Molecular Genetics of Hemophilia A (Factor VIII Deficiency)

The X-linked coagulation disorder, hemophilia A, is due to mutations in the Factor VIII gene (FVIII). The disease affects about 1/5,000 males and has a severity ranging from mild to severe. The gene is located at Xq28 and comprises 26 exons spanning about 186 Kbp. Aside from the common intron 22 inversion found in about 50% of severe hemophilia A (discussed below), the mutations found in this disorder are heterogeneous {Goodeve et al., (1994) Lancet 343:329-330; Becker et al., (1996) Am. J. Hum. Genet. 58:657-670}.

Mutation heterogeneity makes it laborious to screen the gene for a family specific mutation. After a negative result for the presence of the intron 22 inversion, linkage analysis using a variety of highly polymorphic flanking and intragenic markers is indicated. This test requires appropriate individuals in the family and should be undertaken only after consultation with CompGene.

The presence of the intron 22 inversion mutation simplifies the identification of carrier females related to affected males. As depicted in the Southern blot analysis below, lane 1 shows the DNA fragment pattern detected in the sister of an affected male while lane 2 shows the DNA fragment pattern observed in her affected brother. The sister shows the normal pattern while her affected brother carries the common, distal intron 22 inversion. Their mother shows a combination of both fragment patterns consistent with her being a carrier of the distal rearrangement. Approximate sizes of the detected DNA fragments are indicated.