# Analyzing 6211 unique variants in the upgraded interactive FVIII web database reveals novel insights into hemophilia A

## TL;DR

This paper presents an upgraded database of FVIII variants, offering new insights into hemophilia A by analyzing 6211 unique genetic variants from over 10,000 patients.

## Contribution

The paper introduces a new structural model of FVIII and expands the database to better understand the effects of genetic variants on the protein and disease severity.

## Key findings

- The database now includes 6211 variants, with 65% of FVIII residues covered, enabling improved clinical analysis.
- Variants in the disordered B domain were most common, and many altered residue solvent surface accessibility.
- About 7% of variants were associated with inhibitor development in hemophilia A patients.

## Abstract

•Our FVIII database now contains 6211 variants from 10 064 patients and includes 1529 (65%) of the 2351 FVIII residues.•The FVIII upgrade explains the effects of variants on the FVIII protein and enables improved clinical analyses of FVIII genetic variants.

Our FVIII database now contains 6211 variants from 10 064 patients and includes 1529 (65%) of the 2351 FVIII residues.

The FVIII upgrade explains the effects of variants on the FVIII protein and enables improved clinical analyses of FVIII genetic variants.

Hemophilia 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 2014 unique FVIII variants in 5072 patients. Here, we expand our database almost threefold with a new total of 6211 unique FVIII variants in 10 064 patients, spanning 1529 of the 2351 FVIII residues (65%). We have also developed a new full-length FVIII structural model that incorporates both its crystal structure and its disordered B domain, which is not visible in available experimental structures. This enabled the assessment of these variants on FVIII. Of the 6211 unique F8 variants identified, 730 (12%) were associated with mild phenotypes, 526 (8%) with moderate phenotypes, 2509 (39%) with severe phenotypes, 53 (1%) with multiple severities, and 2393 (40%) with unreported phenotypes. Most variants occurred in the disordered B domain (1281 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 FV protein. Our web-accessible FVIII database will enable easier and improved clinical analyses of FVIII genetic variants.