Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, physical abnormalities, and an increased risk of cancer. FA affects one in 100.000 births and is caused by pathogenic variants in up to 22 genes involved in DNA repair, the most frequently affected gene being FANCA, followed by FANCC.
Fanconi anemia genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of Fanconi anemia (FANCC-related) include:
- Bone Marrow Failure: Individuals with Fanconi Anemia often develop bone marrow failure, leading to a decrease in the production of blood cells (anemia, leukopenia, and thrombocytopenia). This can result in fatigue, increased infection susceptibility, and bleeding tendencies.
- Physical Abnormalities: Many individuals with Fanconi Anemia have physical abnormalities, including short stature, abnormal skin pigmentation, malformed thumbs or forearms, and skeletal anomalies.
- Increased Cancer Risk: Individuals with Fanconi Anemia have a significantly higher risk of developing certain cancers, particularly hematological cancers (such as acute myeloid leukemia) and solid tumors (such as squamous cell carcinoma).
- Genetic Inheritance: Fanconi Anemia is typically inherited in an autosomal recessive manner. This means that individuals with Fanconi Anemia inherit two mutated copies of the FANCC gene, one from each parent.
- DNA Repair Deficiency: Fanconi Anemia is associated with impaired DNA repair mechanisms, leading to genomic instability and an increased susceptibility to cancer.
Diagnosis of Fanconi anemia involves clinical evaluation, blood tests, and genetic testing to identify mutations in the FANCC gene or other associated genes. Prenatal and carrier testing are available for families with a known history of Fanconi Anemia.
Treatment for Fanconi anemia may involve supportive care, blood transfusions, and medications to manage complications. Hematopoietic stem cell transplantation (bone marrow transplant) is a potentially curative treatment for bone marrow failure, but it comes with significant risks and is not suitable for all individuals.
Genetic counseling is an essential component of the management of Fanconi anemia. It provides information about the inheritance pattern, helps assess the risk of passing the condition to future generations, and guides family planning decisions.
Due to the multisystem nature of Fanconi Anemia and its potential complications, a multidisciplinary approach involving hematologists, oncologists, geneticists, and other specialists is often necessary for comprehensive care. Early diagnosis and intervention are critical for improving outcomes and managing the associated health risks.
More Information
Fanconi anemia is an autosomal recessive disorder, except for the FANCB (X-linked inheritance) and FANCR (also known as RAD51 with autosomal dominant inheritance) genes. The FANCC gene encodes for a protein that interacts with other AF proteins, forming a complex that maintains the number of centrosomes in mitosis and the mitotic spindle. In addition, FANCC and other AF proteins participate in the checkpoint that ensures proper segregation of chromosomes during cell division. Pathogenic alterations in FA proteins often increase the risk of cell death, increase genomic instability, and predisposition to cancer.
Mutations of the FANCC gene account for approximately 14% of cases of FA. Among all known variants, c.67del and c.456+4A>T, occurring in exon 1 and intron 4, respectively, are the most commonly observed. The c.67del deletion produces a truncated protein, and the c.456+4A>T variant results in the deletion of the entire exon. The c.456+4A>T mutation has been found mainly in patients of Ashkenazi Jewish origin. This same mutation is the most common cause of FANCC-related FA in Japan.
Fanconi anemia genetic testing analyzes the 14 most frequent pathogenic mutation of FANCC gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as e.g. next-generation sequencing (NGS).
