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

Author

Downes K, Megy K, Duarte D, Vries M, Gebhart J, Hofer S, Shamardina O, Deevi SVV, Stephens J, Mapeta R, Tuna S, Al Hasso N, Besser MW, Cooper N, Daugherty L, Gleadall N, Greene D, Haimel M, Martin H, Papadia S, Revel-Vilk S, Sivapalaratnam S, Symington E, Thomas W, Thys C, Tolios A, Penkett CJ, Ouwehand WH, Abbs S, Laffan MA, Turro E, Simeoni I, Mumford AD, Henskens YMC, Pabinger I, Gomez K, and Freson K

Subjects
Female, Gene Dosage, Hemostasis genetics, Humans, Male, Blood Platelet Disorders diagnosis, Blood Platelet Disorders genetics, Hemorrhage diagnosis, Hemorrhage genetics, High-Throughput Nucleotide Sequencing, Thrombosis diagnosis, Thrombosis genetics
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., (© 2019 by The American Society of Hematology.)

Published
2019
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2. Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding.

Author

Westbury SK, Canault M, Greene D, Bermejo E, Hanlon K, Lambert MP, Millar CM, Nurden P, Obaji SG, Revel-Vilk S, Van Geet C, Downes K, Papadia S, Tuna S, Watt C, Freson K, Laffan MA, Ouwehand WH, Alessi MC, Turro E, and Mumford AD

Subjects
Alleles, Base Sequence, Female, Humans, Male, Pedigree, Blood Platelets pathology, Guanine Nucleotide Exchange Factors genetics, Hemorrhage genetics, Mutation genetics
Abstract

Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterized. Pathogenic variants in RASGRP2 , which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in 3 pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5422 controls. Eleven cases harbored 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included 5 high-impact variants predicted to prevent CalDAG-GEFI expression and 6 missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out αIIbβ3 signaling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical, and dental bleeding from childhood, requiring ≥1 blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to adenosine 5'-diphosphate and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a nonsyndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation., (© 2017 by The American Society of Hematology.)

Published
2017
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3. Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia.

Author

Sivapalaratnam S, Westbury SK, Stephens JC, Greene D, Downes K, Kelly AM, Lentaigne C, Astle WJ, Huizinga EG, Nurden P, Papadia S, Peerlinck K, Penkett CJ, Perry DJ, Roughley C, Simeoni I, Stirrups K, Hart DP, Tait RC, Mumford AD, Laffan MA, Freson K, Ouwehand WH, Kunishima S, and Turro E

Subjects
Alleles, Blood Platelets pathology, Case-Control Studies, Female, Gene Expression, Genes, Dominant, Genome, Human, Hemorrhage diagnosis, Hemorrhage metabolism, Hemorrhage pathology, High-Throughput Nucleotide Sequencing, Humans, Male, Pedigree, Platelet Count, Thrombocytopenia diagnosis, Thrombocytopenia metabolism, Thrombocytopenia pathology, Blood Platelets metabolism, Hemorrhage genetics, Mutation, Platelet Glycoprotein GPIb-IX Complex genetics, Thrombocytopenia genetics
Abstract

The von Willebrand receptor complex, which is composed of the glycoproteins Ibα, Ibβ, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, GP1BA, GP1BB, and GP9) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothrombocytopenia, but only 2 tentative reports exist of such a variant in GP1BB By analyzing data from a collection of more than 1000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in GP1BB and macrothrombocytopenia. To strengthen our findings, we sought further cases in 2 additional collections in the United Kingdom and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying 1 of 9 rare variants in GP1BB., (© 2017 by The American Society of Hematology.)

Published
2017
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4. A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders.

Author

Simeoni I, Stephens JC, Hu F, Deevi SV, Megy K, Bariana TK, Lentaigne C, Schulman S, Sivapalaratnam S, Vries MJ, Westbury SK, Greene D, Papadia S, Alessi MC, Attwood AP, Ballmaier M, Baynam G, Bermejo E, Bertoli M, Bray PF, Bury L, Cattaneo M, Collins P, Daugherty LC, Favier R, French DL, Furie B, Gattens M, Germeshausen M, Ghevaert C, Goodeve AC, Guerrero JA, Hampshire DJ, Hart DP, Heemskerk JW, Henskens YM, Hill M, Hogg N, Jolley JD, Kahr WH, Kelly AM, Kerr R, Kostadima M, Kunishima S, Lambert MP, Liesner R, López JA, Mapeta RP, Mathias M, Millar CM, Nathwani A, Neerman-Arbez M, Nurden AT, Nurden P, Othman M, Peerlinck K, Perry DJ, Poudel P, Reitsma P, Rondina MT, Smethurst PA, Stevenson W, Szkotak A, Tuna S, van Geet C, Whitehorn D, Wilcox DA, Zhang B, Revel-Vilk S, Gresele P, Bellissimo DB, Penkett CJ, Laffan MA, Mumford AD, Rendon A, Gomez K, Freson K, Ouwehand WH, and Turro E

