Targeted exome analysis in patients with rare bleeding disorders: data from the Rare Bleeding Disorders in the Netherlands study

Research and Practice in Thrombosis and Haemostasis, vol. 8, pp. 102477

Abstract

Background: Rare coagulation factor deficiencies and disorders of fibrinolysis (defined as rare bleeding disorders [RBDs]) present with a heterogeneous bleeding phenotype, and bleeding severity is difficult to predict. Objectives: Describe underlying rare genetic variants in the Dutch RBD population and investigate the relationship between genotype, laboratory phenotype, and clinical phenotype. Methods: The Rare Bleeding Disorders in the Netherlands is a cross-sectional, nationwide study conducted between October 1, 2017, and November 30, 2019. Bleeding scores and blood samples were collected during a single study visit. Coagulation factor levels were measured centrally, and targeted exome analysis was performed on 156 genes involved in thrombosis and hemostasis. Pathogenicity was assigned according to the Association for Clinical Genetic Science guidelines. Results: = 51) were variants of unknown significance. No explanatory genetic variants were found in patients with plasminogen activator inhibitor type 1 deficiency or hyperfibrinolysis. A correlation existed between factor activity levels and the presence of a genetic variant in the corresponding gene in patients with rare coagulation factor deficiencies and alpha-2-antiplasmin deficiency. Co-occurrence of multiple genetic variants was present in a quarter of patients, but effect on phenotype remains unclear. Conclusion: Targeted exome analysis may offer advantages over single-gene analysis, emphasized by a number of combined deficiencies in this study. Further studies are required to determine the role of co-occurring hemostasis gene variants on the bleeding phenotype in RBDs.

Authors 16

1. Sterre P E Willems

   Radboud University Medical Center

   Affiliation as printed

   Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands

   Hemophilia Treatment Center, Nijmegen - Eindhoven - Maastricht, the Netherlands

2. Annet Simons

   Radboud University Medical Center

   Affiliation as printed

   Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands

3. Joline L. Saes

   Radboud University Medical Center

   Affiliation as printed

   Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands

   Hemophilia Treatment Center, Nijmegen - Eindhoven - Maastricht, the Netherlands

4. Marjan M. Weiss

   Radboud University Medical Center

   Affiliation as printed

   Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands

5. Sanna R. Rijpma

   Radboud University Medical Center

   Affiliation as printed

   Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands

6. Selene Schoormans

   Radboud University Medical Center

   Affiliation as printed

   Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands

7. Karina Meijer

   University Medical Center Groningen

   Affiliation as printed

   Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands

8. Marjon H. Cnossen

   Erasmus MC · Erasmus MC - Sophia Children’s Hospital

   Affiliation as printed

   Department of Pediatric Hematology and Oncology, Erasmus Medical Centre Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, the Netherlands

9. Roger E. G. Schutgens

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Center for Benign Haematology, Thrombosis and Haemostasis, van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands

10. Nick van Es

    Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

    Amsterdam Cardiovascular Sciences, Pulmonary Hypertension & Thrombosis, Amsterdam, the Netherlands

    Department of Vascular Medicine, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands

11. Laurens Nieuwenhuizen
    Affiliation as printed

    Department of Hematology, Máxima Medical Center Eindhoven, Eindhoven, the Netherlands

    Hemophilia Treatment Center, Nijmegen - Eindhoven - Maastricht, the Netherlands

12. Paul L. den Exter Aachen Department of Thrombosis and Hemostasis

    Leiden University Medical Center

    Affiliation as printed

    Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands

13. Ilmar C. Kruis

    Netherlands Haemophilia Society

    Affiliation as printed

    Netherlands Hemophilia Society, Nijkerk, the Netherlands

14. Nicole M. A. Blijlevens

    Radboud University Medical Center

    Affiliation as printed

    Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands

15. Waander L. van Heerde

    Radboud University Medical Center

    Affiliation as printed

    Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands

    Enzyre BV, Novio Tech Campus, Nijmegen, the Netherlands

    Hemophilia Treatment Center, Nijmegen - Eindhoven - Maastricht, the Netherlands

16. Saskia E.M. Schols corresponding

    Radboud University Medical Center

    Affiliation as printed

    Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands

    Hemophilia Treatment Center, Nijmegen - Eindhoven - Maastricht, the Netherlands