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

AuthorsBastida, José María; Lozano, Maria Luisa; Benito, Rocío; Janusz, Kamila; Palma-Barqueros, Verónica; Rey, Mónica del; Hernandez-Sánchez, Jesus M.; Riesco, Susana; Bermejo, Nuria; González-García, Hermenegildo; Rodriguez-Alén, Agustín; Aguilar, Carlos; Sevivas, Teresa; López-Fernández, María F.; Marneth, Anna E.; Reijden, Bert A. van der; Morgan, Neil V.; Watson, Steve P.; Vicente, Vicente; Hernández, Jesús M. ; Rivera, José; González-Porras, José R.
Issue Date2018
PublisherFerrata Storti Foundation
CitationHaematologica 103(1): 148-162 (2018)
AbstractInherited 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.
Publisher version (URL)https://doi.org/10.3324/haematol.2017.171132
Identifiersdoi: 10.3324/haematol.2017.171132
e-issn: 1592-8721
issn: 0390-6078
Appears in Collections:(IBMCC) Artículos
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