Subjects
Case-Control Studies, DNA Copy Number Variations, Female, Genetic Association Studies methods, Humans, Male, Mutation, Polymorphism, Single Nucleotide, Sequence Analysis, DNA methods, Blood Platelet Disorders genetics, Genetic Predisposition to Disease, Hemorrhage genetics, High-Throughput Nucleotide Sequencing methods, Thrombosis genetics
Abstract

Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached, which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants, short insertions/deletions, and large copy number variants (though not inversions) which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an a priori highly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only 8 of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD., (© 2016 by The American Society of Hematology.)

Published
2016
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5. A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies.

Author

Turro E, Greene D, Wijgaerts A, Thys C, Lentaigne C, Bariana TK, Westbury SK, Kelly AM, Selleslag D, Stephens JC, Papadia S, Simeoni I, Penkett CJ, Ashford S, Attwood A, Austin S, Bakchoul T, Collins P, Deevi SV, Favier R, Kostadima M, Lambert MP, Mathias M, Millar CM, Peerlinck K, Perry DJ, Schulman S, Whitehorn D, Wittevrongel C, De Maeyer M, Rendon A, Gomez K, Erber WN, Mumford AD, Nurden P, Stirrups K, Bradley JR, Raymond FL, Laffan MA, Van Geet C, Richardson S, Freson K, and Ouwehand WH

Subjects
Animals, Blood Platelets pathology, COS Cells, Chlorocebus aethiops, Female, Hematopoiesis, Hemorrhage complications, Humans, Male, Pedigree, Phenotype, Primary Myelofibrosis complications, Thrombocytopenia complications, Transfection, Zebrafish, Bone and Bones pathology, Hemorrhage genetics, Mutation genetics, Primary Myelofibrosis genetics, Thrombocytopenia genetics, src-Family Kinases genetics
Abstract

The Src family kinase (SFK) member SRC is a major target in drug development because it is activated in many human cancers, yet deleterious SRC germline mutations have not been reported. We used genome sequencing and Human Phenotype Ontology patient coding to identify a gain-of-function mutation in SRC causing thrombocytopenia, myelofibrosis, bleeding, and bone pathologies in nine cases. Modeling of the E527K substitution predicts loss of SRC's self-inhibitory capacity, which we confirmed with in vitro studies showing increased SRC kinase activity and enhanced Tyr(419) phosphorylation in COS-7 cells overexpressing E527K SRC. The active form of SRC predominates in patients' platelets, resulting in enhanced overall tyrosine phosphorylation. Patients with myelofibrosis have hypercellular bone marrow with trilineage dysplasia, and their stem cells grown in vitro form more myeloid and megakaryocyte (MK) colonies than control cells. These MKs generate platelets that are dysmorphic, low in number, highly variable in size, and have a paucity of α-granules. Overactive SRC in patient-derived MKs causes a reduction in proplatelet formation, which can be rescued by SRC kinase inhibition. Stem cells transduced with lentiviral E527K SRC form MKs with a similar defect and enhanced tyrosine phosphorylation levels. Patient-derived and E527K-transduced MKs show Y419 SRC-positive stained podosomes that induce altered actin organization. Expression of mutated src in zebrafish recapitulates patients' blood and bone phenotypes. Similar studies of platelets and MKs may reveal the mechanism underlying the severe bleeding frequently observed in cancer patients treated with next-generation SFK inhibitors., (Copyright © 2016, American Association for the Advancement of Science.)

