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  • Author: Federica Zarrilli x
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Background: Haemophilia A and B (HA, HB) are the most frequent X-linked bleeding diseases; two-thirds of cases are severe.

Methods: We counselled 51 couples for prenatal diagnosis (PD) of haemophilia. In 7/51 (13.7%) cases, the couple decided not to undergo PD because counselling revealed that they were carriers of a mild form of the disease, while we performed 44 PD for severe HA (36 cases) or HB (8 cases). The indication for PD was a haemophilic child (30/44, 68.2%) or an affected family member (12/44, 27.3%); in two cases the non-carrier mother of isolated haemophilic patients requested PD because of the risk of mosaicism.

Results: We completed PD in 43/44 cases; in one case, the prenatal sample was contaminated by maternal DNA; however, molecular analysis revealed the female sex of the foetus. We performed PD for 16 of the 36 couples at risk of HA (44.4%) by analysing the intron (IVS)22 inversion; in 1/36 cases (2.8%) the mother had the IVS1 inversion, and in 8/36 (22.2%) the family mutation was identified by sequencing; in 11/36 (30.6%) cases the family mutation was unknown, and PD was performed by linkage (no recombination nor uninformative cases occurred). For HB, in 6/8 (75.0%) cases, PD was performed by DHPLC or by sequencing; in 2/8 cases we tested intragenic markers (again with no cases of recombination or uninformative families).

Conclusions: PD in well-equipped laboratories, and multidisciplinary counselling are an aid to planning reproductive and early therapeutic strategies in families with severe haemophilia.


Haemophilia A is the most common inherited bleeding disorder caused by defects in the F8C gene that encodes coagulation factor VIII. This X-linked recessive disorder occurs in approximately 1:5000 males. Haemophilia A is diagnosed based on normal prothrombin time, altered activated partial thromboplastin time and reduced factor VIII activity in plasma. Carrier females are usually asymptomatic and can be identified only by molecular analysis. The most frequent mutations in F8C are intron 22 and 1 inversions, which occur in approximately 50% and 5% of patients, respectively, with a severe phenotype. Large gene deletions are observed in approximately 5% of alleles from patients with severe haemophilia A. The remaining severe cases and all moderate and mild cases result from numerous point mutations and small insertions/deletions, which are de novo mutations in one-third of cases. Thus, molecular diagnosis of carrier status and prenatal diagnosis in families without intron 22 or 1 inversions is based on scanning techniques or gene sequencing. When the disease-causing mutation cannot be identified, molecular diagnosis is performed by linkage analysis of several DNA polymorphic markers linked to F8C. Given the clinical heterogeneity among haemophilic patients, many groups, including our own, have examined the relationships between prothrombotic gene variants and haemophilic phenotype to investigate whether prothrombotic gene variants modify clinical expression of the disease.

Clin Chem Lab Med 2007;45:450–61.