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1. Implementation of individualised polygenic risk score analysis: a test case of a family of four

Author: Manuel Corpas, Karyn Megy, Antonio Metastasio, and Edmund Lehmann
Subjects: Polygenic risk scores, Phenotypes, Genetic risk, Disease prevention, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract: Abstract Background Polygenic risk scores (PRS) have been widely applied in research studies, showing how population groups can be stratified into risk categories for many common conditions. As healthcare systems consider applying PRS to keep their populations healthy, little work has been carried out demonstrating their implementation at an individual level. Case presentation We performed a systematic curation of PRS sources from established data repositories, selecting 15 phenotypes, comprising an excess of 37 million SNPs related to cancer, cardiovascular, metabolic and autoimmune diseases. We tested selected phenotypes using whole genome sequencing data for a family of four related individuals. Individual risk scores were given percentile values based upon reference distributions among 1000 Genomes Iberians, Europeans, or all samples. Over 96 billion allele effects were calculated in order to obtain the PRS for each of the individuals analysed here. Conclusions Our results highlight the need for further standardisation in the way PRS are developed and shared, the importance of individual risk assessment rather than the assumption of inherited averages, and the challenges currently posed when translating PRS into risk metrics.
Published: 2022
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2. De novo variant in tyrosine kinase SRC causes thrombocytopenia: case report of a second family

Author: Lore De Kock, Chantal Thys, Kate Downes, Daniel Duarte, Karyn Megy, Chris Van Geet, and Kathleen Freson
Subjects: platelet dysfunction, src, thrombocytopenia, tyrosine phosphorylation, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: A germline heterozygous gain-of-function p.E527K variant in tyrosine kinase SRC was previously found to cause thrombocytopenia, myelofibrosis, bleeding, bone pathologies, premature edentulism and mild facial dysmorphia in nine patients of a single pedigree. Because of this variant, SRC loses its self-inhibitory capacity, causing constitutively active SRC expression in platelets. These patients have fewer and heterogeneous-sized platelets that are hyporeactive to collagen. We now report a 5-year-old girl with syndromic thrombocytopenia due to the same SRC-E527K variant that occurs de novo. A bone marrow biopsy, blood smear analysis, platelet aggregations, flow cytometric analysis of P-selectin, SRC expression and tyrosine phosphorylation studies were performed to confirm the similarities between the two families. This study strengthens our previous finding that hyperactive SRC kinase results in mild platelet dysfunction and thrombocytopenia with hypogranular platelets and further expands the clinical description of this syndrome to improve early recognition.
Published: 2019
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3. Whole Genome Interpretation for a Family of Five

Author: Manuel Corpas, Karyn Megy, Vanisha Mistry, Antonio Metastasio, and Edmund Lehmann
Subjects: whole genome sequencing, personal genomics, interpretation, precision medicine, genetic risk score, pharmacogenomics, Genetics, QH426-470
Abstract: Although best practices have emerged on how to analyse and interpret personal genomes, the utility of whole genome screening remains underdeveloped. A large amount of information can be gathered from various types of analyses via whole genome sequencing including pathogenicity screening, genetic risk scoring, fitness, nutrition, and pharmacogenomic analysis. We recognize different levels of confidence when assessing the validity of genetic markers and apply rigorous standards for evaluation of phenotype associations. We illustrate the application of this approach on a family of five. By applying analyses of whole genomes from different methodological perspectives, we are able to build a more comprehensive picture to assist decision making in preventative healthcare and well-being management. Our interpretation and reporting outputs provide input for a clinician to develop a healthcare plan for the individual, based on genetic and other healthcare data.
Published: 2021
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4. Genome Sequencing and Comprehensive Rare Variant Analysis of 465 Families with Neurodevelopmental Disorders

Author: Camila Armirola Ricaurte, Detelina Grozeva, Karyn Megy, and Jonathan Stephens
Abstract: PurposeDespite significant progress in unravelling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis following microarray and/or exome sequencing. Here we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in NDD participants from the NIHR BioResource project.MethodsShort-read GS was conducted on 692 individuals (489 affected and 203 unaffected relatives) from 465 families. Additionally, long-read GS was performed on five affected individuals who had structural variants (SVs) in technically challenging regions, complex SVs, or required distal variant phasing.ResultsCausal variants were identified in 36% affected individuals (177/489) and a further 26% (129/489) had a variant of uncertain significance, after multiple rounds of re-analysis. Among all reported variants, 88% (333/380) were SNVs/indels, and the remainder were structural variants (SVs), non-coding, and mitochondrial variants. Furthermore, long-read GS facilitated resolution of challenging SVs and invalidated variants of difficult interpretation from short-read GS.ConclusionThis study demonstrates the value of short-read GS, complemented with long-reads, to investigate the genetic causes of NDDs. GS provides a comprehensive and unbiased method to identify all types of variants throughout the nuclear and mitochondrial genome in NDD individuals.
Published: 2023

5. Multiparameter platelet function analysis of bleeding patients with a prolonged platelet function analyser closure time

Author: Floor C. J. I. Heubel‐Moenen, Sanne L. N. Brouns, Linda Herfs, Lara S. Boerenkamp, Natalie J. Jooss, Rick J. H. Wetzels, Paul W. M. Verhezen, Patric Machiels, Karyn Megy, Kate Downes, Johan W. M. Heemskerk, Erik A. M. Beckers, Yvonne M. C. Henskens, Interne Geneeskunde, RS: Carim - B03 Cell biochemistry of thrombosis and haemostasis, Biochemie, RS: GROW - R2 - Basic and Translational Cancer Biology, MUMC+: MA Hematologie (9), Central Diagnostic Lab, RS: Carim - B04 Clinical thrombosis and Haemostasis, MUMC+: DA CDL Algemeen (9), Heubel-Moenen, Floor CJI [0000-0002-3281-926X], and Apollo - University of Cambridge Repository
Subjects: Blood Platelets, bleeding disorders, VON-WILLEBRAND-DISEASE, Hemostasis, Platelet Aggregation, Platelet Function Tests, MEASURE THROMBUS FORMATION, DISORDERS, platelet function, PFA-100, Hemorrhage, Thrombosis, genetics of thrombosis and haemostasis, CLINICAL UTILITY, Hematology, diagnostic haematology, DEFECTS, DIAGNOSIS, von Willebrand Diseases, flow, von Willebrand Factor, PRIMARY HEMOSTASIS, Humans, ASSAY, SYSTEM
Abstract: Patients referred for evaluation of bleeding symptoms occasionally have a prolonged platelet function analyser (PFA) closure time, without evidence for von Willebrand disease or impaired platelet aggregation. The aim of this study was to establish a shear-dependent platelet function defect in these patients. Patients were included based on high bleeding score and prior PFA prolongation. Common tests of von Willebrand factor (VWF) and platelet function and exome sequencing were performed. Microfluidic analysis of shear-dependent collagen-induced whole-blood thrombus formation was performed. In 14 PFA-only patients, compared to healthy volunteers, microfluidic tests showed significantly lower platelet adhesion and thrombus formation parameters. This was accompanied by lower integrin activation, phosphatidylserine exposure and P-selectin expression. Principal components analysis indicated VWF as primary explaining variable of PFA prolongation, whereas conventional platelet aggregation primarily explained the reduced thrombus parameters under shear. In five patients with severe microfluidic abnormalities, conventional platelet aggregation was in the lowest range of normal. No causal variants in Mendelian genes known to cause bleeding or platelet disorders were identified. Multiparameter assessment of whole-blood thrombus formation under shear indicates single or combined effects of low-normal VWF and low-normal platelet aggregation in these patients, suggesting a shear-dependent platelet function defect, not detected by static conventional haemostatic tests.
Published: 2022

