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 5 57/77) and 50 were compound heterozygous (EU/IR 5 43/7) for VWF variants. In 22 patients, no or only one variant was found. A total of 154 different VWF variants (EU/IR 5 101/58 [5 shared]) were identified among the 379 affected alleles (EU/IR 5 210/169), of which 48 (EU/IR 5 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 5 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.

Genotypes of European and Iranian patients with type 3 von Willebrand disease enrolled in 3WINTERS-IPS / L. Baronciani, I. Peake, R. Schneppenheim, A. Goodeve, M. Ahmadinejad, Z. Badiee, M.-. Baghaipour, O. Benitez, I. Bodo, U. Budde, A. Cairo, G. Castaman, P. Eshghi, J. Goudemand, W. Hassenpflug, H. Hoorfar, M. Karimi, B. Keikhaei, R. Lassila, F.W.G. Leebeek, M.F.L. Fernandez, P.M. Mannucci, R. Marino, N. Niksic, F. Oyen, C. Santoro, A. Tiede, G. Toogeh, A. Tosetto, M. Trossaert, E.M.K. Zetterberg, J. Eikenboom, A.B. Federici, F. Peyvandi. - In: BLOOD ADVANCES. - ISSN 2473-9529. - 5:15(2021 Aug 10), pp. 2987-3001. [10.1182/bloodadvances.2020003397]

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

L. Baronciani
Primo
;
G. Castaman;M. Karimi;P.M. Mannucci;C. Santoro;A.B. Federici
Penultimo
;
F. Peyvandi
Ultimo
2021

Abstract

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 5 57/77) and 50 were compound heterozygous (EU/IR 5 43/7) for VWF variants. In 22 patients, no or only one variant was found. A total of 154 different VWF variants (EU/IR 5 101/58 [5 shared]) were identified among the 379 affected alleles (EU/IR 5 210/169), of which 48 (EU/IR 5 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 5 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.
Genotype; Humans; Iran; Prospective Studies; von Willebrand Disease, Type 3; von Willebrand Diseases
Settore MED/09 - Medicina Interna
10-ago-2021
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/903941
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