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FANCA
FA complementation group A
The FANCA gene provides instructions for a protein crucial to the Fanconi Anaemia pathway, which is vital for repairing DNA damage and maintaining genomic stability. The FANCA gene is involved in DNA repair mechanisms, specifically addressing interstrand cross-links that can impede DNA replication.
FANCA is located on the long (q) arm of chromosome 16, at band 16q24.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The FANCA gene, or FA complementation group A, encodes a protein that plays a central role in the Fanconi Anaemia (FA) pathway. This pathway is essential for the repair of damaged DNA, particularly interstrand cross-links, which are abnormal connections between DNA strands that can halt the DNA replication process. Proper functioning of the FANCA protein is critical for preventing genomic instability and safeguarding against the development of certain inherited conditions and cancers.
Inherited in an autosomal recessive manner, pathogenic variants in the FANCA gene are a common cause of Fanconi Anaemia. This condition is characterised by bone marrow dysfunction, increased cancer predisposition, and various physical manifestations.
What the gene does
The FANCA gene product is a component of the FA core complex, a multi-protein assembly that initiates the Fanconi Anaemia pathway. This pathway becomes active when DNA replication encounters interstrand cross-links (ICLs), which are abnormal bonds between DNA bases on opposing strands. These ICLs prevent DNA from being accurately copied and can arise from toxic substances or specific cancer therapies.
Within the FA core complex, the FANCA protein works alongside seven other FA proteins and two Fanconi Anaemia-associated proteins (FAAPs). This complex is responsible for activating two proteins, FANCD2 and FANCI, through a process called monoubiquitination - attaching a single ubiquitin molecule to each [PMID:17006456]. Activated FANCD2 and FANCI then recruit other DNA repair proteins to the site of the damage, facilitating the removal of the ICL and allowing DNA replication to resume. This intricate repair mechanism is fundamental to preserving genomic integrity [PMID:19019904].
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Chromosome location
The FANCA gene is situated on chromosome 16 at position 16q24.3. This specific genomic location provides the physical address for the gene within the human genome.
Protein structure
The FANCA protein consists of 1455 amino acids. A notable feature of the FANCA protein structure is a Nuclear localization signal motif, located between amino acids 18 and 34. This motif is crucial for directing the FANCA protein into the cell's nucleus, where its DNA repair functions are carried out [PMID:15602580].
Key variants
Variants in the FANCA gene encompass a wide range of changes, including single nucleotide alterations, insertions, and deletions. These genetic changes can impair the FANCA protein's function within the DNA repair pathway, leading to an inability to effectively resolve DNA damage. Such pathogenic variants are primarily associated with inherited conditions.
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.1007-1G>A | - | Pathogenic | ★★☆☆ | Fanconi anemia complementation group A |
c.105T>G | p.Tyr35Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.1197C>A | p.Cys399Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.133G>T | p.Glu45Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.1464C>A | p.Tyr488Ter | Pathogenic | ★★☆☆ | Fanconi anemia |
c.1812dup | p.Glu605fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group A |
c.190-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group A |
c.3446_3449dup | p.Met1151fs | Pathogenic | ★★☆☆ | Fanconi anemia |
c.3494T>G | p.Leu1165Ter | Pathogenic | ★★☆☆ | Fanconi anemia |
c.3715G>T | p.Glu1239Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
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 variants in the FANCA gene are a leading cause of Fanconi Anaemia, an autosomal recessive inherited disorder. This condition is characterised by progressive bone marrow failure, an elevated risk of developing various cancers, and a range of congenital abnormalities. Variants in the FANCA gene are responsible for a significant proportion of Fanconi Anaemia cases.
Inheritance pattern
Conditions caused by pathogenic FANCA 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
The FANCA gene is included in several NHS England Genomic Medicine Service approved panels. These include panels for Adult solid tumours cancer susceptibility, Childhood solid tumours, Childhood solid tumours cancer susceptibility, and Fanconi anaemia or Bloom syndrome (R229). It is also present on panels for Cytopenias and congenital anaemias, Foetal anomalies (R21), Haematological malignancies cancer susceptibility, Haematological malignancies for rare disease, Head and neck cancer pertinent cancer susceptibility, IUGR and IGF abnormalities, Limb disorders, Monogenic short stature (R453), Neurofibromatosis Type 1, Pigmentary skin disorders (R236), Radial dysplasia, and Severe microcephaly (R88).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the FANCA gene?
The FANCA gene provides instructions for a protein that is a key component of the Fanconi Anaemia pathway, essential for repairing specific types of DNA damage known as interstrand cross-links. This repair mechanism helps maintain genomic integrity and proper DNA replication.
What condition is most commonly associated with FANCA gene variants?
Pathogenic variants in the FANCA gene are most commonly associated with Fanconi Anaemia. This is an inherited disorder characterised by bone marrow failure, an increased risk of cancer, and various physical abnormalities.
How is Fanconi Anaemia inherited?
Fanconi Anaemia caused by FANCA gene variants is inherited in an autosomal recessive manner. This means an individual must inherit two pathogenic variants, one from each parent, to develop the condition.
References
- Deakyne JS, Mazin AV. Fanconi anemia: at the crossroads of DNA repair. Biochemistry. Biokhimiia. 2011. PMID: 21568838
- Kee Y, D'Andrea AD. Expanded roles of the Fanconi anemia pathway in preserving genomic stability. Genes & development. 2010. PMID: 20713514
- de Winter JP, Joenje H. The genetic and molecular basis of Fanconi anemia. Mutation research. 2009. PMID: 19061902
- Taniguchi T, D'Andrea AD. Molecular pathogenesis of Fanconi anemia: recent progress. Blood. 2006. PMID: 16493006