Fanconi anemia (Fanconi anemia) - Genes FANCA, FANCC, FANCG, FANCB, FANCD2, FANCE, FANCF, FANCT, FANCL, FANCM and PALB2.

Fanconi anemia is a disease that affects many parts of the body and characterized by cytogenetic instability, hypersensitivity to agents which introduce crosslinks in the DNA, increased chromosome breakage and defective DNA repair. People with this disorder may have insufficient bone marrow, physical alterations, defects organs, and increased risk of certain cancers. The main function of the bone marrow to produce new blood cells including erirocitos transporting oxygen to body tissues, leukocytes that fight infection and platelets needed for blood clotting.

Approximately 90% of people with Fanconi anemia have impaired bone marrow function leading to aplastic anemia. Affected individuals suffer from fatigue due to anemia, frequent infections due to neutropenia and clotting problems due to thrombocytopenia. People with Fanconi anemia may also develop myelodysplastic syndrome, a disorder in which immature blood cells do not develop normally. Over half of people with the disease have physical abnormalities that may involve hypopigmentation. Other possible symptoms of Fanconi anemia include thumbs or forearms malformed and other bone problems, including short stature, absence or malformation of the kidney and other urinary tract defects, gastrointestinal disorders, heart defects, eye abnormalities such as small eyes or so abnormal and misfolded and hearing loss ears. People with this disease may have genital malformations or reproductive system. As a result, men affected, and about half of the affected women are infertile. Other signs and symptoms may include additional abnormalities of the brain and central nervous system, including hydrocephalus or microcephaly. People with Fanconi anemia have a higher risk of developing acute myeloid leukemia (AML) or brain tumors, neck, skin, gastrointestinal system or the genital tract.

This disease is due to mutations in genes:

      • FANCA, located on the long arm of chromosome 16 (16q24.3).
      • FANCC, located on the long arm of chromosome 9
      • FANCG, located on the short arm of chromosome 9 (9p13).
      • FANCB, located on the short arm of chromosome X
      • FANCD2, located on the short arm of chromosome 3 (3p26).
      • FANCE, located on the short arm of chromosome 6 (6p22-p21).
      • FANCF, located on the short arm of chromosome 11 (11p15).
      • FANCI, located in the long arm of chromosome 15 (15q26.1).
      • FANCL, located on the short arm of chromosome 2 (2p16.1).
      • FANCM, located on the long arm of chromosome 14 (14q21.2).
      • PALB2, located on the short arm of chromosome 16 (16p12.2).

The proteins encoded by the FANCA, FANCC, FANCG, FANCB, FANCD2, FANCE, FANCF, FANCT, FANCL and FANCM genes are involved in a cellular process known as the FA pathway. The FA pathway is activated when the DNA copy process is blocked due to DNA damage. The FA pathway sends certain proteins to damaged areas, triggering the DNA repair to DNA copying can continue. The FA pathway is particularly sensitive to a certain type of DNA damage known as guilloche strands links (ICL). ICL occur when two nucleotides joined together abnormally, stopping the copy DNA. ICL may be caused by an accumulation of toxic substances in the body or by treatment with certain drugs for cancer therapy.

PALB2 gene encodes a protein that plays an essential role in homologous recombination repair (HRR) through its ability to locate and stabilize BRCA2 and RAD51 in DNA repair. Strongly stimulates activity RAD1 interaction with DNA, the nucleoprotein filament stabilizes the polypeptide breakover BRC3-BRC4 RAD51 and helps to overcome the suppressing effect replication protein A (RPA). Functionally cooperates with RAD51-AP1 in promoting training bag by RAD51. It also acts as molecular support complex formation BRCA1-PALB2-BRCA2 that is essential for homologous recombination.

This disease is due in 80% to 90% of the cases by mutations in one of the three genes, FANCA, FANCC, and FANCG.

There are more than 450 mutations in the gene FANCA, FANCC 50 mutations in the gene and more than 50 mutations in the gene causing FANCG Fanconi anemia. Mutations in any of the many genes associated with complex FA reduce protein function or result in a nonfunctional protein, causing the FA core complex is non - functional and altering all the FA pathway. As a result, DNA damage is not repaired efficiently and ICL accumulates over time. This accumulation causes cell death abnormal due to the inability to produce new DNA molecules or uncontrolled cell growth due to lack of DNA repair processes. The cells are rapidly dividing, such as bone marrow cells and cells of the developing fetus, they are particularly affected. The death of these cells causes the decrease of blood cells and the characteristics of physical abnormalities Fanconi anemia. When the accumulation of errors in DNA causes uncontrolled cell growth, affected individuals may develop acute myeloid leukemia or other cancers.

In most cases, this disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. Rarely, this disease is inherited in a recessive X - linked pattern. In males, an altered copy of the gene in each cell is sufficient to cause disease. In women, it would have to happen a mutation in both copies of the gene to cause the disorder. Because it is unlikely that women have two altered copies of this gene, males are affected by X - linked recessive disorders chromosome far more often than women. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome.  

Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with Fanconi anemia, by complete PCR amplification of the exons of the FANCA, FANCC, FANCG, FANCB, FANCD2, FANCE, FANCF, FANCT, FANCL, FANCM genes and PALB2, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).