Exploring the global landscape of genetic variation in coagulation factor XI deficiency

Rosanna Asselta, Elvezia Maria Paraboschi, Valeria Rimoldi, Marzia Menegatti, Flora Peyvandi, Ophira Salomon and Stefano Duga

Key points

  • Exome-data analysis revealed that FXI deficiency is from two to twenty times more frequent than expected in most populations.

  • Exome-data analysis evidenced novel recurrent and ethnic-specific mutations other than the well-known type-II and type-III defects.


Factor XI (FXI) deficiency is an autosomal bleeding disorder, usually post trauma or surgery, characterized by reduced levels of coagulation FXI in plasma. The disease is highly prevalent in Ashkenazi Jews (heterozygote frequency ~9%), whereas it is considered a rare condition in most populations (prevalence of the severe deficiency: 1:106 in Caucasians). So far, >190 causative mutations have been identified throughout the F11 gene. To have a global landscape of genetic variation of F11, we explored publicly-available exome-based data obtained from >60,000 individuals belonging to different ethnicities (Exome Aggregation Consortium resource). This analysis revealed profound differences in heterozygote frequencies among populations [African allele frequency (AF)=0.0016; East-Asian AF=0.0045; European AF=0.0036; Finnish AF=0.00030; Latino AF=0.0021; South-Asian AF=0.0015], and a prevalence significantly higher than that reported so far (e.g. the calculated prevalence of the severe deficiency in Europeans would be: 12.9 in 106). In addition, this analysis allowed us to evidence recurrent and ethnic-specific mutations: i) p.Phe223Leu in Africans (23.5% of all mutated alleles), p.Gln263X and p.Leu424CysfsX in East Asians (28.2 and 20.5%, respectively), and p.Ala412Thr in Latinos (25%).

  • Submitted April 18, 2017.
  • Accepted June 12, 2017.