De novo mutation causing sporadic type 2A von Willebrancd's disease: report of three cases

Summary. Chemical mismatch detection has been used to screen selectively part of the A2 domain of exon 28 of the von Willebrand factor gene of three unrelated patients with apparently sporadic type 2A von Willebrand disease (vWD) and their parents and siblings. Mismatches have been defined by DNA sequencing and mutations authenticated by restriction enzyme analysis. While a mutation was identified in all three patients, no evidence of mutation could be found in their asymptomatic/un-affected parents or siblings, proving the disease to be truly sporadic in these cases. Of these, two with severe clinical bleeding had a serine 743 to leucine substitution while the third patient with clinically less severe bleeding had an arginine 834 to tryptophan substitution. The possible genetic mechanisms for sporadic type 2A vWD in these families are discussed.