TY - JOUR
T1 - Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders
AU - Downes, Kate
AU - Megy, Karyn
AU - Duarte, Daniel
AU - Vries, Minka
AU - Gebhart, Johanna
AU - Hofer, Stefanie
AU - Shamardina, Olga
AU - Deevi, Sri V. V.
AU - Stephens, Jonathan
AU - Mapeta, Rutendo
AU - Tuna, Salih
AU - Al Hasso, Namir
AU - Besser, Martin W.
AU - Cooper, Nichola
AU - Daugherty, Louise
AU - Gleadall, Nick
AU - Greene, Daniel
AU - Haimel, Matthias
AU - Martin, Howard
AU - Papadia, Sofia
AU - Revel-Vilk, Shoshana
AU - Sivapalaratnam, Suthesh
AU - Symington, Emily
AU - Thomas, Will
AU - Thys, Chantal
AU - Tolios, Alexander
AU - Penkett, Christopher J.
AU - Ouwehand, Willem H.
AU - Abbs, Stephen
AU - Laffan, Michael A.
AU - Turro, Ernest
AU - Simeoni, Ilenia
AU - Mumford, Andrew D.
AU - Henskens, Yvonne M. C.
AU - Pabinger, Ingrid
AU - Gomez, Keith
AU - Freson, Kathleen
AU - NIHR BioResource
N1 - Funding Information:
This study makes use of data generated by the NIHR BioResource. The authors gratefully acknowledge the participation of all NIHR BioResource volunteers and thank the NIHR BioResource center and staff for their contribution. The authors thank the Locus Reference Genomic team (LRG) for their assistance in curating gene transcripts. This work was supported by the National Institute for Health Research (NIHR) under grant number RG65966. Research in the Ouwehand laboratory received funding from the British Heart Foundation, European Commission (TrainMALTA), International Society on Thrombosis and Haemostasis, Medical Research Council, National Health Service (NHS) Blood and Transplant, and the Rosetrees Trust. The Vienna Bleeding Biobank was supported by an unrestricted grant of CSL Behring. K.D. was supported as an NHS Higher Specialist Scientist Training (HSST) trainee by Health Education England. K.F. was supported by the Research Council of the University of Leuven (Special Research Fund [BOF] KU Leuven, Belgium, OT/14/098) and by an unrestricted grant of Sobi.
Funding Information:
This work was supported by the National Institute for Health Research (NIHR) under grant number RG65966. Research in the Ouwehand laboratory received funding from the British Heart Foundation, European Commission (TrainMALTA), International Society on Thrombosis and Haemostasis, Medical Research Council, National Health Service (NHS) Blood and Transplant, and the Rosetrees Trust. The Vienna Bleeding Biobank was supported by an unrestricted grant of CSL Behring. K.D. was supported as an NHS Higher Specialist Scientist Training (HSST) trainee by Health Education England. K.F. was supported by the Research Council of the University of Leuven (Special Research Fund [BOF] KU Leuven, Belgium, OT/14/098) and by an unrestricted grant of Sobi.
Funding Information:
A diagnostic HTS platform requires careful selection of diagnostic-grade TIER1 genes. The decision to include a gene to the BTPD TIER1 list is made by the GinTH SSC of the ISTH. The designation of genes for diagnostic reporting involved the review of associated literature to evaluate whether a gene is associated with disease in .3 independent pedigrees with convincing co-segregation data or in ,3 pedigrees, but with strong functional evidence (mouse models or cell/protein studies) in addition to cosegregation data. In the future, this task will also be coordinated by the National Institutes of Health (NIH)-supported Hemostasis/ Thrombosis Clinical Domain Working Group in close partnership with the ISTH and the American Society of Hematology (ASH) expert working groups.37
Publisher Copyright:
© 2019 by The American Society of Hematology
PY - 2019/12/5
Y1 - 2019/12/5
N2 - 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.
AB - 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.
KW - GENETIC DIAGNOSIS
KW - INHERITED THROMBOCYTOPENIA
KW - VARIANTS
KW - MUTATION
KW - BIOBANK
KW - DYSFUNCTION
U2 - 10.1182/blood.2018891192
DO - 10.1182/blood.2018891192
M3 - Article
SN - 0006-4971
VL - 134
SP - 2082
EP - 2091
JO - Blood
JF - Blood
IS - 23
ER -