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Haematologica. 2018 Jan;103(1):148-162. doi: 10.3324/haematol.2017.171132. Epub 2017 Oct 5.

Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders.

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Servicio de Hematología, Hospital Universitario de Salamanca-IBSAL-USAL, Spain
On behalf of the Project "Functional and Molecular Characterization of Patients with Inherited Platelet Disorders" of the Hemorrhagic Diathesis Working Group of the Spanish Society of Thrombosis and Haemostasis.
Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CB15/00055-CIBERER, Spain.
IBSAL, IBMCC, CIC, Universidad de Salamanca-CSIC, Spain.
Servicio de Pediatría, Hospital Universitario de Salamanca-IBSAL, Spain.
Servicio de Hematología, Complejo Hospitalario San Pedro Alcántara, Cáceres, Spain.
Servicio de Pediatría, Hospital Clínico Universitario de Valladolid, Spain.
Servicio de Hematología y Hemoterapia, Hospital Virgen de la Salud, Complejo Hospitalario de Toledo, Spain.
Servicio de Hematología, Complejo Asistencial de Soria, Spain.
Serviço de Imunohemoterapia, Sangue e Medicina Transfusional do Centro Hospitalar e Universitário de Coimbra, EPE, Portugal.
Servicio Hematología y Hemoterapia, Complejo Hospitalario Universitario A Coruña, Spain.
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands.
Birmingham Platelet Group, Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, UK.
Servicio de Hematología, Hospital Universitario de Salamanca-IBSAL-USAL, Spain.


Inherited platelet disorders are a heterogeneous group of rare diseases, caused by inherited defects in platelet production and/or function. Their genetic diagnosis would benefit clinical care, prognosis and preventative treatments. Until recently, this diagnosis has usually been performed via Sanger sequencing of a limited number of candidate genes. High-throughput sequencing is revolutionizing the genetic diagnosis of diseases, including bleeding disorders. We have designed a novel high-throughput sequencing platform to investigate the unknown molecular pathology in a cohort of 82 patients with inherited platelet disorders. Thirty-four (41.5%) patients presented with a phenotype strongly indicative of a particular type of platelet disorder. The other patients had clinical bleeding indicative of platelet dysfunction, but with no identifiable features. The high-throughput sequencing test enabled a molecular diagnosis in 70% of these patients. This sensitivity increased to 90% among patients suspected of having a defined platelet disorder. We found 57 different candidate variants in 28 genes, of which 70% had not previously been described. Following consensus guidelines, we qualified 68.4% and 26.3% of the candidate variants as being pathogenic and likely pathogenic, respectively. In addition to establishing definitive diagnoses of well-known inherited platelet disorders, high-throughput sequencing also identified rarer disorders such as sitosterolemia, filamin and actinin deficiencies, and G protein-coupled receptor defects. This included disease-causing variants in DIAPH1 (n=2) and RASGRP2 (n=3). Our study reinforces the feasibility of introducing high-throughput sequencing technology into the mainstream laboratory for the genetic diagnostic practice in inherited platelet disorders.

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