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

Autor: Esteban, J, de la Morena-Barrio, ME, Salloum-Asfar, S, Padilla, J, Minano, A, Roldan, V, Soria, JM, Vidal, F, Corral, J, Vicente, V
Rok vydání: 2017
Předmět:
Zdroj: HAEMOPHILIA
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname
ISSN: 1351-8216
Popis: IntroductionFactor XI (FXI) deficiency is a rare disorder with molecular heterogeneity in Caucasians but relatively frequent and molecularly homogeneous in certain populations. AimTo characterize FXI deficiency in a Spanish town of 60000 inhabitants. MethodsA total of 324764 APTT tests were screened during 20years. 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. ResultsOur 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.1693G>A 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 FXIIa. We identified four mutations previously described in other Caucasian subjects with FXI deficiency (p.Lys536Asn; p.Thr322Ile, p.Arg268Cys and c.325G>A) and four new gene defects: p.(Cys599Tyr) potentially causing a functional deficiency, p.(Ile426Thr), p.(Ile592Thr) and the first worldwide duplication of 1653bp involving exons 8 and 9. Bleeding was rare and mild. ConclusionsOur 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.
Databáze: OpenAIRE
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