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CFH
complement factor H
CFH encodes complement factor H, a critical regulator of the complement immune system that protects healthy cells from damage during immune responses. The CFH gene provides instructions for making complement factor H, a protein that controls part of the body's innate immune defence.
CFH is located on the long (q) arm of chromosome 1, at band 1q31.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The CFH gene, located on chromosome 1, encodes complement factor H, a plasma protein essential for regulating the alternative pathway of the complement system. This ancient immune mechanism destroys pathogens, clears cellular debris, and initiates inflammation, but requires tight control to prevent damage to the body's own tissues. Complement factor H acts as a brake on this system, ensuring that complement activation occurs only where needed.
Variants in CFH can disrupt this regulatory function, leading to inappropriate complement activation on host cell surfaces. This dysregulation underlies several rare kidney disorders and contributes to common age-related eye disease. The gene is clinically important in the UK, appearing on multiple NHS Genomic Medicine Service panels for kidney and immune conditions.
What the gene does
Complement factor H circulates in blood plasma and serves as the primary fluid-phase regulator of the alternative complement pathway. The protein binds to C3b, a key component deposited during complement activation, and accelerates the breakdown of the C3 convertase enzyme complex. This prevents the complement cascade from amplifying on healthy cell surfaces, which display molecular markers that recruit factor H for protection.
The protein also acts as a cofactor for factor I, a serine protease that cleaves and permanently inactivates C3b into smaller fragments. Through these dual mechanisms, complement factor H distinguishes self from non-self surfaces, directing immune attack toward pathogens whilst sparing host tissues. The protein's ability to recognise host cells depends on its affinity for polyanions such as glycosaminoglycans and sialic acid residues present on cell membranes.
Dysfunction in this regulatory process allows uncontrolled complement activation on endothelial cells lining blood vessels, particularly in the kidneys and the retina, where complement turnover is normally high. This inappropriate activation generates inflammatory signals and can cause direct cellular injury.
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Chromosome location
The CFH gene is located on the long arm of chromosome 1 at position 1q31.3. This chromosomal region contains a cluster of related complement regulatory genes, including several genes encoding factor H-related proteins that share structural similarity with CFH. The gene spans a substantial genomic region and encodes a protein of 1,231 amino acids.
Protein structure
Complement factor H consists of 20 repeating structural modules called sushi domains (also known as complement control protein modules) that span the entire mature protein. The N-terminal domains (Sushi 1-4) mediate binding to C3b and regulatory cofactor activity, whilst the C-terminal domains (Sushi 19-20) recognise host cell surface markers such as heparin and sialic acid. This modular architecture allows the protein to simultaneously engage complement components and cell surfaces, positioning its regulatory activity precisely where needed.
The complete domain structure comprises: Sushi 1 (amino acids 19-82), Sushi 2 (amino acids 83-143), Sushi 3 (amino acids 144-207), Sushi 4 (amino acids 208-264), Sushi 5 (amino acids 265-322), Sushi 6 (amino acids 324-386), Sushi 7 (amino acids 387-444), Sushi 8 (amino acids 446-507), Sushi 9 (amino acids 515-566), Sushi 10 (amino acids 567-625), Sushi 11 (amino acids 628-686), Sushi 12 (amino acids 689-746), Sushi 13 (amino acids 751-805), Sushi 14 (amino acids 809-866), Sushi 15 (amino acids 868-928), Sushi 16 (amino acids 929-986), Sushi 17 (amino acids 987-1045), Sushi 18 (amino acids 1046-1104), Sushi 19 (amino acids 1107-1165), and Sushi 20 (amino acids 1170-1230).
Key variants
More than 100 pathogenic variants in CFH have been identified in individuals with complement-related disorders. Most disease-causing variants are missense changes that alter single amino acids in critical functional domains, impairing either C3b binding or host cell surface recognition. Variants in the C-terminal region tend to cause atypical haemolytic uraemic syndrome by reducing the protein's ability to protect endothelial cells. Common polymorphisms in CFH, particularly the Tyr402His variant, modulate risk for age-related macular degeneration in the general population, though with modest effect sizes.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1520-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Atypical hemolytic-uremic syndrome |
c.1707C>A | p.Cys569Ter | Pathogenic | ★★☆☆ | Atypical hemolytic-uremic syndrome |
c.1756C>T | p.Gln586Ter | Pathogenic | ★★☆☆ | Atypical hemolytic-uremic syndrome |
c.1833C>A | p.Cys611Ter | Pathogenic/Likely pathogenic, low penetrance | ★★☆☆ | Atypical hemolytic-uremic syndrome |
c.2575C>T | p.Gln859Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Factor H deficiency |
c.2871C>A | p.Tyr957Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.3676C>T | p.Pro1226Ser | Pathogenic/Likely pathogenic, low penetrance | ★★☆☆ | Atypical hemolytic-uremic syndrome |
c.619+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Basal laminar drusen |
c.1608C>A | p.Cys536Ter | Pathogenic | ★☆☆☆ | not provided |
c.3007G>T | p.Glu1003Ter | Pathogenic | ★☆☆☆ | Hemolytic uremic syndrome, atypical, susceptibility to, 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic CFH variants are associated with several distinct clinical presentations. Atypical haemolytic uraemic syndrome, a rare thrombotic microangiopathy, typically results from variants that abolish complement regulation on kidney endothelium, leading to clot formation in renal blood vessels. Several variants have been identified in individuals with C3 glomerulopathy, a progressive kidney disease characterised by abnormal complement deposits in the glomeruli.
