Genetic and Laboratory Predictors of Bleeding Severity in FVII Deficiency: Insights from PRO-RBDD and EN-RBD Databases.

Factor VII deficiency (FVIID) is among the most common rare bleeding disorders. The ability of FVII coagulant activity (FVII:C) levels and genetic variants to predict clinical outcomes remains limited. We evaluated the discriminative performance of FVII:C, genotype-phenotype associations, and the accuracy of in silico tools in identifying pathogenic variants. In total, 422 FVIID cases from three international registries were analyzed. Overall, 61% experienced bleeding, predominantly spontaneous (73%); 20% had grade I, 27% grade II, and 14% grade III bleeding. Lower FVII:C showed a moderate inverse correlation with EN-RBD bleeding scores and was more frequently observed in individuals with spontaneous bleeding (r=-0.49, p<0.0001). FVII:C showed moderate discrimination for asymptomatic status (AUC=0.72) and strong discrimination for grade III bleeding (AUC=0.84). An optimal cut-off of ≥19 IU/dL improved identification of asymptomatic individuals, while <11 IU/dL was associated with grade III bleeding. We identified 90 variants, including 10 novel; 60% were missense and 63% located in serine protease domain. According to ACMG/AMP criteria, 86% were pathogenic/likely pathogenic. The sensitivity of in silico tools was 96%, 85% and 60% for REVEL, CADD, and AlphaMissense. Severe deficiency was more common in homozygous individuals (90%), while heterozygous individuals predominantly exhibited mild/moderate deficiency (91%). Consistently, bleeding phenotypes were frequent in individuals with homozygous/compound heterozygous variants, whereas most heterozygous were asymptomatic (71%). Collectively, FVII:C showed a moderate ability to stratify bleeding severity. Homozygous/compound heterozygous variants are associated with lower FVII:C and more severe bleeding, whereas heterozygous are mostly asymptomatic. Among in silico tools, REVEL demonstrated the highest sensitivity.