CFI – Complement Factor I Deficiency

Complement factor I deficiency is a rare autosomal recessive immunodeficiency caused by biallelic loss-of-function variants in CFI. Affected individuals present with recurrent pyogenic infections of the respiratory tract, meningitis, sepsis, vasculitis and immune complex glomerulonephritis, reflecting uncontrolled alternative pathway activation due to absent FI activity ([PMID:16138437]).

Inheritance is autosomal recessive, often observed in consanguineous families. In one Turkish sib pair, both sisters exhibited low C3 levels and recurrent bacterial infections, and homozygous CFI variants segregated with disease ([PMID:16138437]).

To date, eight unrelated probands have been reported with homozygous or compound heterozygous CFI variants, including missense (n = 4) and frameshift/deletion (n = 4) alleles that abolish FI expression or function ([PMID:25988862], [PMID:27091480], [PMID:36577522], [PMID:38134378], [PMID:40196760], [PMID:28942469]). These variants span the heavy and light chains and disrupt cofactor-mediated cleavage of C3b and C4b.

Functional assays of recombinant CFI variants, such as c.162C>G (p.Cys54Trp), demonstrate impaired secretion and negligible proteolytic activity against C3b/C4b in fluid-phase and on cell surfaces ([PMID:27091480]; [PMID:19065647]). A mouse model carrying the D288G ortholog exhibits severe C3 deposition upon endotoxin challenge, confirming pathogenic complement dysregulation ([PMID:34149444]).

No conflicting studies have been reported, and heterozygous carriers remain asymptomatic. There is no evidence refuting the causal link between biallelic CFI variants and the immunodeficiency phenotype.

In summary, autosomal recessive CFI deficiency is caused by biallelic loss-of-function variants leading to absent FI activity, profound complement consumption, and life-threatening bacterial infections and autoimmune manifestations. Genetic testing and complement functional assays are essential for diagnosis, enabling prompt prophylactic antibiotics, vaccination, and complement blockade (e.g., eculizumab) to improve clinical outcomes.

References

• Scandinavian journal of infectious diseases | 2005 | Complement factor I deficiency associated with recurrent infections, vasculitis and immune complex glomerulonephritis. PMID:16138437
• Clinical immunology | 2015 | Novel CFI mutation in a patient with leukocytoclastic vasculitis may redefine the clinical spectrum of Complement Factor I deficiency. PMID:25988862
• Immunology letters | 2016 | Clinical laboratory standard capillary protein electrophoresis alerted of a low C3 state and lead to the identification of a Factor I deficiency due to a novel homozygous mutation. PMID:27091480
• Journal of clinical immunology | 2017 | Early Versus Late Diagnosis of Complement Factor I Deficiency: Clinical Consequences Illustrated in Two Families with Novel Homozygous CFI Mutations. PMID:28942469
• Cold Spring Harbor molecular case studies | 2022 | Rapid genome sequencing identifies novel variants in complement factor I. PMID:36577522
• Neurology® Neuroimmunology & Neuroinflammation | 2024 | CNS Inflammation as the First Sign of Complement Factor I Deficiency: A Severe Myelitis Treated With Intense Immunotherapy and Eculizumab. PMID:38134378
• Cureus | 2025 | Pediatric Immunodeficiency Caused by Complement Classical and Alternative Pathway Defects Due to a Homozygous CFI Variant: A Case Report. PMID:40196760
• Gene | 1999 | An initiator element and a proximal cis-acting sequence are essential for transcriptional activation of the complement factor I (CFI) gene. PMID:10524238
• Molecular immunology | 2007 | A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation. PMID:17084897
• European journal of immunology | 2009 | Genetic, molecular and functional analyses of complement factor I deficiency. PMID:19065647
• Frontiers in physiology | 2021 | Generation and Characterization of Mouse Models of C3 Glomerulonephritis With CFI D288G and P467S Mutations. PMID:34149444

Evidence Based Scoring (AI generated)