The MDC has close links with the Comprehensive Care Haemophilia Centres at Manchester Royal Infirmary (MRI) and the Royal Manchester Children's Hospital (RMCH). Genetic diagnosis in heritable bleeding disorders, including clinical scientific interpretation of individual cases, is provided to these haemophilia centres and also, as required, to other centres nationally and internationally.
Comprehensive genetic diagnosis is presently available for haemophilia A, haemophilia B, von Willebrand disease (VWD), FXI deficiency, and FVII deficiency.
It is the referring clinician’s responsibility to obtain and record informed consent prior to genetic diagnosis in all heritable bleeding disorders. In this regard, it is also the referring clinician’s responsibility to inform the laboratory of any restrictions on consent (for example to store genetic information on confidential databases, or to apply an individual’s genetic information in the diagnosis of other family members). A standard consent form and patient information leaflet is in use within the CMFT Comprehensive Care Haemophilia Centres.
Haemophilia A and haemophilia B
Haemophilia A is a heritable bleeding disorder resulting from low or, in severe cases, absent functional levels of coagulation factor VIII. Inheritance is X-linked recessive. Haemophilia A is the most common of the severe bleeding disorders, with an approximate incidence of 1 new case per 5,000 male births. Haemophilia A is caused by mutations in the factor VIII (F8) gene.
Haemophilia B is a heritable bleeding disorder resulting from low or, in severe cases, absent functional levels of coagulation factor IX. Inheritance is X-linked recessive. Haemophilia B has an approximate incidence of 1 new case per 25,000 male births. Haemophilia A is caused by mutations in the factor IX (F9) gene.
Investigations carried out include familial mutation identification and interpretation, carrier diagnosis and prenatal diagnosis (PND).
Genetic PND may be performed early in pregnancy, usually via chorionic villus sampling (CVS) at 11 to 13 weeks of gestation. This allows first trimester diagnosis, avoiding late termination of pregnancy. The large majority of patients, following appropriate expert counselling, do not opt to terminate an affected pregnancy.
Genetic PND may also be performed in the third trimester of pregnancy, usually at about 36 weeks of gestation, by means of amniocentesis. This approach enables diagnosis of the presence or absence of a severe bleeding disorder in the fetus, facilitating important decisions about the clinical management of childbirth.
Genetic diagnosis of the causative mutation can provide important clinical information about the risk for inhibitor development associated with clotting factor replacement therapy. This may particularly be valuable in mild or moderate haemophilia A.
Knowledge of the causative mutation may influence diagnosis and clinical management in specific cases, for example genetic diagnosis of haemophilia B Leyden, where the onset of puberty leads to amelioration of the haemophilia phenotype, or the identification of mutations associated with a 1-stage/2-stage clotting factor VIII assay discrepancy in haemophilia A.
Von Willebrand Disease (VWD)
VWD, the most common of the heritable bleeding disorders, results from qualitative or quantitative deficiencies of von Willebrand factor (VWF). VWF has essential roles in platelet-dependent primary haemostasis, and as a carrier for coagulation factor VIII in the blood circulation. Inheritance of VWD is autosomal. The molecular biology of VWD is complex.
There are three main types of VWD. Type 1 VWD is the most common form of the disorder, resulting from a partial quantitative deficiency of VWF. Type 2 VWD results from VWF qualitative deficiencies, including type 2A, 2B, 2M and 2N VWD variants. Type 3 VWD is a rare, recessive, often severe bleeding disorder, the result of essentially complete quantitative deficiency of VWF.
Genetic diagnosis has an important role in type 3 VWD in carrier diagnosis, where this may not be achievable by phenotypic means, and in PND in affected families (as above for haemophilia A and haemophilia B). Genetic diagnosis also has a role in selected cases of type 2 VWD. Generally speaking there is little application of genetic diagnosis in type 1 VWD.
Heritable FXI deficiency is a rare bleeding disorder resulting from low functional levels of coagulation factor XI. Inheritance is autosomal. The estimated prevalence of major FXI deficiency (FXI:C ≤15 IU/dL) in most populations is about 1:1,000,000, however in Ashkenazi Jews it occurs in about 1:450 individuals.
Most bleeding in FXI deficiency is related to injury, although bleeding risk is unpredictable and not related to genotype. Some patients with major FXI deficiency do not bleed, others with partial FXI deficiency (FXI:C 16 to 60 IU/dL) may bleed.
Heritable FXI deficiency is caused by mutations in the factor XI gene (F11). Major FXI deficiency is generally associated with homozygosity or compound heterozygosity for F11 mutations. Partial FXI deficiency is usually associated with heterozygosity for mutations in F11. Genetic diagnosis has applications in family studies in FXI deficiency.
Heritable FVII deficiency is a rare bleeding disorder resulting from low functional levels of coagulation factor VII. It is characterised by autosomal recessive inheritance, and has a prevalence of about 1:500,000.
FVII deficiency is clinically a very heterogeneous disorder. Bleeding symptoms range in severity from asymptomatic, to mild (most cases), to lethal. A complete lack of FVII is considered to be incompatible with life.
F7 gene mutation(s) can be found in most cases of heritable FVII deficiency, however genotype does not correlate well with FVII level or with bleeding risk. Genetic diagnosis has limited utility in the clinical management of FVII deficiency, although it can have a role in PND in families (frequently consanguineous) with severe FVII deficiency.