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

ABSTRACT: 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.

SUBMITTER: Bastida JM

PROVIDER: S-EPMC5777202 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Bastida José M JM Lozano María L ML Benito Rocío R Janusz Kamila K Palma-Barqueros Verónica V Del Rey Mónica M Hernández-Sánchez Jesús M JM Riesco Susana S Bermejo Nuria N González-García Hermenegildo H Rodriguez-Alén Agustín A Aguilar Carlos C Sevivas Teresa T López-Fernández María F MF Marneth Anna E AE van der Reijden Bert A BA Morgan Neil V NV Watson Steve P SP Vicente Vicente V Hernández-Rivas Jesús M JM Rivera José J González-Porras José R JR

Haematologica 20171005 1

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 <i>via</i> 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 ...[more]

PMID: 28983057

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Dataset Information

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

Publications

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

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