Download PDF
Open Access
CC BY-NC-ND 4.0 · Thromb Haemost
DOI: 10.1055/a-2806-3835
Original Article: Cellular Haemostasis and Platelets

Unveiling the genetic landscape of inherited primary hemostasis disorders by whole-exome sequencing: insights from a multi-center study

Authors

  • Perla Bandini 

    1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits (Ringgold ID: RIN581034), Barcelona, Spain
    2   Medicina Transfusional, Vall d’Hebron Institut de Recerca - Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
    3   Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona (Ringgold ID: RIN16724), Barcelona, Spain

  • Nina Borràs

    4   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
    2   Medicina Transfusional, Vall d’Hebron Institut de Recerca - Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain

  • Laura Martin-Fernandez 

    1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits (Ringgold ID: RIN581034), Barcelona, Spain
    2   Medicina Transfusional, Vall d’Hebron Institut de Recerca - Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain

  • Noèlia Vilalta Setó

    5   Unitat d'Hemostasia i Trombosi, Servei d'Hematologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

  • Marina Carrasco

    5   Unitat d'Hemostasia i Trombosi, Servei d'Hematologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

  • Jose Mateo

    6   Unitat d'Hemostàsia i Trombosi, Servei d'Hematologia, Hospital de la Santa Creu i Sant Pau (Ringgold ID: RIN16689), Barcelona, Spain

  • Olga Benítez

    7   Unidad de Hemofilia, Hospital Universitari Vall d'Hebron (Ringgold ID: RIN16810), Barcelona, Spain

  • Ruben Berrueco

    8   Servicio de Hematología Pediátrica, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Pediàtrica, Hospital San Joan de Déu de Barcelona (IRP‐HSJD), Universitat de Barcelona, Barcelona, Spain
    9   Instituto Nacional de Investigación Biomédica en Enfermedades Raras (CIBER ER), Instituto de Salud Carlos III, Madrid, Spain

  • Susanna Gassiot

    10   Servei de Diagnòstic de Laboratori, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Pediàtrica, Hospital San Joan de Déu de Barcelona (IRP‐HSJD), Universitat de Barcelona, Barcelona, Spain

  • Jose Maria Bastida

    11   Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca (USAL), Salamanca, Spain

  • Nazly Santos

    12   Servei d’Hematologia, Institut Català d’Oncologia (ICO) - Hospital Dr. Josep Trueta, Girona, Spain

  • Ramón Salinas

    13   Servei d’Hematologia i Hemoteràpia, Hospital Universitari Sagrat Cor, Universitat Internacional de Catalunya, Barcelona, Spain

  • Rosa Maria Acevedo

    14   Servicio de Hematología, Complejo Hospitalario Universitario Insular Materno Infantil de Gran Canaria, Gran Canaria, Spain

  • Reyes Aguinaco

    15   Servicio de Hematología, Hospital Universitario Joan XXIII, Tarragona, Spain

  • Eugenia Fernandez-Mellid

    16   Servicio de Hematología, Hospital Clínico Universitario de Santiago de Compostela (CHUS-SERGAS), Santiago de Compostela, Spain

  • Laura López-Andreoni

    17   Servei Laboratori Clínic, Unitat d’Hemostàsia i Trombosi, Hospital Universitari de Bellvitge (Ringgold ID: RIN16383), L'Hospitalet de Llobregat, Spain

  • Olga Ramón

    18   Servei d’Hematologia i Hemoteràpia, Hospital Universitari d'Igualada (Ringgold ID: RIN124870), Igualada, Spain

  • Francisco Javier Lucas

    19   Departamento de Hemostasia y Trombosis, Hospital General Universitario Dr Balmis (Ringgold ID: RIN16802), Alicante, Spain

  • Laura Quintana Paris

    20   Servicio de Hematología y Hemoterapia, Hospital Universitario de Gran Canaria Dr Negrin (Ringgold ID: RIN16461), Las Palmas de Gran Canaria, Spain

