High incidence of FXI FXI deficiency in a Spanish town caused by 11 different mutations and the first duplication of F11 F11 : Results from the Yecla study

摘要

Introduction Factor XI ( FXI ) deficiency is a rare disorder with molecular heterogeneity in Caucasians but relatively frequent and molecularly homogeneous in certain populations. Aim To characterize FXI deficiency in a Spanish town of 60?000 inhabitants. Methods A total of 324?764 APTT tests were screened during 20?years. FXI was evaluated by FXI :C and by Western blot. Genetic analysis of F11 was performed by sequencing, multiplex ligation‐dependent probe amplification and genotyping. Results Our study identified 46 unrelated cases and 170 relatives with FXI deficiency carrying 12 different genetic defects. p.Cys56Arg, described as founder mutation in the French‐Basque population, was identified in 109 subjects from 24 unrelated families. This mutation was also identified in 2% of the general population. p.Cys416Tyr, c.1693GA and p.Pro538Leu were identified in 7, 6 and 2 unrelated families, respectively. NGS analysis of the whole F11 gene revealed a common haplotype for each of the four recurrent mutations, suggesting a founder effect. The analysis of plasma FXI of four p.Pro538Leu homozygous carriers revealed that this variant was not activated by FXII a. We identified four mutations previously described in other Caucasian subjects with FXI deficiency (p.Lys536Asn; p.Thr322Ile, p.Arg268Cys and c.325GA) and four new gene defects: p.(Cys599Tyr) potentially causing a functional deficiency, p.(Ile426Thr), p.(Ile592Thr) and the first worldwide duplication of 1653?bp involving exons 8 and 9. Bleeding was rare and mild. Conclusions Our population‐cohort study supplies new evidences that FXI deficiency in Caucasians is more common than previously thought and confirmed the wide underlying genetic heterogeneity, caused by both recurrent and sporadic mutations.