Carrier detection in the haemophilias

Haemophilia A: 44 families with Haemophilia A have been studied comprising 107 males and 125 females. In 22 families there was only a single isolated affected male whilst in the remaining 22 there was a family history of haemophilia. Of the males 53 were haemophiliacs and of these 37 had severe disease (VIII:C <0.01iu/dl), 7 had moderate disease (VIII:C >0.01 but <0.05iu/dl) and 9 had mild disease (VIII:C >0.05iu/dl). From pedigree analysis 40 women could be established as obligatory carriers, 5 women were considered to be normal and the remaining 80 women were potential carriers. Phenotypic analysis using assays of VIII:C, vWF:Ag, vWF:RCo and the ratios VIII:C/vWF:Ag and VIII:C/vWF:RCo were used to predict carriership and the results compared to those obtained using genotypic analysis with 3 intragenic (Bel I, Bgl I, Xba I) and 2 extragenic (Taq I, Bgl II) restriction fragment length polymorphisms. A control group of 31 age-matched normal females and obligatory carriers was used to establish 'cut-off values for the VIII:C/vWF:Ag and VIII:C/vWF:RCo ratios which correctly classified all of the normal women. Evaluation of this 'cut-off value in the control group demonstrated the VIII:C/vWF:Ag ratio to be 'superior' to the VIII:C/vWF:RCo ratio correctly classifying 65.2% of the obligate carriers compared to only 21.7% using the VIII:C/vWF:RCo ratio. Within the study, of the 40 obligate carriers identified by pedigree analysis, coagulation data was available on 37. Using the VIII:C/vWF:Ag ratio, 21/37 (56.8%) were shown to have an abnormal coagulation phenotype and 16 to have a normal phenotype. Phenotypic analysis of the 80 potential carriers identified within the study showed 27 to have an abnormal coagulation phenotype suggesting carriership, 47 to be normal and in 6 no data was available. Genotypic analysis established 23 of the obligate carriers as informative for one or more of the intragenic polymorphisms, 15 as informative for a linked polymorphism and 2 women were non-informative. Of the 80 potential carriers genotypic analysis alone confirmed 7 as carriers, excluded carriership in 31 but in 42 women carrier status could not be established. However using combined phenotypic/genotypic analysis 10 of this latter group were identified as carriers. Overall, therefore, 48/80 (60%) potential carriers could be offered accurate genetic counselling. In 8 of the 22 families in which there was only a single isolated affected male, RFLP analysis implicated the maternal grandfather as a possible origin for the mutation in 5 cases. Three families were identified in which a recombination between the DXS15 and Bel I loci had occurred giving an overall recombination rate of 7.5%. Significant linkage disequilibrium was demonstrated between the Xba I, Bel I and Bgl I loci. Prenatal diagnosis using intragenic RFLP's was available to 33/89 women; using linked, RFLP's and fetal blood sampling to a further 39 women and finally to 17 women using fetal blood sampling alone. Haemophilia B: 5 families with haemophilia B have been studied comprising 11 males and 12 females. Of the males, 4 were haemophiliacs (IX:C >0.01iu/dl) and the remainder normal. Of the 12 females, 3 could be classified as obligate carriers, 8 as potential carriers and 1 as a probable haemophilic female. Although the mean IX:C for the obligatory carriers was lower than that of a control group, there was a considerable overlap of values. Only limited phenotypic data was available but 2 of 3 obligate carriers and 3 of 4 potential carriers had IX:C assays below the lowest value obtained in a control group of 15 normal women. No CRM+ families were identified. Three intragenic polymorphisms (Taq I, Xmn I and Dde I) were used for gene tracking studies. Genotypic analysis established 2 potential carriers as carriers and demonstrated informative polymorphisms in 3 obligatory carriers. All 'at-risk' women could be offered prenatal diagnosis using one of the intragenic polymorphisms. Studies on the single haemophilic female showed her to be an XO/XX'nv mosaic and additionally demonstrated a 76Valine Glycine mutation in one FIX gene. Adrenoleukodystrophy: Carrier detection, using the FVIII RFLP's was undertaken in a single family with X-linked ALD. The findings confirmed a suspected male as affected and an 'at-risk' female as unlikely to be a carrier. Additionally, a recombination between the DXS15 and DXS52 loci was suspected.

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