Congenital factor XI deficiency caused by a novel F11 missense variant: a case report

Jerčić, Kristina Gotovac; Blažeković, Antonela; Hančević, Mirea; Bilić, Ervina; Borovečki, Fran

doi:10.3325/cmj.2020.61.62

Cited by 2 publications

(2 citation statements)

References 9 publications

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“…In two patients (RBDS0025 and RBDS0045), candidate variants were only identified in coagulation factor genes ( F8 , F11 , VWF ), explaining the bleeding but not the platelet function alterations. In fact, approximately 25% of hemophilia A carriers with FVIII levels > 50% have been found to have an increased bleeding tendency, 39 while Gotovac Jerčić et al 40 reported the case of a woman with FXI deficiency (FXI = 49%) carrying a heterozygous F11 variant who presented menorrhagia, easy bruising, and excessive bleeding during surgery. Finally, patient RBDS0013 had a novel missense variant in ITGA2 , which was recently associated with platelet-type bleeding disorder-9 (OMIM %614200).…”

Section: Discussionmentioning

confidence: 99%

Gaining Insights into Inherited Bleeding Disorders of Complex Etiology in Pediatric Patients: Whole-Exome Sequencing as First-Line Investigation Tool

Bandini,

Borràs,

Berrueco

et al. 2023

Thromb Haemost

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Introduction Investigation of the molecular basis of inherited bleeding disorders (IBD) is mostly performed with gene panel sequencing. However, the continuous discovery of new related genes underlies the limitation of this approach. This study aimed to identify genetic variants responsible for IBD in pediatric patients using whole-exome sequencing (WES), and to provide a detailed description and reclassification of candidate variants. Material and Methods WES was performed for 18 pediatric patients, and variants were filtered using a first-line list of 290 genes. Variant prioritization was discussed in a multidisciplinary team based on genotype-phenotype correlation, and segregation studies were performed with available family members. Results The study identified 22 candidate variants in 17 out of 18 patients (94%). Eleven patients had complete genotype-phenotype correlation, resulting in a diagnostic yield of 61%, 5 (28%) were classified as partially solved, and 2 (11%) remained unsolved. Variants were identified in platelet (ACTN1, ANKRD26, CYCS, GATA1, GFI1B, ITGA2, NBEAL2, RUNX1, SRC, TUBB1), bleeding (APOLD1), and coagulation (F7, F8, F11, VWF) genes. Notably, 9 out of 22 (41%) variants were previously unreported. Variant pathogenicity was assessed according to the American College of Medical Genetics and Genomics guidelines and reclassification of three variants based on family segregation evidence, resulting in the identification of 10 pathogenic or likely pathogenic variants, 6 variants of uncertain significance, and 6 benign or likely benign variants. Conclusion This study demonstrated the high potential of WES in identifying rare molecular defects causing IBD in pediatric patients, improving their management, prognosis, and treatment, particularly for patients at risk of malignancy and/or bleeding due to invasive procedures.

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Section: Discussionmentioning

confidence: 99%

Gaining Insights into Inherited Bleeding Disorders of Complex Etiology in Pediatric Patients: Whole-Exome Sequencing as First-Line Investigation Tool

Bandini,

Borràs,

Berrueco

et al. 2023

Thromb Haemost

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“…Congenital fXI deficiency, known as hemophilia C, is a rare condition in the general population (1 per million) but is relatively common among Ashkenazi Jews with a frequency up to 8%. , Compared to fVIII deficiency (hemophilia A) or fIX deficiency (hemophilia B), people with hemophilia C rarely exhibit spontaneous bleeding but instead bleed excessively after injury or surgery, implying that fXI plays a limited role in normal hemostasis. , However, elevated fXI activity is associated with an increased risk of ischemic stroke, , deep venous thrombosis (DVT), , and myocardial infarction (MI) . These data suggest that fXI plays an important role in thromboembolic diseases, which are leading causes of mortality, responsible for one in four deaths worldwide .…”

Section: Introductionmentioning

confidence: 99%

Fluorescent Activity-Based Probe To Image and Inhibit Factor XIa Activity in Human Plasma

et al. 2023

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Anticoagulation therapy is a mainstay of the treatment of thrombotic disorders; however, conventional anticoagulants trade antithrombotic benefits for bleeding risk. Factor (f) XI deficiency, known as hemophilia C, rarely causes spontaneous bleeding, suggesting that fXI plays a limited role in hemostasis. In contrast, individuals with congenital fXI deficiency display a reduced incidence of ischemic stroke and venous thromboembolism, indicating that fXI plays a role in thrombosis. For these reasons, there is intense interest in pursuing fXI/factor XIa (fXIa) as targets for achieving antithrombotic benefit with reduced bleeding risk. To obtain selective inhibitors of fXIa, we employed libraries of natural and unnatural amino acids to profile fXIa substrate preferences. We developed chemical tools for investigating fXIa activity, such as substrates, inhibitors, and activity-based probes (ABPs). Finally, we demonstrated that our ABP selectively labels fXIa in the human plasma, making this tool suitable for further studies on the role of fXIa in biological samples.

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Congenital factor XI deficiency caused by a novel F11 missense variant: a case report

Cited by 2 publications

References 9 publications

Gaining Insights into Inherited Bleeding Disorders of Complex Etiology in Pediatric Patients: Whole-Exome Sequencing as First-Line Investigation Tool

Gaining Insights into Inherited Bleeding Disorders of Complex Etiology in Pediatric Patients: Whole-Exome Sequencing as First-Line Investigation Tool

Fluorescent Activity-Based Probe To Image and Inhibit Factor XIa Activity in Human Plasma

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