Recurrent mutations in haemophilia a give evidence for CpG mutation hotspots

Haemophilia A is a common disorder of blood coagulation caused by a deficiency of factor VIII¹. It is inherited as an X-linked recessive trait, and one-third of all cases are thought to result from de novo mutations². The clinical severity of haemophilia A varies markedly among different families and a subset of the patients with severe disease develop antibodies against factor VIII, called inhibitors³. Because of this heterogeneity, it is likely that many different molecular lesions result in haemophilia A. Indeed, of the nine mutations described to date, all appear to be unique changes^4-6. However in this study of 83 patients with haemophilia A we have identified two different point mutations, one in exon 18 and one in exon 22, that have recurred independently in unrelated families. Each mutation produces a nonsense codon by a change of CG to TG, and each occurred de novo on the X-chromosome donated by the maternal grandfather. These observations strongly support the view that CpG dinucleotides are mutation hotspots.