A FOUNDER FACTOR VIII MUTATION, VALINE 2016 TO ALANINE, IN A POPULATION WITH EXTRAORDINARILY HIGH PREVALENCE OF MILD HEMOPHILIA A

Y.G. Xie1,2,3, H. Zheng1, D. Macgregor2, J. Leggo4, R. Bagnell5, P. Green5, B. Fernandez2, D. Robb1, M.-F. Scully6, D. Lillicrap

Disciplines of 1 Laboratory Medicine; 2 Genetics; 3 Pediatrics; 6 Medicine, Memorial University of Newfoundland, St. John's, NF, Canada; 4 Dept. of Pathology, Queen's University, Kingston, ON, Canada
5 King's and St. Thomas' School of Medicine, London, UK

An extremely high prevalence of mild hemophilia (approximately 70 in 3,300 males) has been identified in an isolated and rural Newfoundland population suggesting the strong possibility of a causative founder effect. The clinical presentation, plasma FVIII : C levels in affected individuals (0.11-0.25 U/ml) and X linked pattern of inheritance were all compatible with a mild form of hemophilia A. The high prevalence of hemophilia A in a small population raises the potential of a founder effect from one, or at the very most, a small number of factor VIII mutations. Understanding of the molecular nature of the mutation in this population will bring a long term the potential long-term benefit to the community.
To investigate the molecular nature of the mutation in this population, we performed a mutation screening of the FVIII gene in a panel of the selected patients with known clinical status. The entire coding region, the splice sites and the 5 and 3 non-coding regions of the FVIII gene have been analyzed by using the methods of conformation sensitive gel electrophoresis (CSGE) and direct sequencing. A single missense mutation, resulting in a Valine (GTG) to Alanine (GCG) substitution at codon 2016 in exon 19 was identified in all affected patients tested, but in none of their normal siblings or in population controls.
Factor VIII polymophic haplotype analysis appears to be consistent with a founder effect. This mutation has been reported in 5 other patients, all living within a 50 miles radius of in South East England. Haplotype analysis of four of these five British patients has shown that they share the same polymorphic background BclI+/intron 22:27 repeats but that this haplotype is distinct from the Newfoundland haplotype, BclI+/intron 22:19 repeats. This information suggests that the codon 2016 missense mutation has arisen independently in the two geographically distinct locations. Further characterization of this mutation will enable a quick and economic method for screening individuals at-risk in this unique population. Long-term benefits will include accurate carrier detection for at-risk women and early diagnosis of affected patients. Studies of genotype/phenotype correlation and possible gene modifiers are currently under consideration.

This project has been supported by Aventis Behring Canada Research Fund and Janeway Foundation Research Grant.

Presented in the XVIIIth Congress of the International Society on Thrombosis and Haemostasis.