[Analysis of a pedigree affected with hereditary coagulation factor XI deficiency due to compound heterozygous variants of F11 gene].

To analyze the clinical phenotype and genetic basis for a Chinese pedigree affected with coagulation factor XI (FXI) deficiency. Activated partial thromboplastin time (APTT) and other blood coagulation factors, and activities of FXI:C and other relevant coagulation factors for a large Chinese pedigree including 6 patients from 3 generations were determined on a Stago automatic coagulometer. The FXI:Ag was determined with an ELISA method. All exons and flanking regions of the F11 gene were subjected to Sanger sequencing. ClustalX-2.1-win software was used to analyze the conservation of amino acids. Pathogenicity of the variants was predicted with online bioinformatics software including Mutation Taster and Swiss-Pdb Viewer. The APTT of the proband was prolonged to 94.2 s. The FXI:C and FXI:Ag were decreased to 1% and 1.3%, respectively. The APTT of her father, mother, son and daughter was 42.1 s, 43.0 s, 42.5 s and 41.0 s, respectively. The FXI:C and FXI:Ag of them were almost halved compared with the normal values. The APTT, FXI:C and FXI:Ag of her husband were all normal. Genetic testing revealed that the proband has carried a heterozygous missense c.1103G>A (p.Gly350Glu) variant in exon 10 and a heterozygous missense c.1556G>A (p.Trp501stop) variant in exon 13 of the F11 gene. The father and daughter were heterozygous for the c.1103G>A variant, whilst the mother and son were heterozygous for the c.1556G>A variant. Both Gly350 and Trp501 are highly conserved among homologous species, and both variants were predicted to be "disease causing" by Mutation Taster. Protein modeling indicated there are two hydrogen bonds between Gly350 and Phe312 in the wild-type, while the p.Gly350Glu variant may add a hydrogen bond to Glu and Tyr351 and create steric resistance between the two, both may affect the structure and stability of protein. The c.1103G>A and c.1556G>A compound heterozygous variants probably underlay the pathogenesis of congenital FXI deficiency in this pedigree.