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F11 Gene Duplication Causes Elevated FXI Plasma Levels and Is a Risk for Venous ThrombosisFunding This work was supported by KU Leuven BOF grant C14/19/096, FWO grant G072921N, and research grants from Novo Nordisk, CSL Behring, Bayer, and Swedish Orphan Biovitrum AB (Sobi).
Coagulation factor XI (FXI) is the zymogen of a plasma protease encoded by F11 located on 4q35.2 and is mainly synthesized by hepatocytes.  FXI is activated by coagulation factor XIIa and plays an important role in the intrinsic coagulation pathway of thrombin generation resulting in fibrin clot formation.  Bleeding problems can be due to FXI deficiency, but without clear correlations between FXI plasma levels and bleeding severity. FXI deficiency is a rare disorder (1 in 1 million in white population) but with a higher prevalence in some ethnic groups, for instance 9% in Ashkenazi Jews. In contrast, elevated plasma FXI levels are correlated with a higher risk for venous thromboembolism (VTE) and ischemic stroke.    There is no clear correlation between FXI levels and their contribution to myocardial infarction. Different reports describe an association between genetic variability in F11 locus and venous thrombosis with elevated FXI levels.  These genetic factors are noncoding frequent single nucleotide polymorphisms (SNPs) located in F11 introns, e.g., rs2036914 and rs2289252.   Due to these insights related to a potential prothrombotic role of FXI, there is a growing interest in targeting FXI with new anticoagulant therapies.
We here describe a family with inherited thrombophilia ([Fig. 1A]). The 58-year-old proband (II.6) with a history of recurrent VTE and negative routine thrombophilia laboratory screening was screened in the ThromboGenomics study using a targeted panel for known genes associated with bleeding and thrombosis. A F11 duplication was found while no other pathogenic variants could be detected in known thrombophilia genes ([Fig. 1B]). As only F11 exonic regions were captured, the exact size of the duplication remains unknown but it involves at least the complete F11 gene (arr[GRCh37] 4q35.2:(187185980–187209984)x3). Co-segregation analysis of this duplication was performed in the family using real-time polymerase chain reaction to calculate the gene dosage ratio for F11 and its neighboring genes FGG and KLKB1 (upstream) and FAT1 (downstream) ([Fig. 1C], [Supplementary Table S1], available in the online version). In addition, the F11 gene duplication was confirmed in the proband (II.6) and his brother (II.5) using Multiplex Ligation-dependent Probe Amplification (MLPA). For this, 300 ng of DNA from II.5 and II.6 and four normal control samples were assayed using the MRC-Holland MLPA kit for the F11 gene (SALSA MLPA Probemix P440-A2 F10 + F11) as per manufacturer's instructions. Fragments were analyzed using an ABI 3730XL sequencer and interpreted using GeneMarker software (SoftGenetics).
FXI plasma activity levels were measured with the ACL TOP analyzer (Werfen, Brussels, Belgium) according to the manufacturer's recommendations. For patients receiving direct oral anticoagulant (DOAC) therapy, sample pretreatment with DOAC-STOP (Nodia, Boom, Belgium) was performed. The normal range for FXI was 70 to 130%. Control experiments showed that pretreatment of the samples with DOAC-STOP did not bias the FXI assay (data not shown). All five family members (I.2, II.5, II.6, II.8, III.5) carrying the F11 duplication have elevated FXI plasma levels ([Fig. 1A]). The proband (II.6) and his brother (II.5) both had a history of unexplained VTE while his sister (II.8) had no history of thrombosis ([Supplementary Table S2], available in the online version). Their mother (I.2) had pulmonary embolism at the age of 70. Patient III.5, a 30-year-old woman, had no history of thrombosis. Remarkably, elevated FXI levels were also measured for III.2 and IV.1, who have no F11 duplication ([Fig. 1C]). The 33-year-old woman III.2 is healthy while her daughter (IV.1) presented with a neonatal arteria cerebri media infarct with subarachnoid and plexus choroideus hemorrhage. Her FXI level was normal for age at birth (65%), while it was temporary elevated (155%) at the age of 3 years but normalized on a control sample (99%). She carried no pathogenic variants in any of the known thrombosis and hemostasis genes using a panel test. Sanger sequencing of F11 SNP rs3733403, rs3756011, and rs2289252 in members of this pedigree showed that II.3 and III.2 inherited the other F11 allele from affected (grand)mother I.2 than the allele present in index case II.6 and the other family members with duplicated F11 ([Fig. 1A], [Supplementary Table S3], and [Supplementary Figs. S1]–[S3], available in the online version). Family members III.7 and III.8 with normal FXI levels and no F11 deletion carried other F11 SNP than their affected father and mother, respectively, pointing out the presence of frequent chromosomal rearrangements on the duplicated F11 allele. The genetic variant rs2289252 was previously associated with elevated FXI levels and contributed to the risk of VTE, but these values were never higher than the upper value of the normal range.  
This report is the first described case of a family with F11 gene duplication leading to elevated FXI activity levels. As described above, these increased FXI activity levels can be an additional risk factor for thrombosis. In this family the presence of F11 gene duplication is important for thrombophilia risk management.
Received: 31 May 2021
Accepted: 05 October 2021
Article published online:
15 November 2021
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