Abstract Number: PB0475
Meeting: ISTH 2021 Congress
Background: Hemophilia A (HA) and B (HB) are caused by mutations in the F8 or F9 gene. Online databases (e.g. CHAMP/CHBMP or EAHAD) list over 4,200 unique pathogenic variants. However, selective reporting may influence the distribution of mutations reported in these databases.
Aims: We aimed to determine the spectrum of F8 and F9 gene mutations in an international prospective cohort of unselected patients (PedNet Registry).
Methods: The PedNet Registry collects clinical, genetic, and phenotypic data prospectively in children with hemophilia. A total of 2,304 patients registered by January 2020 were included. Data on type and severity of hemophilia and on molecular genetic analysis of F8 and F9 gene variants (HGVS nomenclature) were analyzed.
Results: Genetic information was available on 1,548 out of 1,926 HA patients (80%) and 279 out of 378 HB patients (74%). No abnormalities were found in the respective genes in 32 HA and 5 HB patients (2% each). The distribution of mutations in severe patients is shown in figure 1.
In severe HA (n=1,089), we identified 586 intron 22 inversions (54%), 178 frameshift (16%; mostly exon 14), 125 missense (11%; mostly exons 23, 26), 98 nonsense (9%; mostly exon 14), and 37 splice site mutations (3%), 28 large structural changes (2.5%), 17 intron 1 inversions (2%) and 3 small structural changes (0.3%; in exons 15, 22, 24).
In severe HB (n=140), we found mostly missense (n=65; 46%) and nonsense mutations (n=28; 20%), but also large structural changes (n=17; 12%), frameshift (n=13; 9%), promoter and splice site mutations (n=6; 4% each), and small structural changes (n=3; 2%). In HB, the genetic variants were spread throughout the F9 gene.
Conclusions: In conclusion, we report a wide spectrum of F8 and F9 mutations in a multicenter large cohort of unselected patients, providing a population based reference which could be useful in future studies.
To cite this abstract in AMA style:Labarque V, Mancuso M-, Kartal-Kaess M, Ljung R, Mikkelsen TS, Gretenkort Andersson N, PedNet Study Group . Spectrum of F8/F9 Gene Mutations in the PedNet Cohort [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/spectrum-of-f8-f9-gene-mutations-in-the-pednet-cohort/. Accessed November 29, 2023.
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