Details

Autor(en) / Beteiligte

• Bastida, José M
• Lozano, María L
• Benito, Rocío
• Janusz, Kamila
• Palma-Barqueros, Verónica
• Del Rey, Mónica
• Hernández-Sánchez, Jesús M
• Riesco, Susana
• Bermejo, Nuria
• González-García, Hermenegildo
• Rodriguez-Alén, Agustín
• Aguilar, Carlos
• Sevivas, Teresa
• López-Fernández, María F
• Marneth, Anna E
• van der Reijden, Bert A
• Morgan, Neil V
• Watson, Steve P
• Vicente, Vicente
• Hernández-Rivas, Jesús M
• Rivera, José
• González-Porras, José R

Titel

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

Ist Teil von

• Haematologica (Roma), 2018-01, Vol.103 (1), p.148

Ort / Verlag

Italy

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 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 (n=2) and (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.