Fanconi anemia is caused by inherited mutations in a group of genes responsible for repairing damaged DNA. These genes work together in a complex pathway that detects and fixes breaks in DNA strands, which naturally occur during cell division or due to environmental damage. When these genes are mutated, the DNA repair process is faulty or absent, leading to the accumulation of genetic damage in cells. This damage particularly affects the bone marrow, where blood cells are produced, resulting in bone marrow failure and the characteristic symptoms of Fanconi anemia.
The disorder is primarily inherited in an autosomal recessive pattern, meaning a person must inherit two defective copies of one of the Fanconi anemia (FA) genes—one from each parent—to develop the disease. There are more than 20 known FA genes, with mutations in the FANCA gene being the most common cause. These genes encode proteins that form a complex responsible for recognizing DNA damage and coordinating its repair. When any of these genes are mutated, the repair pathway is disrupted, causing cells to become unstable and prone to breaking chromosomes, which leads to the clinical features of Fanconi anemia.
Because the DNA repair system is compromised, cells accumulate chromosomal abnormalities, which not only cause bone marrow failure but also increase the risk of developing cancers, especially leukemia and solid tumors. The defective DNA repair also explains why patients with Fanconi anemia have increased sensitivity to DNA-damaging agents like chemotherapy or radiation.
In some cases, individuals may carry only one mutated copy of an FA gene (heterozygous carriers) and not show symptoms of the disease but may have a higher risk of certain cancers. However, the full-blown disease requires mutations in both copies of the gene.
The mutations can be diverse, including small changes in the DNA sequence, deletions, or insertions that disrupt the function of the FA proteins. Because the FA pathway involves multiple proteins working together, mutations in any one of these genes can cause the disease, although the severity and specific symptoms may vary depending on which gene is affected.
In summary, Fanconi anemia arises from inherited mutations in genes critical for DNA repair. These mutations impair the cell’s ability to fix DNA damage, leading to bone marrow failure, increased cancer risk, and other clinical problems associated with the disease.
