Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan 10;7(1):100036.
doi: 10.1016/j.rpth.2023.100036. eCollection 2023 Jan.

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  1 , Maria Elisa Mancuso  2   3 , Mutlu Kartal-Kaess  4 , Rolf Ljung  5 , Torben S Mikkelsen  6 , Nadine G Andersson  5   7
Affiliations

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 et al. Res Pract Thromb Haemost. .

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Location of missense variants in moderate and mild hemophilia. (A) Location according to the factor VIII protein domains in moderate or mild hemophilia A; (B) Location according to the factor IX protein structure in moderate or mild hemophilia B. GLA: c-carboxy glutamic acid domain; EGF: epidermal growth factor like domain; ACT-Peptide: activating peptide
Figure 2
Figure 2
Spectrum of variant effects in the PedNet cohort compared with the CHAMP/CHBMP US files and EAHAD database. (A) inversion-negative patients with severe hemophilia A; (B) severe hemophilia B patients. Data are presented in percentages.
See this image and copyright information in PMC

References

    1. Gitschier J., Wood W.I., Goralka T.M., Wion K.L., Chen E.Y., Eaton D.H., et al. Characterization of the human factor VIII gene. Nature. 1984;312:326–330. - PubMed
    1. Kurachi K., Davie E.W. Isolation and characterization of a cDNA coding for human factor IX. Proc Natl Acad Sci U S A. 1982;79:6461–6464. - PMC - PubMed
    1. Oldenburg J., Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. Haemophilia. 2006;12(Suppl 6):15–22. - PubMed
    1. Hamosh A., Scott A.F., Amberger J., Bocchini C., Valle D., McKusick V.A. Online Mendelian Inheritance in Man (OMIM), a KnowledgeBase of human genes and genetic disorders. Nucleic Acids Res. 2002;30:52–55. - PMC - PubMed
    1. Stenson P.D., v Ball E.V., Howells K., Phillips A.D., Mort M., Cooper D.N. The Human Gene Mutation Database: providing a comprehensive central mutation database for molecular diagnostics and personalized genomics. Hum Genomics. 2009;4:69–72. - PMC - PubMed