The genetic spectrum of rare bleeding disorders.

Background: Rare bleeding disorders (RBDs) account for almost 3-5% of bleeding disorders. Because of their rarity, phenotype and genotype analyses have been conducted only on a limited number of cases.

Aims: To characterize the laboratory phenotype and genetic spectrum of a large international cohort of RBDs.

Material and methods: A total of 807 individuals suspected to have RBDs were collected (2001-2020). The severity of RBDs was assessed based on plasma clotting factor activity levels. Gene sequencing was performed to confirm the diagnosis. Novel variants were assessed using in-silico prediction tool (CADD and REVEL scores).

Results: After excluding 46 subjects with normal phenotype and genotype, 761 cases with RBDs from 19 countries were included. Of these, 526 had coagulant activity levels below the normal range with identified variants. FVII deficiency was the most frequent (23%), while FII and compound FV+FVIII (6%) deficiencies were the rarest. The majority of cases (86%) had an autosomal recessive pattern and among their heterozygous cases (22%), 8% were severely affected, suggesting that the second expected variant was not identified. No causative variant was identified in 4% of cases. Among the identified 257 unique variants, 86% were predicted to be pathogenic and 11% were novel. Missense variants were identified in 57% of cases, excluding cases of afibrinogenemia and compound FV+FVIII deficiencies. The majority (48%) affected exons encoding catalytic domains.

Conclusion: In this large group of RBDs, missense variants were the most prevalent, primarily affecting the catalytic domains of proteins, except in cases of afibrinogenemia and FV+FVIII deficiencies.