STUDIES ON HEMOPHILIA-A IN SARDINIA BEARING ON THE PROBLEMS OF MULTIPLE ALLELISM, CARRIER DETECTION, AND DIFFERENTIAL MUTATION-RATE IN THE 2 SEXES

  • 1 January 1984
    • journal article
    • research article
    • Vol. 36  (1) , 44-71
Abstract
A large survey of hemophilia A carried out with almost complete ascertainment on Sardinia suggests that the variation of plasma levels of factor VIII coagulant activity in normal individuals is largely controlled by a series of normal isoalleles or by closely linked modifiers. This variation is expected to affect the laboratory detection of the hemophilia A (HA) heterozygotes in addition to the X-inactivation-dependent mosaicism and the type of deficient mutant present in a given pedigree. The Sardinian pedigrees yielded 13 new cases of nonrecombinants between the loci for HA and glucose-6-phosphate dehydrogenase (G6PD), as well as 4 nonrecombinants between HA and Deutan color blindness. These findings bring to a total of 58 the number of scorable sibs and nonrecombinants thus far known for the linkage HA-G6PD. The 90% upper limit of meiotic recombination between the 2 loci evidently is below 4%, thus justifying the application of the linkage diagnostic test for the detection of HA heterozygotes and the prenatal diagnosis of the hemophilic fetuses in families that segregate at both loci. In 3 of the 5 HA pedigrees of the series that also segregate for G6PD or Deutan color blindness, the observed segregation of the combined phenotypes can be best explained by assuming the occurrence of a fresh mutation in the maternal grandfathers. Such a finding points to a reevaluation of Haldane''s hypothesis of a possible higher incidence of X-linked mutations in the human male. Each of the issues addressed will be amenable to experimental verification as soon as suitable molecular probes become available to screen for common multiallelic DNA polymorphisms in the subtelomeric region of the X-chromosome long arm.