A Novel Heterozygous Point Mutation Causing Coagulation Factor XII Deficiency as the Molecular Mechanism of Fatal Thrombosis Event in a Chinese Pedigree.

Objective: To study on the laboratory diagnosis and molecular mechanism of a pedigree with fatal cerebral thrombosis event caused by hereditary coagulation factor XII deficiency.

Methods: Activated partial thromboplastin time (APTT), prothrombin time (PT), coagulation factor VIII activity (FVIII:C), factor IX activity (FIX:C), factor XI and factor XII activity (FXI:C and FXII:C) were determined in the propositus and the other kindred member for phenotypic analysis. All the 14 exons and their flank sequences of factor XII gene form the propositus were amplified by PCR. The purified PCR products were sequenced directly. After mutation was found, the corresponding gene fragments covering the mutated point from the other member of the kindred were amplified and sequenced.

Results: The APTT of the propositus was significantly elongated (>120 seconds), while her PT was normal. Her FVIII:C,FIX:C and FXI:C were all normal. But her FXII:C was only 1 %, lower than normal. A heterozygous G3774C missense mutation in exon 4 was identified, which has led to the substitution of serine (TCT) 73 for cysteine (TGT). The sequencing results from the pedigree suggested that the other asymptomatic member of the kindred also had the same heterozygous mutation.

Conclusion: The Propositus was diagnosed with inherited coagulation factor XII deficiency. The novel gene mutation found in this pedigree is the molecular mechanism leading to the fatal thrombosis events in the propositus.