The genetic spectrum of rare bleeding disorders

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

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

A total of 807 individuals suspected of having 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 tools (Combined Annotation Dependent Depletion and Rare Exome Variant Ensemble Learner scores).

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. Factor (F)VII 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 the heterozygous cases (22%), 8% were severely affected, suggesting 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%) of affected exons encode catalytic domains.

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.