title: Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): Proposal for a new diagnostic paradigm.
abstract: The diagnosis of von Willebrand disease (VWD) remains difficult in a significant proportion of patients. A Spanish multicentre study investigated a cohort of 556 patients from 330 families who were analysed centrally. VWD was confirmed in 480. Next generation sequencing (NGS) of the whole coding VWF was carried out in all recruited patients, compared with the phenotype, and a final diagnosis established. A total of 238 different VWF mutations were found, 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 463 were found to have VWF mutation/s. A good phenotypic/genotypic association was estimated in 96.5% of the patients. One hundred seventy-four patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred sixteen patients presented with mutations that had previously been associated with increased von Willebrand factor (VWF) clearance. RIPA unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 70 patients. The NGS study facilitated an appropriate classification in 63 of them. The remaining seven patients presented with a VWF novel mutation pending further investigation. In five patients with a type 3 and two with a type 2A or 2B phenotype with no mutation, an acquired von Willebrand syndrome (AVWS) was suspected/confirmed. These data seem to support NGS as a first line efficient and faster paradigm in VWD diagnosis.
authors.affiliation: Francisco Javier Batlle Fonrodona, M. D., Servicio de Hematología y Hemoterapia. INIBIC., Complexo Hospitalario Universitario A Coruña, Edificio Hospital Materno Infantil, Carretera del Pasaje s/n, 15006 - A Coruña, Spain, Tel.: +34 981 178000 Ext. 292113, Fax: +34 981 178392, E-mail: francisco.javier.batlle.fonrodona@sergas.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Batlle
authors.forename: Almudena
authors.initials: A
authors.lastname: Pérez-Rodríguez
authors.forename: Irene
authors.initials: I
authors.lastname: Corrales
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: López-Fernández
authors.forename: Ángela
authors.initials: Á
authors.lastname: Rodríguez-Trillo
authors.forename: Esther
authors.initials: E
authors.lastname: Lourés
authors.forename: Ana Rosa
authors.initials: AR
authors.lastname: Cid
authors.forename: Santiago
authors.initials: S
authors.lastname: Bonanad
authors.forename: Noelia
authors.initials: N
authors.lastname: Cabrera
authors.forename: Andrés
authors.initials: A
authors.lastname: Moret
authors.forename: Rafael
authors.initials: R
authors.lastname: Parra
authors.forename: María Eva
authors.initials: ME
authors.lastname: Mingot-Castellano
authors.forename: Ignacia
authors.initials: I
authors.lastname: Balda
authors.forename: Carmen
authors.initials: C
authors.lastname: Altisent
authors.forename: Rocío
authors.initials: R
authors.lastname: Pérez-Montes
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Fisac
authors.forename: Gemma
authors.initials: G
authors.lastname: Iruín
authors.forename: Sonia
authors.initials: S
authors.lastname: Herrero
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Soto
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Rueda
authors.forename: Victor
authors.initials: V
authors.lastname: Jiménez-Yuste
authors.forename: Nieves
authors.initials: N
authors.lastname: Alonso
authors.forename: Dolores
authors.initials: D
authors.lastname: Vilariño
authors.forename: Olga
authors.initials: O
authors.lastname: Arija
authors.forename: Rosa
authors.initials: R
authors.lastname: Campos
authors.forename: María José
authors.initials: MJ
authors.lastname: Paloma
authors.forename: Nuria
authors.initials: N
authors.lastname: Bermejo
authors.forename: Teresa
authors.initials: T
authors.lastname: Toll
authors.forename: José
authors.initials: J
authors.lastname: Mateo
authors.forename: Karmele
authors.initials: K
authors.lastname: Arribalzaga
authors.forename: Pascual
authors.initials: P
authors.lastname: Marco
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Palomo
authors.forename: Lizheidy
authors.initials: L
authors.lastname: Sarmiento
authors.forename: Belén
authors.initials: B
authors.lastname: Iñigo
authors.forename: María del Mar
authors.initials: Mdel M
authors.lastname: Nieto
authors.forename: Rosa
authors.initials: R
authors.lastname: Vidal
authors.forename: María Paz
authors.initials: MP
authors.lastname: Martínez
authors.forename: Reyes
authors.initials: R
authors.lastname: Aguinaco
authors.forename: Jesús María
authors.initials: JM
authors.lastname: César
authors.forename: María
authors.initials: M
authors.lastname: Ferreiro
authors.forename: Javier
authors.initials: J
authors.lastname: García-Frade
authors.forename: Ana María
authors.initials: AM
authors.lastname: Rodríguez-Huerta
authors.forename: Jorge
authors.initials: J
authors.lastname: Cuesta
authors.forename: Ramón
authors.initials: R
authors.lastname: Rodríguez-González
authors.forename: Faustino
authors.initials: F
authors.lastname: García-Candel
authors.forename: Rosa
authors.initials: R
authors.lastname: Cornudella
authors.forename: Carlos
authors.initials: C
authors.lastname: Aguilar
authors.forename: Nina
authors.initials: N
authors.lastname: Borràs
authors.forename: Francisco
authors.initials: F
authors.lastname: Vidal
mesh_terms: D016022:Case-Control Studies; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D017720:Molecular Epidemiology; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D012042:Registries; D012307:Risk Factors; D013030:Spain; D014842:von Willebrand Diseases / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D014841:von Willebrand Factor
keywords: NGS; VWD; VWF; genotype; phenotype