Published
2016
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6. Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding

Author

Westbury, Sarah K, Canault, Matthias, Greene, Daniel, Bermejo, Emilse, Hanlon, Katharine, Lambert, Michele P, Millar, Carolyn M, Nurden, Paquita, Obaji, Samya G, Revel-Vilk, Shoshana, Van Geet, Chris, Downes, Kate, Papadia, Sofia, Tuna, Salih, Watt, Christopher, NIHR BioResource–Rare Diseases Consortium, Freson, Kathleen, Laffan, Michael A, Ouwehand, Willem H, Alessi, Marie-Christine, Turro, Ernest, and Mumford, Andrew D

Subjects
Blood Platelets, Male, Base Sequence, Mutation, Guanine Nucleotide Exchange Factors, Humans, Female, Hemorrhage, Alleles, 3. Good health, Pedigree
Abstract

Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterized. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in 3 pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5422 controls. Eleven cases harbored 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included 5 high-impact variants predicted to prevent CalDAG-GEFI expression and 6 missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out αIIbβ3 signaling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical, and dental bleeding from childhood, requiring ≥1 blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to adenosine 5'-diphosphate and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a nonsyndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation.

7. Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding

Author

Emilse Bermejo, Michele P. Lambert, Chris Van Geet, Samya Obaji, Marie-Christine Alessi, Sofia Papadia, Matthias Canault, Shoshana Revel-Vilk, Daniel Greene, Andrew D Mumford, Ernest Turro, Salih Tuna, Sarah K Westbury, Kate Downes, Willem H. Ouwehand, Carolyn M. Millar, Christopher Watt, Kathleen Freson, Katharine Hanlon, Paquita Nurden, Michael Laffan, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biostatistics Unit, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Hematological Research Institute, National Academy of Medicine, Department of Haematology [Glasgow Royal Infirmary], University of Glasgow-Glasgow Royal Infirmary, Institut Parisien de Recherche Architecture Urbanistique Société (IPRAUS), Architecture Urbanisme Société : Savoir Enseignement Recherche (UMR AUSser), Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture et de la Communication (MCC)-École nationale supérieure d'architecture de Paris-Belleville (ENSA PB)-École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV)-École nationale supérieure d'architecture de Paris-Malaquais (ENSAPM)-École Nationale Supérieure d'Architecture de la Ville et des Territoires à Marne-la-Vallée (éavt&t)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture et de la Communication (MCC)-École nationale supérieure d'architecture de Paris-Belleville (ENSA PB)-École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV)-École nationale supérieure d'architecture de Paris-Malaquais (ENSAPM)-École Nationale Supérieure d'Architecture de la Ville et des Territoires à Marne-la-Vallée (éavt&t), IHU-LIRYC, CHU Bordeaux [Bordeaux]-Université Bordeaux Segalen - Bordeaux 2, Pediatric Hematology/Oncology Department, Hadassah Hebrew University Medical Center [Jerusalem], Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, Université Catholique de Louvain = Catholic University of Louvain (UCL), NIHR BioResource - Rare Diseases, Cambridge University Hospitals (CUH), Department of Haematology, Queens Elizabeth Hospital [Birmingham], NHS Blood and Transplant, Center for Molecular and Vascular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Cambridge [UK] (CAM), The Wellcome Trust Sanger Institute [Cambridge], Nutrition, obésité et risque thrombotique ( NORT ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CRLCC Antoine Lacassagne, Institut Parisien de Recherche Architecture Urbanistique Société ( IPRAUS ), Architecture Urbanisme Société : Savoir Enseignement Recherche ( UMR AUSser ), École nationale supérieure d'architecture de Paris-La Villette ( ENSAPLV ) -École nationale supérieure d'architecture de Paris-Belleville ( ENSA PB ) -Ministère de la Culture et de la Communication ( MCC ) -École nationale supérieure d'architecture de Paris-Malaquais ( ENSAPM ) -Centre National de la Recherche Scientifique ( CNRS ) -École nationale supérieure d'architecture de Paris-La Villette ( ENSAPLV ) -École nationale supérieure d'architecture de Paris-Belleville ( ENSA PB ) -Ministère de la Culture et de la Communication ( MCC ) -École nationale supérieure d'architecture de Paris-Malaquais ( ENSAPM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Université Catholique de Louvain, Cambridge University Hospitals ( CUH ), Queen Elizabeth Hospital, Catholic University of Leuven ( KU Leuven ), University of Cambridge [UK] ( CAM ), Medical Research Council (MRC), Downes, Kate [0000-0003-0366-1579], Papadia, Sofia [0000-0002-9222-3812], Tuna, Salih [0000-0003-3606-4367], Ouwehand, Willem [0000-0002-7744-1790], Turro Bassols, Ernest [0000-0002-1820-6563], Apollo - University of Cambridge Repository, École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-École nationale supérieure d'architecture de Paris-Belleville (ENSA PB)-Ministère de la Culture et de la Communication (MCC)-École nationale supérieure d'architecture de Paris-Malaquais (ENSAPM)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Architecture de la Ville et des Territoires à Marne-la-Vallée (éavt&t)-École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV), and HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-École nationale supérieure d'architecture de Paris-Belleville (ENSA PB)-Ministère de la Culture et de la Communication (MCC)-École nationale supérieure d'architecture de Paris-Malaquais (ENSAPM)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Architecture de la Ville et des Territoires à Marne-la-Vallée (éavt&t)

