO) cell model (PMID:17027083) and Human cell culture model (PMID: 30958843). The effect of reduced levels of wild-type CD46 showed that cells with lowered expression levels were less efficient in inhibiting alternative pathway activation (PMID:1588280). Further, a dysfunctional CD46 mutant, expressed at normal levels and identified in five patients with aHUS (S206P), failed to protect against C3b amplification on CHO cells, even if expression levels were increased 10-fold (PMID:1588280). Cell lysates were used to analyze the functional profile of the mutated proteins (PMID:16762990). CD46 E145Q, variant has approximately 50% of expected C4b cofactor activity, whereas G162R has no detectable C4b cofactor activity. Because G162R binds C4b normally, this is a mutation that selectively alters protease cleavage of C4b by factor I (PMID:1588280). In Chinese Hamster ovary cell model, reduced expression of wild-type CD46, as seen in aHUS patients, decreased protection against C3b deposition by the alternative pathway (PMID:17027083). A dysfunctional, but normally expressed form of CD46 (S206P) found in the two unrelated families with aHUS, was ~10% as effective as wild type against C3b amplification mediated by the alternative pathway or its feedback loop (PMID:17027083). In a human cell culture model, CD46 is localized to glomeruli, but especially also to proximal tubular epithelial cells (RPTECs). Factor I and CD46-mediated cleavage of C4b into soluble C4c and membrane deposited C4d was clearly reduced in the knock-out cell line as compared to the maternal cells (PMID:30958843).

In summary, there is definitive evidence supporting the relationship between CD46 and semidominant 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 Disease GCEP on the meeting date July 6, 2023. (SOP Version [9])].