https://orcid.org/0000-0002-8784-290X
KEY POINT
Our Factor VIII (FVIII) database now contains 6,211 variants; from 10,064 patients, and includes 1,529 (65%) of the 2,351 FVIII residues.
The FVIII upgrade explains the effect of variants on the FVIII protein and enables improved clinical analyses of FVIII genetic variants
ABSTRACT
Haemophilia A is a rare genetic disease that occurs with mild, moderate or severe phenotypes, and involves dysfunctional or reduced amounts of plasma factor VIII (FVIII). Identifying causal genetic variants in the F8 gene is vital for patient care. Our original interactive MySQL database for FVIII in 2013 presented clinical data on 2,014 unique FVIII variants in 5,072 patients. Here, we expand our database almost three-fold with a new total of 6,211 unique FVIII variants in 10,064 patients spanning 1,529 (65%) of the 2,351 FVIII residues. We have also developed a new full-length FVIII structural model that incorporates both its crystal structure and its disordered B domain that is not visible in available experimental structures. This enabled assessment of these variants on FVIII. Out of the 6,211 unique F8 variants identified, 730 (12%) were associated with mild phenotypes, 526 (8%) with moderate phenotypes, 2,509 (39%) with severe phenotypes, 53 (1%) with multiple severities, and 2,393 (40%) with unreported phenotypes. The most variants occurred in the disordered B domain (1,281 variants), followed by the A1, A2 and A3 domains (1130, 1071 and 923 variants respectively), and the C1 and C2 domains (442 and 439 variants respectively). Inhibitors were associated with 451 variants (7%). Our new structural analyses often revealed changes to the residue solvent surface accessibilities caused by many FVIII variants. The FVIII variant analyses are supported by similar observations in the structurally-related Factor V protein. Our web-accessible FVIII database will enable easier and improved clinical analyses of FVIII genetic variants.
