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

Blood Vessels, Thrombosis & Hemostasis Pub Date : 2025-01-21 DOI:10.1016/j.bvth.2025.100053

Emily H. T. Print , Anna M. Simmons , Holly J. Spencer , Christos Efthymiou , Victoria A. Harris , Stephen J. Perkins

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Abstract

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.

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分析升级的交互式FVIII网络数据库中的6211个独特变体，揭示了对血友病A的新见解

嗜血友病A是一种罕见的遗传性疾病，发生在轻度、中度或重度表型，涉及血浆因子VIII （FVIII）功能失调或减少。确定F8基因的因果遗传变异对患者护理至关重要。我们最初的2013年FVIII交互式MySQL数据库提供了5072例患者2014年独特FVIII变体的临床数据。在这里，我们将数据库扩展了近三倍，在10064例患者中发现了6211个独特的FVIII变体，涵盖了2351个FVIII残基中的1529个（65%）。我们还开发了一个新的全长FVIII结构模型，该模型结合了其晶体结构和无序B域，这在现有的实验结构中是不可见的。这使得对FVIII变异的评估成为可能。在鉴定的6211个独特的F8变异中，730个（12%）与轻度表型相关，526个（8%）与中度表型相关，2509个（39%）与重度表型相关，53个（1%）与多重严重表型相关，2393个（40%）与未报告的表型相关。变异最多的是无序的B结构域（1281个），其次是A1、A2、A3结构域（1130个、1071个、923个）和C1、C2结构域（442个、439个）。抑制剂与451个变异相关（7%）。我们的新结构分析经常揭示由许多FVIII变体引起的残留溶剂表面可及性的变化。FVIII变异分析得到了结构相关FV蛋白类似观察结果的支持。我们的网络访问FVIII数据库将使FVIII基因变异的临床分析更容易和改进。

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Blood Vessels, Thrombosis & Hemostasis

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