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CME Evaluation

Oral Communication Session

Inherited Bleeding Disorders and Inhibitors

Session: Inhibitors, genetics and mechanisms

OC 41.1 - Cluster of deleterious variants in A3 domain of factor VIII in patients with haemophilia A and inhibitors

Monday, June 24, 2024
14:45 – 15:00 ICT
Room: Ballroom B1
Background: Congenital haemophilia A (HA) results from deleterious variants in the factor VIII (FVIII) gene (F8). Inhibitors are the main complication of HA and null F8 variants are a risk factor to their development. However, few studies have reported F8 variants related with inhibitors in admixed populations.

Aims: To evaluate the spectrum of F8 mutations in the context of inhibitor development in a large (n = 268) population with PwHA.

Methods: F8 sequencing was performed using NGS. Inversion of introns 22 (Inv22) and intron 1 (Inv1) were detected by inverse shifting and allelic specific PCRs.

Results: Deleterious mutations were found in 254 (94.8%) PwHA, of which Inv 22 was the most prevalent (44.0%) (Table 1). Inv22, nonsense and frameshift variants were more prevalent in PwHA with inhibitors [inh (+)]. Conversely, missense variants were more prevalent in inh (-) (31.4%) (Table 1, Figure 1A-B). We found 111 unique deleterious variants, of which 33 were new. Additionally, 18 large deletions (>50 base pairs) were detected. Missense, nonsense and frameshift tended to be variably distributed along the A1-C2 domains of FVIII in inh (+) and inh (-) (p < 0.01; chi-square) (Figure 1C). Variants had different locations according to inh: they clustered in the A3 domain in inh (+) more than inh (-) (30.9% vs 8.8%; p = 0.01), with frameshift and nonsense representing the majority (42.9% each) in inh (+). In inh (-), missense variants clustered at C1 (23.5%) in contrast to inh (+) (4.4%). The haplotypes H1 and H2 of F8 were the most prevalent, but were not associated with inhibitor development.

Conclusion(s): Pathogenic variants were clustered in A3 domain in PwHA with inhibitors. Haplotypes of F8 did not associate with inhibitor development in our cohort. These findings emphasize the contribution of F8 genotype-risk profile in development of inhibitors in an admixed population.