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

Autor:	Borràs N; Banc de Sang i Teixits, Barcelona, Spain.; Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Spain., Batlle J; Complexo Hospitalario Universitario A Coruña, INIBIC, Spain., Pérez-Rodríguez A; Complexo Hospitalario Universitario A Coruña, INIBIC, Spain., López-Fernández MF; Complexo Hospitalario Universitario A Coruña, INIBIC, Spain., Rodríguez-Trillo Á; Complexo Hospitalario Universitario A Coruña, INIBIC, Spain., Lourés E; Complexo Hospitalario Universitario A Coruña, INIBIC, Spain., Cid AR; Hospital Universitario y Politécnico La Fe, Valencia, Spain., Bonanad S; Hospital Universitario y Politécnico La Fe, Valencia, Spain., Cabrera N; Hospital Universitario y Politécnico La Fe, Valencia, Spain., Moret A; Hospital Universitario y Politécnico La Fe, Valencia, Spain., Parra R; Banc de Sang i Teixits, Barcelona, Spain.; Hospital Universitari Vall d'Hebron, Barcelona, Spain., Mingot-Castellano ME; Hospital Regional Universitario de Málaga, Spain., Balda I; Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain., Altisent C; Hospital Universitari Vall d'Hebron, Barcelona, Spain., Pérez-Montes R; Hospital Universitario Marqués de Valdecilla, Santander, Spain., Fisac RM; Salud Castilla y León, Segovia, Spain., Iruín G; Hospital Universitario Cruces, Barakaldo, Spain., Herrero S; Hospital Universitario de Guadalajara, Spain., Soto I; Hospital Universitario Central de Asturias, Oviedo, Spain., de Rueda B; Hospital Universitario Miguel Servet, Zaragoza, Spain., Jiménez-Yuste V; Hospital Universitario La Paz, Madrid, Spain., Alonso N; Hospital Infanta Cristina, Badajoz, Spain., Vilariño D; Complejo Hospitalario Universitario Santiago de Compostela, Spain., Arija O; Hospital Universitario Lucus Augusti, Lugo, Spain., Campos R; Hospital Jerez de la Frontera, Cádiz, Spain., Paloma MJ; Hospital Virgen del Camino, Pamplona, Spain., Bermejo N; Hospital San Pedro de Alcántara, Cáceres, Spain., Berrueco R; Hospital Sant Joan de Deu, Barcelona, Spain., Mateo J; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain., Arribalzaga K; Hospital Universitario Fundación de Alcorcón, Madrid, Spain., Marco P; Hospital General de Alicante, Spain., Palomo Á; Hospital Regional Universitario de Málaga, Spain., Sarmiento L; Hospital Universitario 12 de Octubre, Madrid, Spain., Iñigo B; Hospital Clínico San Carlos, Madrid, Spain., Nieto MDM; Complejo Hospitalario de Jaén, Spain., Vidal R; Fundación Jiménez Díaz, Madrid, Spain., Martínez MP; Hospital Nuestra Señora de Sonsoles, Ávila, Spain., Aguinaco R; Hospital Universitario de Tarragona Joan XXIII, Spain., César JM; Hospital Ramón y Cajal, Madrid, Spain., Ferreiro M; Hospital Montecelo, Pontevedra, Spain., García-Frade J; Hospital del Río Hortega, Valladolid, Spain., Rodríguez-Huerta AM; Hospital Gregorio Marañón, Madrid, Spain., Cuesta J; Hospital Virgen de la Salud, Toledo, Spain., Rodríguez-González R; Hospital Severo Ochoa, Madrid, Spain., García-Candel F; Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain., Cornudella R; Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain., Aguilar C; Hospital Santa Bárbara, Soria, Spain., Vidal F; Banc de Sang i Teixits, Barcelona, Spain icorrales@bst.cat fvidal@bst.cat.; Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Spain.; CIBER de Enfermedades Cardiovasculares, Spain., Corrales I; Banc de Sang i Teixits, Barcelona, Spain icorrales@bst.cat fvidal@bst.cat.; Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Spain.
Jazyk:	angličtina
Zdroj:	Haematologica [Haematologica] 2017 Dec; Vol. 102 (12), pp. 2005-2014. Date of Electronic Publication: 2017 Sep 29.
DOI:	10.3324/haematol.2017.168765
Abstrakt:	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. (Copyright© 2017 Ferrata Storti Foundation.)
Databáze:	MEDLINE
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