Genotypes of European and Iranian patients with type 3 von Willebrand disease enrolled in 3WINTERS-IPS

• Published in: Blood advances Vol. 5; no. 15; pp. 2987 - 3001
• Main Authors: Baronciani, Luciano, Peake, Ian, Schneppenheim, Reinhard, Goodeve, Anne, Ahmadinejad, Minoo, Badiee, Zahra, Baghaipour, Mohammad-Reza, Benitez, Olga, Bodó, Imre, Budde, Ulrich, Cairo, Andrea, Castaman, Giancarlo, Eshghi, Peyman, Goudemand, Jenny, Hassenpflug, Wolf, Hoorfar, Hamid, Karimi, Mehran, Keikhaei, Bijan, Lassila, Riitta, Leebeek, Frank W.G., Lopez Fernandez, Maria Fernanda, Mannucci, Pier Mannuccio, Marino, Renato, Nikšić, Nikolas, Oyen, Florian, Santoro, Cristina, Tiede, Andreas, Toogeh, Gholamreza, Tosetto, Alberto, Trossaert, Marc, Zetterberg, Eva M.K., Eikenboom, Jeroen, Federici, Augusto B., Peyvandi, Flora
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.08.2021; American Society of Hematology
• Subjects: Genotype; Humans; Iran - epidemiology; Prospective Studies; Thrombosis and Hemostasis; von Willebrand Disease, Type 3 - diagnosis; von Willebrand Disease, Type 3 - epidemiology; von Willebrand Disease, Type 3 - genetics; von Willebrand Diseases; Iran
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2020003397

Type 3 von Willebrand disease (VWD3) is a rare and severe bleeding disorder characterized by often undetectable von Willebrand factor (VWF) plasma levels, a recessive inheritance pattern, and heterogeneous genotype. The objective of this study was to identify the VWF defects in 265 European and Iranian patients with VWD3 enrolled in 3WINTERS-IPS (Type 3 Von Willebrand International Registries Inhibitor Prospective Study). All analyses were performed in centralized laboratories. The VWF genotype was studied in 231 patients with available DNA (121 [115 families] from Europe [EU], and 110 [91 families] from Iran [IR]). Among 206 unrelated patients, 134 were homozygous (EU/IR = 57/77) and 50 were compound heterozygous (EU/IR = 43/7) for VWF variants. In 22 patients, no or only one variant was found. A total of 154 different VWF variants (EU/IR = 101/58 [5 shared]) were identified among the 379 affected alleles (EU/IR = 210/169), of which 48 (EU/IR = 18/30) were novel. The variants p.Arg1659*, p.Arg1853*, p.Arg2535*, p.Cys275Ser, and delEx1_Ex5 were found in both European and Iranian VWD3 patients. Sixty variants were identified only in a single allele (EU/IR = 50/10), whereas 18 were recurrent (≥3 patients) within 144 affected alleles. Nine large deletions and one large insertion were found. Although most variants predicted null alleles, 21% of patients carried at least 1 missense variant. VWD3 genotype was more heterogeneous in the European population than in the Iranian population, with nearly twice as many different variants. A higher number of novel variants were found in the Iranian VWD3 patients. •This is the largest study on the genotype of patients with VWD3.•The VWD3 genotype was more heterogeneous in the European population than in the Iranian population. [Display omitted]