Correlation of Genotype and Phenotype in Congenital FXI Deficiency

Background: Factor XI is a plasma glycoprotein responsible for thrombin generation on the surface of activated platelets. Factor XI deficiency, indicated by a decrease in the activity of FXI in plasma, is a RBD inherited in an autosomal-recessive trait. It is associated with mild to moderate, mostly injury-related bleeding diathesis.

Materials and methods: Over 10 years 180 unrelated patients (IP) with FXI-deficiency were screened for causative mutations in the F11. All 15 exons and flanking regions of the F11 gene were amplified and directly sequenced from genomic DNA. MLPA was performed following the manufacturer's instructions.

Results: Patient: 180 IPs (FXI:C 1–70IU/dl) were screened for causative mutations in the F11. 146 IPs showed genetic defects (in total 189 mutations), with an overall mutation detection rate (MDR) of 84%. In 36 IPs no any genetic alterations were detected. In 37 IPs the factor XI deficiency causative mutation was confirmed in additional family members. 40 patients presented with severely reduced FXI:C (< 20IU/dl), 106 patients showed variable FXI:C levels ranging from 20 to 70IU/dl. Mutation profile: All causative mutations, except one were localized within the F11 coding region and intron/exon boundaries: missense mutations -104 (55%), nonsense mutations - 53(28%), small deletions/ insertions - 22 (11%), spice-site mutations - 9 (5%). Heterozygous large deletion of the whole F11 was detected in one patient. From 40 patients with severe FXI-deficiency 18 patients were homozygous, 24 compound heterozygous. 3 patients with moderate FXI-deficiency were compound heterozygous (probable both defects are localized on the same allele). Mutations were distributed along the whole F11 without clustering to any exons. Two nonsense mutations were detected with high recurrence - p.Glu135Stop in exon 5 and p.Glu135Stop in exon 9.

Discussion: The diagnosis of inherited factor XI deficiency is often challenging because of high variability of clinical symptoms and poor correlation between the factor XI plasma levels and bleeding phenotype. Thus, genetic testing is an important tool in the diagnostic process. A high mutation detection rate was found in our cohort and a correlation of FXI:C and availability of genetic defect was demonstrated.

No conflict of interest has been declared by the author(s).