F8/F9 variants in the population-based PedNet Registry cohort compared with locus-specific genetic databases of the European Association for Haemophilia and Allied Disorders and the Centers for Disease Control and Prevention Hemophilia A or Hemophilia B Mutation Project

Veerle Labarque; Maria Elisa Mancuso; Mutlu Kartal-Kaess; Rolf Ljung; Torben S Mikkelsen; Nadine G Andersson

doi:10.1016/j.rpth.2023.100036

F8/F9 variants in the population-based PedNet Registry cohort compared with locus-specific genetic databases of the European Association for Haemophilia and Allied Disorders and the Centers for Disease Control and Prevention Hemophilia A or Hemophilia B Mutation Project

Res Pract Thromb Haemost. 2023 Jan 10;7(1):100036. doi: 10.1016/j.rpth.2023.100036. eCollection 2023 Jan.

Authors

Veerle Labarque¹, Maria Elisa Mancuso^{2

3}, Mutlu Kartal-Kaess⁴, Rolf Ljung⁵, Torben S Mikkelsen⁶, Nadine G Andersson^{5

7}

Affiliations

¹ Department of Paediatrics, Paediatric Haematology and Oncology, University Hospitals Leuven, Leuven, Belgium.
² Center for Thrombosis and Hemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
³ Humanitas University, Rozzano, Milan, Italy.
⁴ Division of Pediatric Hematology and Oncology, Department of Pediatrics, Inselspital, University Hospital, University of Bern, Bern, Switzerland.
⁵ Department of Clinical Sciences and Paediatrics, Lund University, Lund, Sweden.
⁶ Department of Paediatric Oncology and Haematology, University Hospital, Aarhus, Denmark.
⁷ Centre for Thrombosis and Haemostasis, Skåne University Hospital, Lund, Sweden.

Abstract

Background: Hemophilia A and B are caused by variants in the factor (F) VIII or FIX gene. Selective reporting may influence the distribution of variants reported in genetic databases.

Objectives: To compare the spectrum of F8 and F9 variants in an international population-based pediatric cohort (PedNet Registry) with the spectrum found in the European Association for Haemophilia and Allied Disorders (EAHAD) and the Centers for Disease Control and Prevention Hemophilia A or Hemophilia B Mutation Project (CHAMP/CHBMP) databases.

Methods: All patients registered in the PedNet Registry on January 1, 2021 were included in this study. As comparators, data from patients with severe hemophilia included in the CHAMP/CHBMP registry (US center data) and EAHAD were used.

Results: Genetic information was available for 1941 patients. Intron 22 inversion was present in 52% of patients with severe hemophilia A; frameshift (36%), missense (28%), and nonsense (20%) were the most frequent variants in patients with severe hemophilia A who were inversion-negative. The most frequent variants in severe hemophilia B were missense (48%). In nonsevere disease, most variants were missense variants (moderate hemophilia A: 91%; mild hemophilia A: 95%, moderate and mild hemophilia B: 86% each). Comparison with the databases demonstrated a higher proportion of missense variants associated with severe hemophilia B in EAHAD (68%) than in PedNet (48%) and CHBMP (46%).

Conclusion: The PedNet population-based cohort provides an alternative to the established databases, which collect data by selective reporting, as it is a well-maintained database covering the full spectrum of pathogenic F8 and F9 variants, and indicates the number of patients affected by each particular variant.

Keywords: factor IX; factor VIII; genetic databases; hemophilia A; hemophilia B; population.