Genetic analysis in Factor XI deficient patients from central China: Identification of one novel and seven recurrent mutations

• Confirm the diagnosis of FXI deficiency by molecular genetic tests
• FXI levels and TGT cannot distinguish bleeders from non-bleeders.
• Further proof for pathology of the F11 p.Thr40Ile variant
• F11 p.Thr40Ile causes FXI deficiency by impairing protein secretion and function.
• F11 p.Thr40Ile do not produce a dominant-negative effect.

Factor XI (FXI) deficiency is a rare bleeding disorder with a range of manifestations from asymptomatic to trauma related bleeding. To identify mutations in FXI-deficient patients and characterize the phenotype–genotype relationship, we studied six patients and their 18 family members in central China. Five patients were identified by presurgical or routine laboratory screening but had no bleeding symptoms. Only one patient exhibited excessive injury- and surgical-related bleeding. Eight mutations were detected, including five nonsense mutations (p.Tyr369*, p.Arg72*, p.Gln281*, p.Trp519*, and p.Trp246*), two missense mutations (p.Thr40Ile and p.Ala430Thr), and a 4-bp deletion in a splice site (c.1136-4delGTTG); one mutation was novel (p.Thr40Ile). In vitro, the p.Thr40Ile mutant protein exhibited impaired secretion and function. Five of the patients were homozygous or compound heterozygous, but only one nonsense mutation was found in Patient 2. In these patients, bleeding tendency was not correlated with FXI levels or with a single heterozygous mutation. Thrombin generation tests could not distinguish the bleeder from non-bleeders. In conclusion, we reported 8 mutations in the FXI gene (F11) leading to FXI deficiency. Moreover, the functional consequences of a novel mutation leading to FXI deficiency have been elucidated. More cases are needed to find any signature of founder effect in the Chinese population and its potential relationship with other Asian population.