Subjects
Male, 0301 basic medicine, genetic disorde, 030204 cardiovascular system & hematology, Bioinformatics, Biochemistry, ACTIVATION, 0302 clinical medicine, ISTH, GENETIC-VARIANTS, [SDV.IDA]Life Sciences [q-bio]/Food engineering, 1114 Paediatrics And Reproductive Medicine, Guanine Nucleotide Exchange Factors, Missense mutation, Platelet, WORLDWIDE SURVEY, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, ComputingMilieux_MISCELLANEOUS, Blood Platelet Disorders, Hematology, [ SDV.IDA ] Life Sciences [q-bio]/Food engineering, DEFECTS, Phenotype, trouble génétiq, Pedigree, 3. Good health, phénotype, thrombocytopath, Female, Life Sciences & Biomedicine, Blood Platelets, medicine.medical_specialty, DISORDERS, NIHR BioResource–Rare Diseases Consortium, Platelet disorder, Immunology, Hemorrhage, DIAGNOSIS, 1102 Cardiovascular Medicine And Haematology, 03 medical and health sciences, Internal medicine, Journal Article, medicine, Humans, Alleles, Science & Technology, Base Sequence, MUTATIONS, business.industry, Genetic heterogeneity, THROMBOCYTOPENIA, séquençage à ha, 1103 Clinical Sciences, Cell Biology, activation plaq, 030104 developmental biology, Platelet transfusion, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, CALDAG-GEFI, business
Abstract

International audience; Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterised. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in three pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2,042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5,422 controls. Eleven cases harboured 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included five high-impact variants predicted to prevent CalDAG-GEFI expression and six missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out αIIbβ3 signalling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical and dental bleeding from childhood, requiring at least one blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to ADP and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a non-syndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation.

Published
2017
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8. Rare variants in $\textit{GP1BB}$ are responsible for autosomal dominant macrothrombocytopenia

Author

Sivapalaratnam, S, Westbury, SK, Stephens, JC, Greene, D, Downes, K, Kelly, AM, Lentaigne, C, Astle, WJ, Huizinga, EG, Nurden, P, Papadia, S, Peerlinck, K, Penkett, CJ, Perry, DJ, Roughley, C, Simeoni, I, Stirrups, K, Hart, DP, Tait, RC, Mumford, AD, NIHR BioResource, Laffan, MA, Freson, K, Ouwehand, WH, Kunishima, S, Turro, E, Stephens, Jonathan [0000-0003-2020-9330], Downes, Kate [0000-0003-0366-1579], Astle, William [0000-0001-8866-6672], Papadia, Sofia [0000-0002-9222-3812], Simeoni, Ilenia [0000-0001-5039-2194], Johnson, Kathleen [0000-0002-6823-3252], Ouwehand, Willem [0000-0002-7744-1790], Turro Bassols, Ernest [0000-0002-1820-6563], and Apollo - University of Cambridge Repository

Subjects
Blood Platelets, Male, Genome, Human, Platelet Count, Gene Expression, High-Throughput Nucleotide Sequencing, Hemorrhage, Thrombocytopenia, Pedigree, Platelet Glycoprotein GPIb-IX Complex, Case-Control Studies, Mutation, Humans, Female, Alleles, Genes, Dominant
Abstract

The von Willebrand receptor complex, which is composed of the glycoproteins Ibα, Ibβ, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, $\textit{GP1BBA}$, $\textit{GP1BB}$, and $\textit{GP9}$) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in $\textit{GP1BA}$ have been reported to cause a milder and dominant form of macrothrombocytopenia, but only 2 tentative reports exist of such a variant in $\textit{GP1BB}$ By analyzing data from a collection of more than 1000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in $\textit{GP1BB}$ and macrothrombocytopenia. To strengthen our findings, we sought further cases in 2 additional collections in the United Kingdom and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying 1 of 9 rare variants in $\textit{GP1BB}$.

