Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable clinical severity. In contrast to haemophilia A or B the clinical symptoms do not correlate well with plasma levels of factor XI; it is therefore difficult to predict the bleeding tendency from either the factor level or the molecular defect. FXI deficiency is particularly common in the Ashkenazi Jews with a heterozygous frequency of ~9%, associated with two common founder mutations - E117X (Type II) and F283L (Type III). Recent studies have shown that mutations causing Factor XI deficiency are heterogeneous outside the Ashkenazi Jewish population. We have studied 116 index cases from an ethnically diverse U.K. population in order to better understand the spectrum of mutations responsible for factor XI deficiency. Of the index cases, 25 were of Ashkenazi Jewish ancestry, 2 were of Afro-Caribbean origin, 9 Asian, 3 Arabic, 1 New Zealand Maori and 73 white Caucasian; ancestry was unknown in three patients. We have identified a total of 141 causative mutations in 107 patients. Of the nine patients in whom a mutation remained unidentified, six were reproducibly factor XI deficient with no evidence of inhibitors, but in three the diagnosis was inconclusive. The 141 mutations included 54 different sequence variants and 5 whole gene deletions of which there are at least two forms. Of the variants, forty-one are missense mutations, eight nonsense mutations, four splice site mutations and one small deletion. Twenty-seven of these varients are novel and reported here for the first time. Three common mutations were identified, with similar frequencies. The Type II mutation (E117X) accounted for 14.9% of the total mutations, the Type III mutation (F283L) 12.1% and the C128X “UK mutation” 11.3%. Together these three mutations account for more than a third (38.3%) of the total. Outside of these three ‘common’ mutations, no other mutation was identified in more than 3 individuals. Despite the heterogeneous nature of factor XI mutations, with mutations being identified in all 15 exons of the factor XI gene, almost two thirds (65%) of the mutations could be covered in just 3 amplicons - exons 5, 15 and 8/9/10. All patients with Ashkenazi Jewish ancestry had Type II and/or Type III mutations. Three Jewish patients were compound heterozygous for the Type II mutation and another ‘non-Jewish’ mutation. One Arabic patient was homozygous for the Type II mutation. The C128X mutation was only identified in patients with a clear British ancestry. However, not all repeat mutations were restricted to a single ethnic group. Four mutations were identified in more than one ethnic group, three of which were located at CpG sites.
This study confirms the ethnic and molecular heterogeneity of factor XI deficiency despite its historical association with the Ashkenazi Jewish population and the Type II & Type III mutations. Our study also reinforces the difficulty of predicting clinical phenotype from molecular defect in factor XI deficiency.