Hemophilia A: genetic prediction and linkage studies in all available families in Finland

RFLP studies were done in 82 (75%) of all known hemophilia A families in the Finnish population (approximately 5 million). Two intragenic RFLPs (BcII/F8A, Xbal/p482.6) and two extragenic markers (Taql/St14, BglII/DX13) were used. Among 263 females at risk, carriership could be evaluated with an intragenic marker in 47% and with an extragenic marker in 26%. In 27% of the females, carriership could be neither excluded nor confirmed; 68% of these females were relatives of an isolated patient. Eight recombinations between the factor VIII gene (F8C) and DXS52 (lod 25.02 at θ max 0.06), eight recombinations between F8C and DXS15 (lod 21.91 at θ max 0.05), and two recombinations between DXS52 and DXS15 (lod 33.56 at θ max 0.01) were found. Using multipoint linkage analysis, the most likely order of loci supported by the data was: F8C‐DXS15‐DXS52‐DXS134. RFLP segregation analysis provides a highly useful method of carrier detection and prenatal diagnosis of hemophilia A, but its limitations must be carefully taken into account.