Genetic variants of VWF gene in type 2 von Willebrand disease

• Published in: Haemophilia : the official journal of the World Federation of Hemophilia Vol. 25; no. 2; pp. e78 - e85
• Main Authors: Freitas, Samuel da Silva, Rezende, Suely Meireles, de Oliveira, Luciana Correa, Prezotti, Alessandra Nunes Loureiro, Renni, Marília Sande, Corsini, Camila Amormino, Amorim, Marcos Vinícius de Almeida, Matosinho, Carolina Guimarães Ramos, Carvalho, Maria Raquel Santos, Chaves, Daniel Gonçalves
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-03-2019
• Subjects: Bleeding; Desmopressin; Exons; gene; Genetic diversity; genetic variants; Health risk assessment; sequencing; von Willebrand disease; VWF gene; genetic variants; von Willebrand disease; bleeding; gene; sequencing
• ISSN: 1351-8216; 1365-2516
• DOI: 10.1111/hae.13714

Introduction
von Willebrand disease (VWD) is the most common inherited bleeding disorder. Few studies have explored the molecular basis of type 2 VWD.
Aim
This study aimed to identify variants associated with type 2 VWD.
Methods
We collected clinical and laboratory data, as well as response to desmopressin and bleeding assessment tool (BAT) score in patients diagnosed with type 2 VWD. We sequenced exons 17, 18, 20 and 28 of the VWF gene.
Results
We identified 19 different variants in 40 unrelated patients (47.5%). Most of the variants (84.2%) were found in exon 28. A total of 10/19 variants (52.6%) were identified as “likely causative” in 17/40 patients (42.5%), according to the ISTH‐SSC and EAHAD VWF gene mutations databases. Nine variants were initially identified as potentially benign. However, through analyses in silico, four of these variants were reclassified as “likely pathogenic” (Ile1380Val, Asn1435Ser, Ser1486Leu and Tyr1584Cys). Response to desmopressin was associated with three variants: Met740Ile, Arg1597Gln and Tyr1584Cys. Major bleeding was associated with variants related to VWD subtypes 2B and 2M.
Conclusion
In conclusion, we identified 19 variants, of which 14 are “likely pathogenic” and therefore associated with VWD. We suggest a possible association of pathogenic variants with major bleeding, response to desmopressin and BAT score ≥10, although this requires further confirmation.