  • César Velásquez Escandón

    21   Departamento de Hematología, Fundación Sanitaria de Mollet, Mollet del Vallès, Spain

  • Albert Tugues

    22   Departament d’Hematologia, Hospital Universitari Arnau de Vilanova (Ringgold ID: RIN16296), Lleida, Spain

  • Shally Marcellini

    23   Servicio de Hematología, Complejo Asistencial de Segovia (Ringgold ID: RIN16828), Segovia, Spain

  • Eva Alonso

    24   Banc de Sang i Teixits - Hospital Universitari Germans Trias i Pujol, Barcelona, Spain

  • Rafael Parra

    2   Medicina Transfusional, Vall d’Hebron Institut de Recerca - Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain

  • Iris Garcia-Martínez 

    1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits (Ringgold ID: RIN581034), Barcelona, Spain
    2   Medicina Transfusional, Vall d’Hebron Institut de Recerca - Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain

  • Carlos Hobeich

    1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits (Ringgold ID: RIN581034), Barcelona, Spain
    2   Medicina Transfusional, Vall d’Hebron Institut de Recerca - Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain

  • Noemí González

    1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits (Ringgold ID: RIN581034), Barcelona, Spain
    25   Medicina Tansfusional, Vall d’Hebron Institut de Recerca - Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain

  • Carina Lera

    1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits (Ringgold ID: RIN581034), Barcelona, Spain
    2   Medicina Transfusional, Vall d’Hebron Institut de Recerca - Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain

  • Natàlia Comes

    1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits (Ringgold ID: RIN581034), Barcelona, Spain
    2   Medicina Transfusional, Vall d’Hebron Institut de Recerca - Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain

  • Lorena Ramírez

    1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits (Ringgold ID: RIN581034), Barcelona, Spain
    2   Medicina Transfusional, Vall d’Hebron Institut de Recerca - Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain

  • Francisco Vidal 

    1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits (Ringgold ID: RIN581034), Barcelona, Spain
    2   Medicina Transfusional, Vall d’Hebron Institut de Recerca - Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
    26   Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (Ringgold ID: RIN38176), Madrid, Spain

  • Irene Corrales

    1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits (Ringgold ID: RIN581034), Barcelona, Spain
    2   Medicina Transfusional, Vall d’Hebron Institut de Recerca - Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
    26   Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (Ringgold ID: RIN38176), Madrid, Spain

Supported by: Instituto de Salud Carlos III PI18/01492, PI23/01672, PI24/01458
Further Information
 PDF Download

Inherited primary hemostasis disorders (IPHD) comprise a clinically and genetically heterogeneous spectrum, including inherited platelet disorders (IPD), heritable disorders of connective tissue (HDCT) associated with bleeding, and bleeding disorders of unknown cause (BDUC). Their phenotypic overlap and limited access to specific functional testing make genetic analysis essential for accurate diagnosis. This study aimed to investigate the genetic basis of patients with IPHD through Whole-exome sequencing (WES), providing genotype-phenotype correlations to guide clinical management. A total of 170 probands were included: 114 with IPD (67%), 28 with HDCT (16%), and 28 with BDUC (16%). Definitive genotype-phenotype correlation was achieved in 83 probands (49%), identifying 98 unique candidate variants across 48 genes. Notably, 19 patients carried variants in different genes that can contribute to the phenotype. A partial genotype-phenotype correlation was achieved in 19 probands (11%), while no variants were identified in the remaining 68 (40%), especially in the BDUC group. This multicenter study represents the first integrated analysis using a single workflow for patients with IPHD, encompassing not only IPD and BDUC but also HDCT. The high rate of genotype-phenotype correlations achieved, the identification of 68 previously undescribed variants, and the evidence of a shared and overlapped genetic and phenotypic profile among IPHD patients demonstrate the clinical value of WES. The study advocates for a paradigm shift in the clinical diagnosis of IPHD, from traditional phenotype-driven assesment to genotype-informed strategies, positioning WES as a first-line tool together with basic laboratory tests, allowing faster and more accurate diagnosis and personalized patient care.



Publication History

Received: 24 October 2025

Accepted after revision: 04 February 2026

Accepted Manuscript online:
11 February 2026

© . The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany