Type I mutation in the F11 gene is a third ancestral mutation which causes factor XI deficiency in Ashkenazi Jews

Background Factor XI (FXI) deficiency is one of the most frequent inherited disorders in Ashkenazi Jews (AJ). Two predominant founder mutations termed type II (p.Glu117Stop) and type III (p.Phe283Leu) account for most cases. Objectives To present clinical aspects of a third FXI mutation, type I (c.1716+1G>A), which is also prevalent in AJ and to discern a possible founder effect. Methods Bleeding manifestations, FXI levels and origin of members of 13 unrelated families harboring the type I mutation were determined. In addition, eight intragenic and five extragenic polymorphisms were analyzed in patients with a type I mutation, in 16 unrelated type II homozygotes, in 23 unrelated type III homozygotes and in Ashkenazi Jewish controls. Analysis of these polymorphisms enabled haplotype analysis and estimation of the age of the type I mutation. Results Four of 16 type I heterozygotes (25%) and 6 of 12 (50%) compound heterozygotes for type I mutation (I/II and I/III), or a type I homozygote had bleeding manifestations. Haplotype analysis disclosed that like type II and type III mutations, the type I is also an ancestral mutation. An age estimate revealed that the type I mutation occurred approximately 600years ago. The geographic distribution of affected families suggested that there was a distinct origin of the type I mutation in Eastern Europe. Conclusions The rather rare type I mutation in the FXI gene is a third founder mutation in AJ.