Common variants in and near CFH contribute to age-related macular degeneration, a leading cause of vision loss in older adults. Polymorphisms also show association with diabetic retinopathy, though the genetic architecture of this condition is complex and involves multiple genes. The clinical spectrum reflects the protein's dual importance in protecting vascular endothelium and retinal tissues from complement-mediated injury.
Inheritance pattern
Conditions caused by pathogenic CFH variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
CFH holds green (diagnostic-grade evidence) status on several NHS Genomic Medicine Service gene panels. These include the Atypical haemolytic uraemic syndrome panel (R201), the Membranoproliferative glomerulonephritis including C3 glomerulopathy panel (R197), the Retinal disorders panel (R32), and the Primary immunodeficiency or monogenic inflammatory bowel disease panel (R15). The gene also appears on panels for Unexplained kidney failure in young people and COVID-19 research. This multi-panel presence reflects the broad clinical relevance of complement dysregulation across renal, immunological, and ophthalmological specialties.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is CFH inherited?
The inheritance pattern for CFH-related conditions varies depending on the specific disorder and variant. Whilst CFH appears on carrier screening panels, many CFH-associated conditions show autosomal dominant inheritance with variable penetrance, meaning a single altered copy may increase disease risk. For example, atypical haemolytic uraemic syndrome often results from heterozygous variants (one altered copy), whilst associations with age-related macular degeneration involve common single-copy polymorphisms. Genetic counselling is essential to understand the inheritance pattern relevant to specific variants and family history.
What is the difference between complement factor H and factor H-related proteins?
Complement factor H is the main circulating regulator of the alternative complement pathway, encoded by CFH. Factor H-related proteins are structurally similar molecules encoded by nearby genes (CFHR1-5) that share some sushi domains with factor H but generally lack full regulatory activity. These related proteins can modulate factor H function and, in some cases, compete with it for binding sites.
Can CFH variants be detected through routine carrier screening?
CFH is categorised as an autosomal recessive carrier screening gene, meaning it may be included on comprehensive carrier screening panels that assess recessive conditions. However, the complex nature of some CFH-associated conditions means the gene is often analysed through targeted gene panels for kidney disease, complement disorders, or retinal conditions when specific clinical features are present. Genetic counselling can help determine the most appropriate testing approach for individual circumstances.
References
- Zipfel PF, Skerka C, Chen Q. The role of complement in C3 glomerulopathy. Molecular immunology. 2015. PMID: 25929733
- Xiao X, Pickering MC, Smith RJ. C3 glomerulopathy: the genetic and clinical findings in dense deposit disease and C3 glomerulonephritis. Seminars in thrombosis and hemostasis. 2014. PMID: 24799308
- Servais A, Noël LH, Roumenina LT. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney international. 2012. PMID: 22456601
- Donoso LA, Vrabec T, Kuivaniemi H. The role of complement Factor H in age-related macular degeneration: a review. Survey of ophthalmology. 2010. PMID: 20385334
- Boon CJ, van de Kar NC, Klevering BJ. The spectrum of phenotypes caused by variants in the CFH gene. Molecular immunology. 2009. PMID: 19297022
- Boon CJ, Klevering BJ, Hoyng CB. Basal laminar drusen caused by compound heterozygous variants in the CFH gene. American journal of human genetics. 2008. PMID: 18252232
- Atkinson JP, Goodship TH. Complement factor H and the hemolytic uremic syndrome. The Journal of experimental medicine. 2007. PMID: 17548524
- Francis PJ, Schultz DW, Hamon S. Haplotypes in the complement factor H (CFH) gene: associations with drusen and advanced age-related macular degeneration. PloS one. 2007. PMID: 18043728
- Abrera-Abeleda MA, Nishimura C, Smith JL. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). Journal of medical genetics. 2006. PMID: 16299065
- Despriet DD, Klaver CC, Witteman JC. Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA. 2006. PMID: 16849663
- Li M, Atmaca-Sonmez P, Othman M. CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nature genetics. 2006. PMID: 16936733