Molecular and clinical profile of von willebrand disease in Spain (PCM-EVW-ES): Comprehensive genetic analysis by next-generation sequencing of 480 patients

Nina Borràs, Javier Batlle, Almudena Pérez-Rodríguez, María Fernanda López-Fernández, Ángela Rodríguez-Trillo, Esther Lourés, Ana Rosa Cid, Santiago Bonanad, Noelia Cabrera, Andrés Moret, Rafael Parra, María Eva Mingot-Castellano, Ignacia Balda, Carme Altisent, Rocío Pérez-Montes, Rosa María Fisac, Gemma Iruín, Sonia Herrero, Inmaculada Soto, Beatriz De RuedaVíctor Jiménez-Yuste, Nieves Alonso, Dolores Vilariño, Olga Arija, Rosa Campos, María José Paloma, Nuria Bermejo, Rubén Berrueco, José Mateo, Karmele Arribalzaga, Pascual Marco, Ángeles Palomo, Lizheidy Sarmiento, Belén Iñigo, María Del Mar Nieto, Rosa Vidal, María Paz Martínez, Reyes Aguinaco, Jesús María César, María Ferreiro, Javier García-Frade, Ana María Rodríguez-Huerta, Jorge Cuesta, Ramón Rodríguez-González, Faustino García-Candel, Rosa Cornudella, Carlos Aguilar, Irene Corrales

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    19 Citations (Scopus)


    © 2017 Ferrata Storti Foundation. Molecular diagnosis of patients with von Willebrand disease is pending in most populations due to the complexity and high cost of conventional molecular analyses. The need for molecular and clinical characterization of von Willebrand disease in Spain prompted the creation of a multicenter project (PCM-EVW-ES) that resulted in the largest prospective cohort study of patients with all types of von Willebrand disease. Molecular analysis of relevant regions of the VWF, including intronic and promoter regions, was achieved in the 556 individuals recruited via the development of a simple, innovative, relatively low-cost protocol based on microfluidic technology and next-generation sequencing. A total of 704 variants (237 different) were identified along VWF, 155 of which had not been previously recorded in the international mutation database. The potential pathogenic effect of these variants was assessed by in silico analysis. Furthermore, four short tandem repeats were analyzed in order to evaluate the ancestral origin of recurrent mutations. The outcome of genetic analysis allowed for the reclassification of 110 patients, identification of 37 asymptomatic carriers (important for genetic counseling) and re-inclusion of 43 patients previously excluded by phenotyping results. In total, 480 patients were definitively diagnosed. Candidate mutations were identified in all patients except 13 type 1 von Willebrand disease, yielding a high genotype-phenotype correlation. Our data reinforce the capital importance and usefulness of genetics in von Willebrand disease diagnostics. The progressive implementation of molecular study as the first-line test for routine diagnosis of this condition will lead to increasingly more personalized and effective care for this patient population. Identifier: 02869074.
    Original languageEnglish
    Pages (from-to)2005-2014
    Issue number12
    Publication statusPublished - 30 Nov 2017


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