Dataset Information

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

ABSTRACT: 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 multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number variants (CNVs) and intronic variants, as pathogenic, likely pathogenic, or variants of uncertain significance. Half of these variants (50.9%) are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPDs. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD.

SUBMITTER: Downes K

PROVIDER: S-EPMC6993014 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Downes Kate K Megy Karyn K Duarte Daniel D Vries Minka M Gebhart Johanna J Hofer Stefanie S Shamardina Olga O Deevi Sri V V SVV Stephens Jonathan J Mapeta Rutendo R Tuna Salih S Al Hasso Namir N Besser Martin W MW Cooper Nichola N Daugherty Louise L Gleadall Nick N Greene Daniel D Haimel Matthias M Martin Howard H Papadia Sofia S Revel-Vilk Shoshana S Sivapalaratnam Suthesh S Symington Emily E Thomas Will W Thys Chantal C Tolios Alexander A Penkett Christopher J CJ Ouwehand Willem H WH Abbs Stephen S Laffan Michael A MA Laffan Michael A MA Turro Ernest E Simeoni Ilenia I Mumford Andrew D AD Henskens Yvonne M C YMC Pabinger Ingrid I Gomez Keith K Gomez Keith K Freson Kathleen K

Blood 20191201 23

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 multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known ...[more]

PMID: 31064749

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Dataset Information

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

Publications

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

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