scholarly journals Strengths and limitations of high‐throughput sequencing for the diagnosis of inherited bleeding and platelet disorders

2020 ◽  
Vol 18 (8) ◽  
pp. 1839-1845 ◽  
Author(s):  
Fabienne Ver Donck ◽  
Kate Downes ◽  
Kathleen Freson
Keyword(s):  
High Throughput ◽  
High Throughput Sequencing ◽  
Platelet Disorders

scholarly journals Use of Targeted High-Throughput Sequencing for Genetic Classification of Patients with Bleeding Diathesis and Suspected Platelet Disorder

TH Open ◽  
2018 ◽  
Vol 02 (04) ◽  
pp. e445-e454 ◽  
Author(s):  
Oliver Andres ◽  
Eva-Maria König ◽  
Karina Althaus ◽  
Tamam Bakchoul ◽  
Peter Bugert ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Sequencing ◽  
Genetic Diagnosis ◽  
Individual Risk ◽  
Recurrent Bleeding ◽  
Bleeding Diathesis ◽  
Genetic Classification ◽  
Diagnostic Algorithms ◽  
Platelet Disorder ◽  
Platelet Disorders

AbstractInherited platelet disorders (IPD) form a rare and heterogeneous disease entity that is present in about 8% of patients with non-acquired bleeding diathesis. Identification of the defective cellular pathway is an important criterion for stratifying the patient's individual risk profile and for choosing personalized therapeutic options. While costs of high-throughput sequencing technologies have rapidly declined over the last decade, molecular genetic diagnosis of bleeding and platelet disorders is getting more and more suitable within the diagnostic algorithms. In this study, we developed, verified, and evaluated a targeted, panel-based next-generation sequencing approach comprising 59 genes associated with IPD for a cohort of 38 patients with a history of recurrent bleeding episodes and functionally suspected, but so far genetically undefined IPD. DNA samples from five patients with genetically defined IPD with disease-causing variants in WAS, RBM8A, FERMT3, P2YR12, and MYH9 served as controls during the validation process. In 40% of 35 patients analyzed, we were able to finally detect 15 variants, eight of which were novel, in 11 genes, ACTN1, AP3B1, GFI1B, HPS1, HPS4, HPS6, MPL, MYH9, TBXA2R, TPM4, and TUBB1, and classified them according to current guidelines. Apart from seven variants of uncertain significance in 11% of patients, nine variants were classified as likely pathogenic or pathogenic providing a molecular diagnosis for 26% of patients. This report also emphasizes on potentials and pitfalls of this tool and prospectively proposes its rational implementation within the diagnostic algorithms of IPD.

scholarly journals A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders

Blood ◽  
2016 ◽  
Vol 127 (23) ◽  
pp. 2791-2803 ◽  
Author(s):  
Ilenia Simeoni ◽  
Jonathan C. Stephens ◽  
Fengyuan Hu ◽  
Sri V. V. Deevi ◽  
Karyn Megy ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Sequencing ◽  
Genetic Test ◽  
Targeted Sequencing ◽  
Sequencing Platform ◽  
Key Points ◽  
Platelet Disorders

Key Points Developed a targeted sequencing platform covering 63 genes linked to heritable bleeding, thrombotic, and platelet disorders. The ThromboGenomics platform provides a sensitive genetic test to obtain molecular diagnoses in patients with a suspected etiology.

scholarly journals Diagnostic high-throughput sequencing of 2,390 patients with bleeding, thrombotic and platelet disorders

2018 ◽  
Author(s):  
Kate Downes ◽  
Karyn Megy ◽  
Daniel Duarte ◽  
Minka Vries ◽  
Johanna Gebhart ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Sequencing ◽  
Clinical Phenotype ◽  
Careful Consideration ◽  
Clinical Diagnostics ◽  
Genomic Variation ◽  
Panel Test ◽  
Platelet Disorders ◽  
Normal Hemostasis ◽  
And Function

A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multi-disciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2,390 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbour variants associated with rare bleeding, thrombotic or platelet disorders (BPD). The diagnostic rate was determined by the clinical phenotype, with an overall rate of 50.4% for all thrombotic, coagulation, platelet count and function disorder patients and a rate of 6.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 756 unique variants, including copy number and intronic variants, as Pathogenic, Likely Pathogenic or Variants of Uncertain Significance. Almost half (49.7%) of these variants are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BPD. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 897 index patients providing evidence that introducing a HTS genetic test for BPD patients is meeting an important unmet clinical need.

scholarly journals Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders

Blood ◽  
2019 ◽  
Vol 134 (23) ◽  
pp. 2082-2091 ◽  
Author(s):  
Kate Downes ◽  
Karyn Megy ◽  
Daniel Duarte ◽  
Minka Vries ◽  
Johanna Gebhart ◽  
...  
Keyword(s):  
High Throughput ◽  
Genetic Screening ◽  
High Throughput Sequencing ◽  
Platelet Disorders

This paper reports on the use of a high-throughput diagnostic genetic screening for coagulation, platelet, or thrombotic disorders in a series of more than 2000 patients.

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

Haematologica ◽  
2017 ◽  
Vol 103 (1) ◽  
pp. 148-162 ◽  
Author(s):  
José M. Bastida ◽  
María L. Lozano ◽  
Rocío Benito ◽  
Kamila Janusz ◽  
Verónica Palma-Barqueros ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Sequencing ◽  
Genetic Diagnosis ◽  
Platelet Disorders
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