6. Effectiveness and costs of a stepwise versus an all-in-one approach to diagnose mild bleeding disorders

Author: Floor C. J. I. Heubel‐Moenen, Loes E. M. Ansems, Paul W. M. Verhezen, Rick J. H. Wetzels, Rene G. M. van Oerle, Ron J. M. H. E. Straat, Karyn Megy, Kate Downes, Yvonne M. C. Henskens, Erik A. M. Beckers, Manuela A. Joore, Heubel-Moenen, Floor CJI [0000-0002-3281-926X], Apollo - University of Cambridge Repository, Interne Geneeskunde, MUMC+: MA Hematologie (9), MUMC+: DA CDL Analytisch cluster 3 (9), MUMC+: DA CDL Analytisch cluster 1K (9), MUMC+: DA CDL Algemeen (9), RS: Carim - B04 Clinical thrombosis and Haemostasis, Central Diagnostic Lab, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, RS: CAPHRI - R2 - Creating Value-Based Health Care, and MUMC+: KIO Kemta (9)
Subjects: Adult, coagulation disorders, Fibrinolysis, Cost-Benefit Analysis, cost-effectiveness analysis, Humans, Hemorrhage, Hematology, health benefits, Blood Coagulation Disorders, algorithms, Hemorrhagic Disorders, diagnostic testing
Abstract: The diagnostic work-up of patients referred to the haematologist for bleeding evaluation is performed in a stepwise way: bleeding history and results of screening laboratory tests guide further diagnostic evaluation. This can be ineffective, time-consuming and burdensome for patients. To improve this strategy, the initial laboratory investigation can be extended. In a model-based approach, effectiveness and costs of a conventional stepwise versus a newly proposed all-in-one diagnostic approach for bleeding evaluation were evaluated and compared, using data from an observational patient cohort study, including adult patients referred for bleeding evaluation. In the all-in-one approach, specialized platelet function tests, coagulation factors, and fibrinolysis tests were included in the initial investigation. Final diagnosis, hospital resource use and costs and patient burden were compared. A total of 150 patients were included. Compared to the stepwise approach, in the all-in-one approach, 19 additional patients reached a diagnosis and patient burden was lower, but total costs per patient were higher [€359, 95% bootstrapped confidence interval (BCI) 283-518, p = 0.001]. For bleeding evaluation of patients referred to the haematologist, an all-in-one diagnostic approach has a higher diagnostic yield and reduces patient burden, at a higher cost. This raises the question what costs justify the diagnosis of a bleeding disorder and a less burdensome diagnostic strategy.
Published: 2022
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7. Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model

Author: Agnieszka Bierzynska, Katherine Bull, Sara Miellet, Philip Dean, Chris Neal, Elizabeth Colby, Hugh J. McCarthy, Shivaram Hegde, Manish D. Sinha, Carmen Bugarin Diz, Kathleen Stirrups, Karyn Megy, Rutendo Mapeta, Chris Penkett, Sarah Marsh, Natalie Forrester, Maryam Afzal, Hannah Stark, NIHR BioResource, Maggie Williams, Gavin I. Welsh, Ania B. Koziell, Paul S. Hartley, Moin A. Saleem, Saleem, Moin A [0000-0002-9808-4518], and Apollo - University of Cambridge Repository
Subjects: Adult, Nephrotic Syndrome, Podocytes, Nephrocyte, Drug Resistance, Podocyte, High-Throughput Nucleotide Sequencing, Nuclear Pore Complex Proteins, FSGS, Disease Models, Animal, Drosophila melanogaster, Nephrology, SRNS, Pediatrics, Perinatology and Child Health, Mutation, Animals, Humans, NUP93, Child, Glucocorticoids
Abstract: Background Variants in genes encoding nuclear pore complex (NPC) proteins are a newly identified cause of paediatric steroid-resistant nephrotic syndrome (SRNS). Recent reports describing NUP93 variants suggest these could be a significant cause of paediatric onset SRNS. We report NUP93 cases in the UK and demonstrate in vivo functional effects of Nup93 depletion in a fly (Drosophila melanogaster) nephrocyte model. Methods Three hundred thirty-seven paediatric SRNS patients from the National cohort of patients with Nephrotic Syndrome (NephroS) were whole exome and/or whole genome sequenced. Patients were screened for over 70 genes known to be associated with Nephrotic Syndrome (NS). D. melanogaster Nup93 knockdown was achieved by RNA interference using nephrocyte-restricted drivers. Results Six novel homozygous and compound heterozygous NUP93 variants were detected in 3 sporadic and 2 familial paediatric onset SRNS characterised histologically by focal segmental glomerulosclerosis (FSGS) and progressing to kidney failure by 12 months from clinical diagnosis. Silencing of the two orthologs of human NUP93 expressed in D. melanogaster, Nup93-1, and Nup93-2 resulted in significant signal reduction of up to 82% in adult pericardial nephrocytes with concomitant disruption of NPC protein expression. Additionally, nephrocyte morphology was highly abnormal in Nup93-1 and Nup93-2 silenced flies surviving to adulthood. Conclusion We expand the spectrum of NUP93 variants detected in paediatric onset SRNS and demonstrate its incidence within a national cohort. Silencing of either D. melanogaster Nup93 ortholog caused a severe nephrocyte phenotype, signaling an important role for the nucleoporin complex in podocyte biology. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information
Published: 2022
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8. Advances in understanding the pathogenesis of hereditary macrothrombocytopenia

