Afibrinogenemia, Familial afibrinogenemia, Congenital afibrinogenemia
Congenital afibrinogenemia is a rare inherited disease resulting from a defect in fibrinogen and characterized by uncontrolled bleeding. The most common manifestations of afibrinogenemia include umbilical cord bleeding, nose-bleeds (epistaxis), hemarthrosis and others. Uncontrolled bleeding in people with congenital afibrinogenemia results from abnormal process of blood clotting. Normally, blood clots protect the body after an injury by sealing off injured blood vessels to prevent further bleeding, i.e. blood loss. However, if the fibrinogen system is abnormal, bleeding cannot be stopped normally.
Congenital afibrinogenemia is a rare condition that occurs in approximately 1 in 1,000,000 newborns 1. According to the 2010 World Federation Hemophilia Annual Global Survey (data from 106 countries), afibrinogenemia accounts for 7% of cases of rare bleeding disorders and is more frequent in women than men 2.
The most common clinical features of afibrinogenemia include the following:
- Umbilical cord bleeding present at birth and postpartum hemorrhage
- Epistaxis (nose bleeding)
- Hemarthrosis (bleeding in joint space)
- Gastrointestinal bleeding
- Traumatic and surgical bleeding
- Intracranial hemorrhage in rare cases
- Recurrent spontaneous abortions may occur in affected female patients.
Congenital afibrinogenemia results from mutations in one of the fibrinogen genes: FGA, FGB, or FGG. These genes provide instructions for making fibrinogen subunits and they are essential for blood coagulation. Most FGA, FGB, and FGG gene mutations which cause afibrinogenemia result in a premature stop signal in the instructions for making the respective protein, and if any subunit is missing the fibrinogen protein is not assembled, which results in the absence of fibrin. Consequently, blood clots do not form in response to injury, leading to the excessive bleeding seen in people with congenital afibrinogenemia.
The first causative mutation described was a deletion of approximately 11 kb in FGA gene 3. Numerous other mutations have been described in the FGA, FGB, or FGG genes, all with the effect of null mutation, resulting in the absence of the protein product (frameshift, nonsense, or splice-site mutations). Missense mutations are distributed within the highly conserved C-terminal portion of the fibrinogen chains and they are scattered throughout all 3 genes. A few of these mutations are reported more frequently, suggesting possible hotspots, for example IVS4+1G>T, Arg149stop in the FGA gene. 4 Research studies performed so far on hereditary cases of afibrinogenemia have shown that the majority of mutations (~70%) are truncated and mostly unique for every affected family.
Congenital afibrinogenemia can be successfully treated using replacement therapy. Affected patients receive fresh frozen plasma, cryoprecipitate, or fibrinogen concentrates 5. The conventional treatment should be administered as soon as possible after onset of bleeding. An important part of the therapy is prophylaxis which consists of giving either fibrinogen concentrates from an early age to prevent bleeding and, in case of pregnancy, to prevent miscarriage.
CENTOGENE offers the Afibrinogenemia panel, including sequencing and deletion/duplication analysis of these genes: FGA, FGB, and FGG. In addition, any of the genes in the Afibrinogenemia panel can also be ordered individually.
The differential diagnosis of afibrinogenemia-related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Congenital clotting factor deficiencies (Factors II, V, VII, X, XI, VIII, IX and XIII)
- Acquired fibrinogen deficiency (consumptive coagulopathy, hepatic failure)
- Congenital or acquired thrombophilia (antithrombin deficiency, protein C or S deficiency, factor V Leiden mutation, lupus anticoagulant
- Consumption coagulopath.
CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free Whole Genome Sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for afibrinogenemia using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Afibrinogenemia panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no mutation is identified after analysis of the Afibrinogenemia panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.
The following individuals are candidates for afibrinogenemia gene testing:
- Individuals with a family history of afibrinogenemia and presentation of the most common symptoms
- Individuals without a positive family history, but with symptoms resembling afibrinogenemia
- Individuals with a negative but suspected family history of afibrinogenemia, in order to perform proper genetic counseling.
Sequencing, deletion/duplication of Afibrinogenemia panel and related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.
Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.