Carrier detection and prenatal diagnosis in families with haemophilia

Abstract

Background: Haemophilias are the commonest X-linked disorders affecting approximately 1 in 10,000 male births. Detection of carrier women in families with haemophilia and subsequent antenatal diagnosis of confirmed carriers are important services for these patients and their relatives. Over the last 6 years we performed carrier detection and antenatal diagnosis in families with patients of haemophilia A and B.

Methods: During the last 6 years, 159 families with haemophilia A and B were analysed for carrier detection by DNA analysis, using various polymorphic markers of factors VIII and IX genes. The polymorphisms used were intron 18 Bcl I, intron 19 Hind III, intron 22 Xbal and DXS52/St14 of the factor VIII gene and intron I Ddel, intron 4 Taql, 3 Hhal and Residue 148 codon Mnll of the factor IX gene. There were 189 probable carriers (whose carrier status was not known) and 99 obligatory carriers (confirmed carriers by family pedigree analysis) from 102 families with haemophilia A. Of the 57 families with haemophilia B analysed, there were 98 probable and 52 obligatory carriers. All the analyses were carried out by polymerase chain reaction. For antenatal diagnosis, prior to polymorphism analysis, the sex of the foetus was detected by Y chromosome-specific amplification.

Results: One hundred and four females were diagnosed as carriers and 63 as non-carriers by the intragenic polymorphic markers in families with haemophilia A. Eighteen women were informative with only the extragenic marker of factor VIII gene. Four women were not informative with any of the markers used. In families with haemophilia B, 37 women were diagnosed as carriers and 34 as non-carriers by the intragenic markers and 34 were informative only with the extragenic markers. Seventeen women were not informative with any of the markers used. Of the 25 antenatal diagnoses performed (20 haemophilia A, 5 haemophilia B) using the same markers as those used in carrier detection, 14 were male foetuses and 11 female as detected by Y chromosome-specific polymerase chain reaction. Eight were affected males and 6 unaffected. Among the females, 5 were carriers and 6 normal.

Conclusion: Using the above polymorphic markers of factors VIII and IX genes, a diagnosis could be made in the majority of families.