Author: Janine Collins, Karyn Megy, Andrew D Mumford, Dragana Vuckovic, and William J. Astle
Subjects: Adult, Blood Platelets, Male, Multifactorial Inheritance, medicine.medical_specialty, Adolescent, Genomics, Biology, Quantitative trait locus, Bioinformatics, Cohort Studies, Genetic Heterogeneity, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genotype, medicine, Humans, Mean platelet volume, Aged, Cell Size, Genetic association, Hematology, Platelet Count, Middle Aged, Thrombocytopenia, Biobank, Genetic architecture, Phenotype, 030220 oncology & carcinogenesis, Female, Mean Platelet Volume, Genome-Wide Association Study, Transcription Factors, 030215 immunology
Abstract: Low platelet count, or thrombocytopenia, is a common haematological abnormality, with a wide differential diagnosis, which may represent a clinically significant underlying pathology. Macrothrombocytopenia, the presence of large platelets in combination with thrombocytopenia, can be acquired or hereditary and indicative of a complex disorder. In this review, we discuss the interpretation of platelet count and volume measured by automated haematology analysers and highlight some important technical considerations relevant to the analysis of blood samples with macrothrombocytopenia. We review how large cohorts, such as the UK Biobank and INTERVAL studies, have enabled an accurate description of the distribution and co-variation of platelet parameters in adult populations. We discuss how genome-wide association studies have identified hundreds of genetic associations with platelet count and mean platelet volume, which in aggregate can explain large fractions of phenotypic variance, consistent with a complex genetic architecture and polygenic inheritance. Finally, we describe the large genetic diagnostic and discovery programmes, which, simultaneously to genome-wide association studies, have expanded the repertoire of genes and variants associated with extreme platelet phenotypes. These have advanced our understanding of the pathogenesis of hereditary macrothrombocytopenia and support a future clinical diagnostic strategy that utilises genotype alongside clinical and laboratory phenotype data.
Published: 2021

9. Corrigendum to GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis [J Thromb Haemost. 2021 Oct;19(10):2612-2617]

Author: Karyn Megy, Kate Downes, Marie-Christine Morel-Kopp, José M. Bastida, Shannon Brooks, Loredana Bury, Eva Leinoe, Keith Gomez, Neil V. Morgan, Maha Othman, Willem H. Ouwehand, Juliana Perez Botero, José Rivera, Harald Schulze, David-Alexandre Trégouët, and Kathleen Freson
Subjects: Hematology
Published: 2023

10. First genotype-phenotype study in TBX4 syndrome: gain-of-function mutations causative for lung disease

Author: Marc Humbert, David Montani, Mauro Lago Docampo, Karyn Megy, Wendy Chung, Carrie Welch, Emilia Swietlik, and Matina Prapa
Abstract: RationaleDespite the increasing frequency ofTBX4-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights.MethodsWe assembled a multi-center cohort of 137 patients harboring monoallelicTBX4variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with PAH patients withBMPR2causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the NIHR BioResource - Rare Diseases (NBR).ResultsFunctional assessment ofTBX4missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared to loss-of-function (p = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (p = 0.005) and increased incidence of interstitial lung disease (p = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (p = 0.022) although age had a significant effect in the hazard model (p = 0.0461). Carriers ofTBX4variants were diagnosed at a younger age (p < 0.001) and had worse baseline lung function (FEV1, FVC) (p = 0.009) compared to theBMPR2and no identified causal variant groups.ConclusionsWe demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain-of-function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.
Published: 2022

11. GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis

Author: Juliana Perez Botero, Keith Gomez, Maha Othman, Willem H. Ouwehand, Kate Downes, Kathleen Freson, Marie-Christine Morel-Kopp, David-Alexandre Trégouët, Neil V. Morgan, José María Bastida, Shannon Brooks, Harald Schulze, Loredana Bury, José Rivera, Eva Leinoe, Karyn Megy, University of Cambridge [UK] (CAM), Cambridge University Hospitals - NHS (CUH), Royal North Shore Hospital (RNSH), The University of Sydney, Instituto de Investigación Biomédica de Salamanca [Salamanca, Spain] (IBSAL/CIC), Università degli Studi di Perugia (UNIPG), National University Hospital, Rigshospitalet, Copenhagen, Royal Free London NHS Foundation Trust, University of Birmingham [Birmingham], Queen's University [Kingston, Canada], Medical College of Wisconsin [Milwaukee] (MCW), Universidad de Murcia, University Hospital Wuerzburg, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)
Subjects: Platelets, Platelet disorder, Hemorrhage, Genomics, Computational biology, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Resource (project management), blood, MANAGEMENT, Humans, Medicine, genes, thrombosis, 030304 developmental biology, Hemostasis, 0303 health sciences, Science & Technology, business.industry, Communication, Genetic variants, Thrombosis, Hematology, Pathogenicity, medicine.disease, 3. Good health, Blood, Genes, Peripheral Vascular Disease, Mutation, platelets, Cardiovascular System & Cardiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Blood Platelet Disorders, hemorrhage, mutation, business, Life Sciences & Biomedicine
Abstract: The implementation of high-throughput sequencing (HTS) technologies in research and diagnostic laboratories has linked many new genes to rare bleeding, thrombotic, and platelet disorders (BTPD), and revealed multiple genetic variants linked to those disorders, many of them being of uncertain pathogenicity when considering the accepted evidence (variant consequence, frequency in control datasets, number of reported patients, prediction models, and functional assays). The sequencing effort has also resulted in resources for gathering disease-causing variants associated with specific genes, but for BTPD, such well-curated databases exist only for a few genes. On the other hand, submissions by individuals or diagnostic laboratories to the variant database ClinVar are hampered by the lack of a submission process tailored to capture the specific features of hemostatic diseases. As we move toward the implementation of HTS in the diagnosis of BTPD, the Scientific and Standardization Committee for Genetics in Thrombosis and Haemostasis has developed and tested a REDCap-based interface, aimed at the community, to submit curated genetic variants for diagnostic-grade BTPD genes. Here, we describe the use of the interface and the initial submission of 821 variants from 30 different centers covering 14 countries. This open-access variant resource will be shared with the community to improve variant classification and regular bulk data transfer to ClinVar. ispartof: JOURNAL OF THROMBOSIS AND HAEMOSTASIS vol:19 issue:10 pages:2612-2617 ispartof: location:England status: published
Published: 2021

12. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

Author: Emilia M. Swietlik, Daniel Greene, Na Zhu, Karyn Megy, Marcella Cogliano, Smitha Rajaram, Divya Pandya, Tobias Tilly, Katie A. Lutz, Carrie C.L. Welch, Michael W. Pauciulo, Laura Southgate, Jennifer M. Martin, Carmen M. Treacy, Christopher J. Penkett, Jonathan C. Stephens, Harm J. Bogaard, Colin Church, Gerry Coghlan, Anna W. Coleman, Robin Condliffe, Christina A. Eichstaedt, Mélanie Eyries, Henning Gall, Stefano Ghio, Barbara Girerd, Ekkehard Grünig, Simon Holden, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Jim Lordan, Rajiv D. Machado, Robert V. MacKenzie Ross, Colm McCabe, Shahin Moledina, David Montani, Horst Olschewski, Joanna Pepke-Zaba, Laura Price, Christopher J. Rhodes, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Anton Vonk Noordegraaf, John Wharton, James M. Wild, Stephen John Wort, Allan Lawrie, Martin R. Wilkins, Richard C. Trembath, Yufeng Shen, Wendy K. Chung, Andrew J. Swift, William C. Nichols, Nicholas W. Morrell, Stefan Gräf, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David J. Allsup, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, David L. Bennett, Agnieszka Bierzynska, Tina Biss, Maria A.K. Bitner-Glindzicz, Graeme C. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Sara Boyce, John R. Bradley, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Oliver S. Burren, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Keren Carss, Ruth Casey, Mark J. Caulfield, Jenny Chambers, John Chambers, Melanie M.Y. Chan, Floria Cheng, Patrick F. Chinnery, Manali Chitre, Martin T. Christian, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Elizabeth Colby, Trevor R.P. Cole, Janine Collins, Peter W. Collins, Cecilia J. Compton, H. Terence Cook, Stuart Cook, Nichola Cooper, Paul A. Corris, Nicola S. Curry, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Sri V.V. Deevi, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Peter H. Dixon, Sofia Douzgou, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Hiva Fassihi, Remi Favier, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Mattia Frontini, Abigail Furnell, Daniel P. Gale, Vijeya Ganesan, Michael Gattens, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, Rosie Hague, William M. Hague, Matthias Haimel, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Rita Horvath, Henry Houlden, Arjan C. Houweling, Fengyuan Hu, Gavin Hudson, Aarnoud P. Huissoon, Matthew Hurles, Melita Irving, Louise Izatt, Roger James, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M Kelly, Wilf Kelsall, Carly Kempster, Nathalie Kingston, Nils Koelling, Myrto Kostadima, Ania Koziell, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Michael A. Laffan, Fiona Lalloo, Michele Lambert, Hana Lango Allen, D. Mark Layton, Claire Lentaigne, Tracy Lester, Adam P. Levine, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Bella Madan, Eamonn R. Maher, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Rutendo Mapeta, Kevin J. Marchbank, Stephen Marks, Hugh S. Markus, Hanns-Ulrich Marschall, Andrew Marshall, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Stuart Meacham, Adam J. Mead, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrew D. Mumford, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O’Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Kai Ren Ong, S. Helen Oram, Elizabeth Ormondroyd, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, Kathelijne Peerlinck, Romina Petersen, Clarissa Pilkington, Kenneth E.S. Poole, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Augusto Rendon, Tara Renton, Andrew S.C. Rice, Alex Richter, Leema Robert, Irene Roberts, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Noemi B.A. Roy, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Moin A. Saleem, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, Genevieve Sayer, John A. Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Arjune Sen, W.A. Carrock Sewell, Denis Seyres, Neil Shah, Olga Shamardina, Susan E. Shapiro, Adam C. Shaw, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Kenneth G.C. Smith, Katie Snape, Nicole Soranzo, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Hannah Stark, Kathleen E. Stirrups, Alex Stuckey, Petros Syrris, R. Campbell Tait, Kate Talks, Rhea Y.Y. Tan, Jenny C. Taylor, John M. Taylor, James E. Thaventhiran, Andreas C. Themistocleous, David Thomas, Ellen Thomas, Moira J. Thomas, Patrick Thomas, Kate Thomson, Adrian J. Thrasher, Chantal Thys, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Ian P. Tomlinson, Matthew Traylor, Paul Treadaway, Salih Tuna, Ernest Turro, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Anthony M Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Annette Wagner, Quinten Waisfisz, Neil Walker, Suellen M. Walker, James S. Ware, Hugh Watkins, Christopher Watt, Andrew R. Webster, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, Deborah Whitehorn, James Whitworth, Andrew O.M. Wilkie, Catherine Williamson, Brian T. Wilson, Edwin K.S. Wong, Nicholas Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Austen Worth, Michael Wright, Katherine Yates, Patrick F.K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, Eliska Zlamalova, Russel Hirsch, R. James White, Marc Simon, David Badesch, Erika Rosenzweig, Charles Burger, Murali Chakinala, Thenappan Thenappan, Greg Elliott, Robert Simms, Harrison Farber, Robert Frantz, Jean Elwing, Nicholas Hill, Dunbar Ivy, James Klinger, Steven Nathan, Ronald Oudiz, Ivan Robbins, Robert Schilz, Terry Fortin, Jeffrey Wilt, Delphine Yung, Eric Austin, Ferhaan Ahmad, Nitin Bhatt, Tim Lahm, Adaani Frost, Zeenat Safdar, Zia Rehman, Robert Walter, Fernando Torres, Sahil Bakshi, Stephen Archer, Rahul Argula, Christopher Barnett, Raymond Benza, Ankit Desai, Veeranna Maddipati, University of Cambridge [UK] (CAM), Columbia University [New York], University of Sheffield [Sheffield], University of Cincinnati (UC), St George's, University of London, Vrije Universiteit Amsterdam [Amsterdam] (VU), Golden Jubilee National Hospital, Glasgow, Royal Free Hospital [London, UK], Heidelberg University Hospital [Heidelberg], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen] (THM), Fondazione IRCCS Policlinico San Matteo, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universität Heidelberg [Heidelberg], Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Imperial College London, Royal Hallamshire Hospital, University of Graz, Freeman Hospital, Royal United Hospitals Bath (RUH), Great Ormond Street Hospital for Children [London] (GOSH), Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom., King‘s College London, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität [Graz, Autriche], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Swietlik, Emilia [0000-0002-4095-8489], Megy, Karyn [0000-0002-2826-3879], Tilly, Tobias [0000-0002-6762-5342], Stephens, Jonathan [0000-0003-2020-9330], Toshner, Mark [0000-0002-3969-6143], Morrell, Nicholas [0000-0001-5700-9792], Graf, Stefan [0000-0002-1315-8873], Apollo - University of Cambridge Repository, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität Graz, HAL-SU, Gestionnaire, British Heart Foundation, and The Academy of Medical Sciences
Subjects: 0301 basic medicine, Candidate gene, Cardiac & Cardiovascular Systems, genetic association studies, 030204 cardiovascular system & hematology, Biology, Bayesian inference, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, pulmonary hypertension, medicine, Family history, Gene, Genetics & Heredity, Genetics, family history, Science & Technology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Kinase insert domain receptor, computed tomography, General Medicine, Original Articles, medicine.disease, Pulmonary hypertension, Phenotype, 3. Good health, 030104 developmental biology, Cardiovascular System & Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, vascular endothelial growth factor receptor
Abstract: Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
Published: 2020

13. Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia

Author: Karyn Megy, Willem H. Ouwehand, Loren Kell, Jonathan Stephens, Kate Downes, Abigail Shurr, Claire L. Shovlin, Ilenia Simeoni, D Patel, Maria E. Bernabeu-Herrero, Micheala A. Aldred, Zoe C. Frazer, Christopher J. Penkett, Luca Jovine, Jennifer Brimley, Isobel G. Turbin, Ernest Turro, Imperial College Trust, Imperial College Healthcare NHS Trust, Imperial College Healthcare NHS Trust - CLRN Funding, and Imperial College Healthcare NHS Trust- BRC Funding
Subjects: 0301 basic medicine, Male, Models, Molecular, Clinical Trials and Observations, Activin Receptors, Type II, DNA Mutational Analysis, ALK1, Biochemistry, Cohort Studies, 0302 clinical medicine, Genotype, Growth Differentiation Factor 2, 1102 Cardiorespiratory Medicine and Haematology, Smad4 Protein, Massive parallel sequencing, medicine.diagnostic_test, Endoglin, GENETIC-VARIATION, High-Throughput Nucleotide Sequencing, TGF-BETA, Hematology, Genomics, GENOTYPE, PREVALENCE, Phenotype, Medical genetics, ARTERIOVENOUS-MALFORMATIONS, Female, Telangiectasia, Hereditary Hemorrhagic, Life Sciences & Biomedicine, medicine.medical_specialty, Heterozygote, Immunology, Context (language use), Computational biology, Biology, HHT, 03 medical and health sciences, Human Phenotype Ontology, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Genetic Association Studies, Genetic testing, Retrospective Studies, Science & Technology, IDENTIFICATION, 1103 Clinical Sciences, Cell Biology, Sequence Analysis, DNA, 030104 developmental biology, Mutation, 1114 Paediatrics and Reproductive Medicine, JUVENILE POLYPOSIS, 030217 neurology & neurosurgery
Abstract: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Care delivery for HHT patients is impeded by the need for laborious, repeated phenotyping and gaps in knowledge regarding the relationships between causal DNA variants in ENG, ACVRL1, SMAD4 and GDF2, and clinical manifestations. To address this, we analyzed DNA samples from 183 previously uncharacterized, unrelated HHT and suspected HHT cases using the ThromboGenomics high-throughput sequencing platform. We identified 127 rare variants across 168 heterozygous genotypes. Applying modified American College of Medical Genetics and Genomics Guidelines, 106 variants were classified as pathogenic/likely pathogenic and 21 as nonpathogenic (variant of uncertain significance/benign). Unlike the protein products of ACVRL1 and SMAD4, the extracellular ENG amino acids are not strongly conserved. Our inferences of the functional consequences of causal variants in ENG were therefore informed by the crystal structure of endoglin. We then compared the accuracy of predictions of the causal gene blinded to the genetic data using 2 approaches: subjective clinical predictions and statistical predictions based on 8 Human Phenotype Ontology terms. Both approaches had some predictive power, but they were insufficiently accurate to be used clinically, without genetic testing. The distributions of red cell indices differed by causal gene but not sufficiently for clinical use in isolation from genetic data. We conclude that parallel sequencing of the 4 known HHT genes, multidisciplinary team review of variant calls in the context of detailed clinical information, and statistical and structural modeling improve the prognostication and treatment of HHT.
Published: 2020

14. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

Author: Suthesh Sivapalaratnam, Erica De Candia, Janine Collins, Anthony D. Whetton, Nihr BioResource, Rachel Reed, Wadie F. Bahou, Denis Seyres, Daniel Greene, Hanna Shalev, Anne M. Kelly, Sandra Le Quellec, Paolo Gresele, Thierry M Leblanc, Elizabeth Chalmers, Tadbir K. Bariana, Rémi Favier, John Pasi, Albert Sickmann, Kathleen Freson, Sri V V Deevi, Daniel P. Hart, Dave Lee, Ernest Turro, Rutendo Mapeta, Luigi Grassi, John K. Wu, Matthew C Sims, Sara Morais, Mattia Frontini, Barbara Zieger, Diane J. Nugent, Mallika Sekhar, Louisa Mayer, Loredana Bury, Man-Chiu Poon, Soo J. Park, William J. Astle, Frances Burden, Paquita Nurden, Jonathan Stephens, Cécile Lavenu-Bombled, Andreas Greinacher, Rachael Da Silva, Marie-Françoise Hurtaud, Jose A. Guerrero, Robert Campbell Tait, Sofia Papadia, Eva Leinoe, Antonio Rodriguez-Romera, Karyn Megy, Wendy N. Erber, Gian Marco Podda, Ron Kerr, Willem H. Ouwehand, Laxmikanth Kollipara, Marie-Christine Alessi, Keith Gomez, Harriet McKinney, Taco W. Kuijpers, Alan D. Michelson, Kate Downes, Samantha Farrow, and Orna Steinberg-Shemer
Subjects: Autoimmune disease, 0303 health sciences, business.industry, Autoantibody, Inflammation, Immune dysregulation, medicine.disease_cause, medicine.disease, 3. Good health, Gray platelet syndrome, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine.anatomical_structure, Megakaryocyte, Immunology, medicine, Bone marrow, medicine.symptom, business, 030304 developmental biology, 030215 immunology
Abstract: Gray platelet syndrome (GPS) is a rare recessive disorder caused by variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet ɑ-granules, splenomegaly and bone marrow (BM) fibrosis. Due to its rarity, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathological features, we performed a detailed clinical genotypic and phenotypic study of 47 GPS patients. We identified 33 new causal variants in NBEAL2. Our GPS patient cohort exhibited known phenotypes, including macro-thrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. We also observed novel clinical phenotypes; these include reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4-lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data demonstrate that, in addition to the well-described platelet defects in GPS, there are also immune defects. The abnormal immune cells may be the drivers of systemic abnormalities, such as autoimmune disease.
Published: 2020

15. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author: Jean-Claude Tardif, Kelly Cho, Adolfo Correa, Na Cai, Koichi Matsuda, Paul L. Auer, Ken Sin Lo, Jennifer A. Brody, Dragana Vuckovic, Oluf Pedersen, Eric Jorgenson, Cassandra N. Spracklen, Jennifer E. Huffman, Stefan Weiss, Tim Kacprowski, Nicholas A. Watkins, Yoichiro Kamatani, Michele K. Evans, John Danesh, Masahiro Kanai, Karyn Megy, Kumaraswamy Naidu Chitrala, Michael H. Guo, James S. Floyd, Savita Karthikeyan, Ani Manichaikul, Petra Schubert, Vijay G. Sankaran, Torben Hansen, Traci M. Bartz, Laura M. Raffield, Regina Manansala, Parsa Akbari, Scott C. Ritchie, Ruth J. F. Loos, Manuel Tardaguila, Willem H. Ouwehand, Peter W.F. Wilson, Emanuele Di Angelantonio, Abdou Mousas, Jeffrey Haessler, Yoav Ben-Shlomo, Benjamin Rodriguez, Karen L. Mohlke, Girish N. Nadkarni, Oliver Stegle, Paul Elliott, Erwin P. Bottinger, Nathan Pankratz, Hélène Choquet, Julian C. Knight, Niels Grarup, Niki Dimou, Leslie A. Lange, Stephan B. Felix, William J. Astle, Jerome I. Rotter, Frank J. A. van Rooij, Andreas Greinacher, Yongmei Liu, Tao Jiang, Michael Inouye, Ming-Huei Chen, Jingzhong Ding, Uwe Völker, Huijun Qian, Henry Völzke, Alan B. Zonderman, Evangelos Evangelou, Wei Huang, Jonathan D. Rosen, Christopher J. Penkett, Michel Georges, Kousik Kundu, Mohsen Ghanbari, Hannes Ponstingl, Adam S. Butterworth, Joanna M. M. Howson, Praveen Surendran, Terho Lehtimäki, Allan Linneberg, Emilie M. Wigdor, Michael Preuss, Olli T. Raitakari, Arden Moscati, Yukinori Okada, Yoshinori Murakami, Guillaume Lettre, Leo-Pekka Lyytikäinen, Hua Tang, Caleb A. Lareau, David J. Roberts, Saori Sakaue, Mika Kähönen, Alexander P. Reiner, VA Million Veteran Program, Fotis Koskeridis, Nina Mononen, Linda Broer, Kjell Nikus, Andrew D. Johnson, Patrick K. Albers, Stephen B. Watt, Erik L. Bao, Yun Li, Klaudia Walter, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Andrew D Beswick, Tõnu Esko, Jette Bork-Jensen, and Masato Akiyama
Subjects: Genetics, Gene regulatory network, Oxygen transport, Genome-wide association study, Biology, Genetic architecture, Blood cell, symbols.namesake, medicine.anatomical_structure, medicine, Mendelian inheritance, symbols, Allele, Allele frequency
Abstract: SummaryBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.
Published: 2020
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16. Development and validation of a universal blood donor genotyping platform: A multinational prospective study

Author: Augusto Rendon, John M. Jongerius, Nicholas A. Watkins, Kim Brügger, Nicholas Gleadall, Daniel Duarte, Tiffany C. Timmer, Sara Trompeter, Matthew R. Walker, Jennifer G. Sambrook, David J. Roberts, Christopher J. Penkett, Carolin M. Sauer, Nieke van der Bolt, Barbera Veldhuisen, Shane Grimsley, Colin Brown, Adam S. Butterworth, Michael J. Sweeting, Salih Tuna, Emanuele Di Angelantonio, John Ord, Karyn Megy, Jessie S Luken, C. Ellen van der Schoot, Ilenia Simeoni, Gail Miflin, William J. Lane, Nicole Thornton, Ram Varma, William J. Astle, Connie M. Westhoff, Christopher S. Nelson, Katja van den Hurk, Jeremy Gollub, Kathleen Stirrups, Willem H. Ouwehand, Femmeke J. Prinsze, Alexander T. Dilthey, John Danesh, Public and occupational health, Graduate School, AII - Inflammatory diseases, APH - Methodology, and Landsteiner Laboratory
Subjects: medicine.medical_specialty, Blood transfusion, Genotype, medicine.medical_treatment, Concordance, Blood Donors, Human leukocyte antigen, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Isoantibodies, medicine, Humans, Blood Transfusion, Prospective Studies, Typing, Genotyping, biology, Transfusion Medicine, business.industry, Transfusion medicine, Hematology, Biobank, Immunology, biology.protein, Antibody, business, 030215 immunology
Abstract: Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non–self-antigens is an unavoidable adverse side effect of transfusion. We describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates. This DNA-based test is capable of simultaneously typing most clinically relevant red blood cell (RBC), human platelet (HPA), and human leukocyte (HLA) antigens. Validation was performed, using samples from 7927 European, 27 South Asian, 21 East Asian, and 9 African blood donors enrolled in 2 national biobanks. We illustrated the usefulness of the platform by analyzing antibody data from patients sensitized with multiple RBC alloantibodies. Genotyping results demonstrated concordance of 99.91%, 99.97%, and 99.03% with RBC, HPA, and HLA clinically validated typing results in 89 371, 3016, and 9289 comparisons, respectively. Genotyping increased the total number of antigen typing results available from 110 980 to >1 200 000. Dense donor typing allowed identification of 2 to 6 times more compatible donors to serve 3146 patients with multiple RBC alloantibodies, providing at least 1 match for 176 individuals for whom previously no blood could be found among the same donors. This genotyping technology is already being used to type thousands of donors taking part in national genotyping studies. Extraction of dense antigen-typing data from these cohorts provides blood supply organizations with the opportunity to implement a policy of genomics-based precision matching of blood.
Published: 2020

17. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

Author: Tadbir K. Bariana, William J. Astle, Paquita Nurden, Jonathan Stephens, Sandra Le Quellec, Suthesh Sivapalaratnam, Andreas Greinacher, Jose A. Guerrero, Karyn Megy, Laxmikanth Kollipara, Hanna Shalev, Rachel Reed, Marie-Christine Alessi, Ron Kerr, Anthony D. Whetton, Matthew C Sims, Nihr BioResource, Man-Chiu Poon, Kathleen Freson, Samantha Farrow, Orna Steinberg-Shemer, Wendy N. Erber, Diane J. Nugent, Harriet McKinney, Cécile Lavenu-Bombled, Robert Campbell Tait, Mallika Sekhar, Rutendo Mapeta, Eva Leinoe, Anne M. Kelly, Louisa Mayer, Janine Collins, Mattia Frontini, Thierry M Leblanc, Elizabeth Chalmers, Albert Sickmann, Willem H. Ouwehand, Barbara Zieger, Taco W. Kuijpers, Antonio Rodriguez-Romera, Gian Marco Podda, Daniel P. Hart, Paolo Gresele, Daniel Greene, Keith Gomez, Wadie F. Bahou, Soo J. Park, Erica De Candia, Dave Lee, Luigi Grassi, Alan D. Michelson, Sara Morais, Denis Seyres, Kate Downes, John Pasi, Sri V V Deevi, John K. Wu, Loredana Bury, Frances Burden, Rachael Da Silva, Sofia Papadia, Marie-Françoise Hurtaud, Ernest Turro, Rémi Favier, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, ARD - Amsterdam Reproduction and Development, University of Cambridge [UK] (CAM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., University of Manchester [Manchester], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Stony Brook University [SUNY] (SBU), State University of New York (SUNY), University of Perugia, Royal Hospital for Sick Children [Edinburgh], Catholic University School of Medicine, Royal Free London NHS Foundation Trust, Universitätsmedizin Greifswald, Queen Mary University of London (QMUL), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Ninewells Hospital and Medical School [Dundee], Hospices Civils de Lyon (HCL), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Harvard Medical School [Boston] (HMS), Centro Hospitalar Universitário do Porto, Children's Hospital of Orange County, University of California, Università degli Studi di Milano [Milano] (UNIMI), University of Calgary, Manchester Academic Health Science Centre (MAHSC), Ben-Gurion University of the Negev (BGU), Tel Aviv University [Tel Aviv], Glasgow Royal Infirmary, University of British Columbia (UBC), University of Freiburg [Freiburg], VU University Medical Center [Amsterdam], University of Aberdeen, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), The University of Western Australia (UWA), Hôpital Xavier Arnozan, Università degli Studi di Perugia = University of Perugia (UNIPG), University of California (UC), Università degli Studi di Milano = University of Milan (UNIMI), Tel Aviv University (TAU), and Prémilleux, Annick
Subjects: Biopsy, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, medicine.disease_cause, GUIDELINES, NBEAL2, Biochemistry, Cohort Studies, 0302 clinical medicine, Megakaryocyte, Gene Frequency, Medicine, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, ABNORMALITIES, Hematology, Blood Proteins, ASSOCIATION, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Phenotype, BEACH-DOMAIN, Immune System Diseases, medicine.symptom, BLOOD Commentary, Platelet disease, NEUROBEACHIN-LIKE 2, PROTEINS, Immunology, education, Inflammation, Cytoplasmic Granules, Gray Platelet Syndrome, CLASSIFICATION, Gray platelet syndrome, Diagnosis, Differential, 03 medical and health sciences, Genetic Heterogeneity, Immune system, Humans, Genetic Association Studies, 030304 developmental biology, Autoimmune disease, business.industry, Autoantibody, Grey platelet syndrome, Cell Biology, Immune dysregulation, medicine.disease, Bleeding disease, PROTEOME, Settore MED/15 - MALATTIE DEL SANGUE, Case-Control Studies, Immune System, Mutation, Bone marrow, business, PATHOGENICITY, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease. ispartof: BLOOD vol:136 issue:17 pages:1956-1967 ispartof: location:United States status: published
Published: 2020

18. Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals with 56 Distinct Heterozygous NFKB1 Mutations

