A novel case of compound heterozygosity with "Normandy"/type I von Willebrand disease (vWD). Direct demonstration of the segregation of one allele with a defective expression at the mRNA level causing type I vWD.

We report the case of a family with type I von Willebrand disease (vWD), characterized by a quantitative defect in von Willebrand factor (vWF), associated with a defective binding of vWF to factor VIII (FVIII) also called the "Normandy" variant of vWD. PCR products from genomic DNA of the family members were analysed in the region coding for the binding domain of vWF to FVIII. It showed that the proposita and one of her sons were heterozygous for the Arg91Gln missense mutation, abolishing an MspI restriction enzyme site located in exon 20. The transcription of the normal and mutated alleles was tested by the amplification of cDNA after reverse transcription of platelet mRNA in this region. A total lack of expression of the normal allele was observed in the proposita, who appeared as a compound heterozygous with one allele mutated at Arg91 and a "silent" expression of the other one. The segregation of the "silent" allele was studied in the family with the exonic BstEII RFLP both at the DNA and mRNA levels. The proposita has transmitted her "silent" allele to her daughter and to another son. As this son was informative for this RFLP, the absence of expression of the allele could be demonstrated at the mRNA level, providing evidence that this defect was responsible for his type I vWD.