Published
2017

9. A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders

Author

Sol Schulman, Daniel J. Hampshire, Jennifer Jolley, Peter A. Smethurst, Willem H. Ouwehand, Alan T. Nurden, Ilenia Simeoni, William Stevenson, Paolo Gresele, Ri Liesner, Kathleen Freson, Christel Van Geet, Walter H. A. Kahr, Tadbir K. Bariana, Paquita Nurden, Minka J A Vries, David A. Wilcox, Mary Mathias, Fengyuan Hu, Maha Othman, Marguerite Neerman-Arbez, Pawan Poudel, Matthias Ballmaier, Pieter H. Reitsma, Peter William Collins, Jose A. Lopez, Artur J. Szkotak, Jose A. Guerrero, Marie-Christine Alessi, Manuela Germeshausen, Jonathan Stephens, Cedric Ghevaert, Michael Gattens, Carolyn M. Millar, Gareth Baynam, Marian Hill, Marco Cattaneo, Antony P. Attwood, Shoshana Revel-Vilk, Matthew T. Rondina, Anne M. Kelly, Sri V V Deevi, Sofia Papadia, Amit C. Nathwani, Paul F. Bray, Daniel B. Bellissimo, Michael Laffan, Deborah L. French, Daniel P. Hart, Shinji Kunishima, Bin Zhang, Rutendo Mapeta, Salih Tuna, Anne Goodeve, Keith Gomez, Nancy Hogg, Ernest Turro, Johan W. M. Heemskerk, Marta Bertoli, Karyn Megy, Ron Kerr, Christopher J. Penkett, David J. Perry, Claire Lentaigne, Deborah Whitehorn, Daniel Greene, Suthesh Sivapalaratnam, Myrto Kostadima, Andrew D Mumford, Bruce Furie, Emilse Bermejo, Rémi Favier, Michele P. Lambert, Louise C. Daugherty, Yvonne M. C. Henskens, Augusto Rendon, Loredana Bury, Kathelijne Peerlinck, Sarah K Westbury, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medical Research Council (MRC), Simeoni, Ilenia [0000-0001-5039-2194], Stephens, Jonathan [0000-0003-2020-9330], Megy, Karyn [0000-0002-2826-3879], Papadia, Sofia [0000-0002-9222-3812], Ghevaert, Cedric [0000-0002-9251-0934], Tuna, Salih [0000-0003-3606-4367], Rendon Restrepo, Augusto [0000-0001-8994-0039], Ouwehand, Willem [0000-0002-7744-1790], Turro Bassols, Ernest [0000-0002-1820-6563], Apollo - University of Cambridge Repository, Biochemie, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, Promovendi CD, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Medische Microbiologie, and MUMC+: DA CDL Algemeen (9)

Subjects
Male, 0301 basic medicine, 030204 cardiovascular system & hematology, Bioinformatics, Biochemistry, thrombotic, 0302 clinical medicine, [SDV.IDA]Life Sciences [q-bio]/Food engineering, Copy-number variation, 1102 Cardiorespiratory Medicine and Haematology, UNITED-KINGDOM, POPULATION, Blood Platelet Disorders, education.field_of_study, Hematology, High-Throughput Nucleotide Sequencing, 3. Good health, GENOME, Female, Developed a targeted sequencing platform covering 63 genes linked to heritable bleeding, Life Sciences & Biomedicine, and platelet disorders. The ThromboGenomics platform provides a sensitive genetic test to obtain molecular diagnoses in patients with a suspected etiology, VON-WILLEBRAND-DISEASE, medicine.medical_specialty, DNA Copy Number Variations, Platelet disorder, Immunology, Population, FACTOR-VIII GENE, Hemorrhage, WISKOTT-ALDRICH SYNDROME, Polymorphism, Single Nucleotide, 03 medical and health sciences, Internal medicine, MANAGEMENT, LINKAGE, Von Willebrand disease, medicine, Humans, Genetic Predisposition to Disease, education, POLYMORPHISMS, Genetic Association Studies, Science & Technology, MUTATIONS, business.industry, Case-control study, 1103 Clinical Sciences, Thrombosis, Sequence Analysis, DNA, Cell Biology, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, Mutation, Etiology, 1114 Paediatrics and Reproductive Medicine, business, 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
Abstract

Inherited bleeding, thrombotic and platelet disorders (BPDs) are diseases affecting approximately 300 individuals per million births. With the exception of haemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialised tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing (HTS) platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants (SNVs), short insertions/deletions (indels) and large copy number variants (CNVs), though not inversions, which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples respectively from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology while the remainder had ana priorihighly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only eight of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD.

Published
2016
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