Determination of haemophilia A carrier status by mutation analysis

A reliable method for determination of carrier status and genetic counselli ng is required for effective control of haemophilia. Linkage analysis is cu rrently the most widely used method for this purpose; however, in cases whe re there is no prior family history and/or unavailability of informative po lymorphic markers it is less applicable. Detection of a mutation characteri zed in each family may be an alternative method for determination of the ca rrier status. In this study, linkage analysis using four polymorphic DNA ma rkers, and direct mutation analysis were compared to determine the carrier status in six unrelated Thai haemophilia A families, two with a family hist ory and four without. In the two families with a family history of haemophi lia A, the carrier and noncarrier statuses could readily be determined in e ight females by either linkage or direct mutation analysis. In the four fam ilies without a family history, the polymorphic DNA markers for linkage ana lysis were informative in two families and uninformative in the other two. The carrier status could be excluded in all four female siblings of the pat ients in the former. However, the specific FVIII gene mutation was not obse rved in the mother of one patient, who should have carried the mutation. In the remaining two families with uninformative polymorphic DNA markers, the carrier and noncarrier statuses of four female members could only be deter mined by direct mutation analysis. Therefore, direct mutation analysis coul d circumvent the limitations of linkage analysis in the determination of ha emophilia A carrier status in families without a previous history or inform ative polymorphic markers.