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

Baronciani, L.; Peake, I.; Schneppenheim, R.; Goodeve, A.; Ahmadinejad, M.; Badiee, Z.; Baghaipour, M.R.; Benitez, O.; Bodo, I.; Budde, U.; Cairo, A.; Castaman, G.; Eshghi, P.; Goudemand, J.; Hassenpflug, W.; Hoorfar, H.; Karimi, M.; Keikhaei, B.; Lassila, R.; Leebeek, F.W.G.; Fernandez, M.F.L.; Mannucci, P.M.; Marino, R.; Niksic, N.; Oyen, F.; Santoro, C.; Tiede, A.; Toogeh, G.; Tosetto, A.; Trossaert, M.; Zetterberg, E.M.K.; Eikenboom, J.; Federici, A.B.; Peyvandi, F.

doi: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...Show moreType 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.Show less

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