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

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.

© 2023 The Authors.

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.

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