OC 73.1 - The genetic spectrum of patients with rare bleeding disorders

Background: Rare bleeding disorders (RBDs) are inherited deficiencies of some coagulation factors (i.e., fibrinogen, prothrombin, FV, FVII, FV+FVIII, FX, FXI, FXIII and Vitamin K-dependent) that are mostly inherited in an autosomal recessive manner. Due to the rarity of these disorders, the genetic background is not well-understood.

Aims: To investigate the genetic spectrum of RBDs using a large international cohort.

Methods: Laboratory phenotype (factor levels) and genotype (sanger-sequencing) characterizations were performed for all suspected subjects of bleeding disorders referred to our center from 18 countries. HGMD, LOVD and GFHT databases were used to identify reported variants. Using an in-silico tool (CADD) and ClinVar classification the functional effects of identified variants were evaluated.

Results: Of 810 cases, 547 had low factor activity levels including 296 homozygous, 69 compound and 163 heterozygous (Table 1). 186 cases had normal factor levels of which 140 were heterozygous and 46 were wild-type. Missing laboratory assay was found in 77 cases. In our cohort, major RBD was FVII deficiency (24%), followed by fibrinogen deficiencies (19%-Figure 1). A total of 804 variants were identified that 264 were distinct and were mostly missense (57%-Figure 1), however, frameshift was the most common in FV+FVIII deficiency. Most variants (92%) were predicted as pathogenic/likely pathogenic (Table 1). Of note, 32 novel variants have also been detected. Among heterozygous affected cases, 94 patients (58%) had a disorder with an autosomal recessive inheritance, 12% being severely factor-deficient, therefore a second variant was expected to be found. In 20 (4%) of patients no variant was found. Hotspots are as follows: FGG-Exon 8 (57%), FGA-exon 5 (41%), F5-exon 13 (19%), F7-exon 9 (46%) and F5-exon 8 (32%).

Conclusion(s): This largest cohort of RBDs indicates that the CADD-score can predict the variants' pathogenicity with a high accuracy. Further studies are warranted for heterozygote patients with autosomal-recessive disorders presenting severely reduced factor levels.