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Complement factor I (CFI) is a serine protease that regulates activation of the alternative complement pathway by cleaving C3b and C4b in the presence of cofactors. Heterozygous CFI variants have emerged as important risk factors for thrombotic microangiopathy (TMA; MONDO:0019737), a disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia and end-organ injury, particularly in the kidney.
The association of CFI (HGNC:5394) with TMA meets a Strong ClinGen level. To date, 13 probands across 7 unrelated reports have been described with heterozygous CFI missense variants in TMA presentations ([PMID:22834933]; [PMID:26613809]; [PMID:29940891]; [PMID:29732228]; [PMID:36070894]). Although family segregation data are limited, independent case series and cohort studies demonstrate consistent enrichment of rare CFI variants in TMA.
CFI-related TMA follows an autosomal dominant inheritance with incomplete penetrance. Across case reports, 6 distinct missense variants have been identified in heterozygous form in patients presenting with pregnancy-induced or transplant-associated TMA, neurological TMA without renal impairment, infection-triggered TMA, and de novo aHUS post-transplant. One representative allele is c.805G>A (p.Gly269Ser) ([PMID:26613809]). No multigenerational segregation beyond first-degree relatives has been documented, and affected_relatives data remain limited.
All reported CFI variants in TMA are missense substitutions clustering in the serine protease and heavy chain domains. There are no recurrent or founder alleles to date. Phenotypically, carriers present with microangiopathic hemolytic anemia (HP:0001878), thrombocytopenia (HP:0001873) and acute kidney injury (HP:0001919), often triggered by pregnancy, transplantation or infection.
Functional assays demonstrate that many TMA-associated CFI variants impair secretion or catalytic activity. In vitro cofactor activity studies show reduced cleavage of C3b/C4b for multiple CFI mutants, including p.Arg502Trp and p.Ile340Thr, confirming a loss-of-function mechanism consistent with complement overactivation in TMA ([PMID:17597211]; [PMID:19877009]). Mouse models of CFI deficiency further support that impaired alternative pathway regulation precipitates glomerular microvascular injury under stress.
The G261D variant, initially reported in a mother–daughter TMA pair, exhibited normal plasma levels and in vitro activity, suggesting that additional modifiers or triggers are required for disease manifestation ([PMID:17084897]). This underscores variable penetrance and the likely need for environmental or genetic cofactors in CFI-mediated TMA.
Collectively, heterozygous CFI variants confer a strong predisposition to complement-mediated TMA under environmental triggers. Genetic testing for CFI should be considered in patients with unexplained TMA, particularly in pregnancy, post-transplant or infection-associated cases. Functional assays aid variant classification. Early identification of CFI defects informs prognosis and supports timely initiation of complement-targeted therapies (e.g., eculizumab).
Key Take-Home: Heterozygous loss-of-function CFI variants cause autosomal dominant TMA with incomplete penetrance; genetic and functional testing of CFI variants is critical for diagnosis and therapeutic decision-making.
Gene–Disease AssociationStrong13 probands from 7 unrelated reports with CFI variants and consistent TMA phenotype Genetic EvidenceStrongHeterozygous CFI missense variants in 13 unrelated TMA cases across multiple cohorts and case series Functional EvidenceModerateIn vitro assays and animal models demonstrate impaired CFI secretion or activity leading to complement dysregulation |