Genetic mutation analysis of a pedigree with hereditary coagulation factor XII deficiency caused by two compound heterozygous mutations: Arg36Gln and Ala324Pro

Abstract

Objective To analyze the clinical phenotype and gene mutation of the genetic coagulation factor Ⅻ(FⅫ) deficiency pedigree and explore the molecular pathogenesis. Methods The activated partial thromboplastin time (APTT) and other blood coagulation test items of the proband and their family members (4 people of 2 generations in total) were tested on a Sysmexautomatic coagulometer. The activity of blood coagulation factor Ⅻ (FⅫ: C) was also tested on the instrument. The FⅫ antigen (FⅫ: Ag) was tested with ELISA method. Genomic DNA was extracted and all exons and flanks of F12 gene were determined by direct sequencing. The Clustalx and PolyPhen-2 online bioinformatics softwares were used to analyze the conservatism of amino acids at the mutation sites and whether the mutations were harmful. Results The APTT of the proband was prolonged to 55.0s. The FⅫ: C and FⅫ: Ag decreased to 19% and 21%, respectively. The APTT of the father, mother and sister were all prolonged compared to the normal. The FⅫ: C and FⅫ: Ag were almost half of the normal value. Gene sequencing found that the proband carried two heterozygous missense mutations, one was a chr5: 176833014C>T (c.164G>A) in exon 3, which led to Arg36Gln (p.R55Q)(NC_000005.10); the other was chr5: 176831083C>G(c.1027G>C), resulting in Ala324Pro(p.A343P) (NC_000005.10). Both father and sister caught the Arg36Gln heterozygous missense mutation and the mother found the Ala324Pro . Conclusion The Arg36Gln and Ala324Pro compound heterozygous mutations were the molecular pathogenesis of the congenital FⅫ deficiency pedigree. In addition, the Arg36Gln mutation was a novel mutation, which was the first report in the domestic and overseas. Key words: Blood coagulation factor Ⅻ deficiency; Gene mutation; Pedigree chart; Molecular pathogenesis