Author: Tiziana Lorenzini, Manfred Fliegauf, Nils Klammer, Natalie Frede, Michele Proietti, Alla Bulashevska, Nadezhda Camacho-Ordonez, Markku Varjosalo, Matias Kinnunen, Esther de Vries, Jos W.M. van der Meer, Rohan Ameratunga, Chaim M. Roifman, Yael D. Schejter, Robin Kobbe, Timo Hautala, Faranaz Atschekzei, Reinhold E. Schmidt, Claudia Schröder, Polina Stepensky, Bella Shadur, Luis A. Pedroza, Michiel van der Flier, Mónica Martínez-Gallo, Luis Ignacio Gonzalez-Granado, Luis M. Allende, Anna Shcherbina, Natalia Kuzmenko, Victoria Zakharova, João Farela Neves, Peter Svec, Ute Fischer, Winnie Ip, Oliver Bartsch, Safa Barış, Christoph Klein, Raif Geha, Janet Chou, Mohammed Alosaimi, Lauren Weintraub, Kaan Boztug, Tatjana Hirschmugl, Maria Marluce Dos Santos Vilela, Dirk Holzinger, Maximilian Seidl, Vassilios Lougaris, Alessandro Plebani, Laia Alsina, Monica Piquer-Gibert, Angela Deyà-Martínez, Charlotte A. Slade, Asghar Aghamohammadi, Hassan Abolhassani, Lennart Hammarström, Outi Kuismin, Merja Helminen, Hana Lango Allen, James E. Thaventhiran, Alexandra F. Freeman, Matthew Cook, Shahrzad Bakhtiar, Mette Christiansen, Charlotte Cunningham-Rundles, Niraj C. Patel, William Rae, Tim Niehues, Nina Brauer, Jaana Syrjänen, Mikko R.J. Seppänen, Siobhan O. Burns, Paul Tuijnenburg, Taco W. Kuijpers, Klaus Warnatz, Bodo Grimbacher, Zoe Adhya, Hana Alachkar, Ariharan Anantharachagan, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William J. Astle, Anthony Attwood, Chiara Bacchelli, Joana Batista, Helen E. Baxendale, Claire Bethune, Shahnaz Bibi, Marta Bleda, Barbara Boardman, Claire Booth, John R. Bradley, Gerome Breen, Matthew Brown, Michael J. Browning, Mary Brownlie, Matthew S. Buckland, Oliver S. Burren, Keren Carss, John Chambers, Anita Chandra, Naomi Clements Brod, Hayley Clifford, Nichola Cooper, Louise C. Daugherty, E.G. Davies, Sophie Davies, John Davis, Sarah Deacock, Sri V.V. Deevi, John Dempster, Lisa A. Devlin, Eleanor F. Dewhurst, Kate Downes, Elizabeth Drewe, Daniel Duarte, J. David M. Edgar, Karen Edwards, William Egner, Tariq El-Shanawany, Marie Erwood, Debra Fletcher, James Fox, Amy J. Frary, Mattia Frontini, Abigail Furnell, H. Bobby Gaspar, Rohit Ghurye, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Pavels Gordins, Stefan Gräf, Luigi Grassi, Daniel Greene, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Matthias Haimel, Lorraine Harper, Grant Hayman, Archana Herwadkar, Fengyuan Hu, Stephen Hughes, Aarnoud P. Huissoon, Roger James, Stephen Jolles, Jennifer Jolley, Julie Jones, Yousuf Karim, Mary A. Kasanicki, Peter Kelleher, Carly Kempster, Sorena Kiani, Nathalie Kingston, Nigel Klein, Myrto Kostadima, Roman Kreuzhuber, Dinakantha Kumararatne, James Laffan, Sara E. Lear, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Paul A. Lyons, Jesmeen Maimaris, Ania Manson, Rutendo Mapeta, Jennifer Martin, Mark I. McCarthy, Elizabeth M. McDermott, Harriet McKinney, Stuart Meacham, Karyn Megy, Hazel Millar, Anoop Mistry, Valerie Morrisson, Sai H.K. Murng, Iman Nasir, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Christopher J. Penkett, Romina Petersen, Mark J. Ponsford, Waseem Qasim, Ellen Quinn, Isabella Quinti, F. Lucy Raymond, Paula J. Rayner-Matthews, Alex Richter, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Sinisa Savic, Suranjith L. Seneviratne, W.A. Carrock Sewell, Denis Seyres, Fiona Shackley, Olga Shamardina, Ilenia Simeoni, Michael A. Simpson, Kenneth G.C. Smith, Simon Staines, Emily Staples, Hannah Stark, Hans Stauss, Cathal L. Steele, Jonathan Stephens, Kathleen E. Stirrups, David Thomas, Moira J. Thomas, Patrick Thomas, Adrian J. Thrasher, Tobias Tilly, Catherine Titterton, Paul Treadaway, Salih Tuna, Ernest Turro, Rafal Urniaz, Julie von Ziegenweidt, Neil Walker, Christopher Watt, Steven B. Welch, Deborah Whitehorn, Lisa Willcocks, Nicholas Wood, Yvette Wood, Sarita Workman, Austen Worth, Katherine Yates, Nigel Yeatman, Patrick F.K. Yong, Timothy Young, Ping Yu, Eliska Zlamalova, Tranzo, Scientific center for care and wellbeing, Huisarts & Ziekenhuis, Lorenzini, Tiziana, Fliegauf, Manfred, Klammer, Nils, Frede, Natalie, Proietti, Michele, Bulashevska, Alla, Camacho-Ordonez, Nadezhda, Varjosalo, Markku, Kinnunen, Matias, de Vries, Esther, van der Meer, Jos W. M., Ameratunga, Rohan, Roifman, Chaim M., Schejter, Yael D., Kobbe, Robin, Hautala, Timo, Atschekzei, Faranaz, Schmidt, Reinhold E., Schroeder, Claudia, Stepensky, Polina, Shadur, Bella, Pedroza, Luis A., van der Flier, Michiel, Martinez-Gallo, Monica, Ignacio Gonzalez-Granado, Luis, Allende, Luis M., Shcherbina, Anna, Kuzmenko, Natalia, Zakharova, Victoria, Neves, Joao Farela, Svec, Peter, Fischer, Ute, Ip, Winnie, Bartsch, Oliver, Baris, Safa, Klein, Christoph, Geha, Raif, Chou, Janet, Alosaimi, Mohammed, Weintraub, Lauren, Boztug, Kaan, Hirschmugl, Tatjana, Dos Santos Vilela, Maria Marluce, Holzinger, Dirk, Seidl, Maximilian, Lougaris, Vassilios, Plebani, Alessandro, Alsina, Laia, Piquer-Gibert, Monica, Deya-Martinez, Angela, Slade, Charlotte A., Aghamohammadi, Asghar, Abolhassani, Hassan, Hammarstrom, Lennart, Kuismin, Outi, Helminen, Merja, Allen, Hana Lango, Thaventhiran, James E., Freeman, Alexandra F., Cook, Matthew, Bakhtiar, Shahrzad, Christiansen, Mette, Cunningham-Rundles, Charlotte, Patel, Niraj C., Rae, William, Niehues, Tim, Brauer, Nina, Syrjanen, Jaana, Seppanen, Mikko R. J., Burns, Siobhan O., Tuijnenburg, Paul, Kuijpers, Taco W., Warnatz, Klaus, Grimbacher, Bodo, Experimental Immunology, Graduate School, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Molecular Systems Biology, Institute of Biotechnology, University of Helsinki, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Children's Hospital, HUS Children and Adolescents, Clinicum, Department of Medicine, and Pediatric surgery
Subjects: 0301 basic medicine, Male, NF-KAPPA-B, Medizin, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Fluorescent Antibody Technique, Autoimmunity, Disease, NUCLEAR-FACTOR, Kaplan-Meier Estimate, medicine.disease_cause, Hypogammaglobulinemia, 0302 clinical medicine, NFKB1 variants and mutations, autosomal dominant inheritance, common variable immunodeficiency, reduced penetrance, variable expressivity, HDE PED, Immunology and Allergy, variants and mutations, NF-κB1-related phenotype, Immunodeficiency, IMMUNODEFICIENCY, NF-?B1-related phenotype, 1184 Genetics, developmental biology, physiology, Disease Management, Middle Aged, NF-kappa B1-related phenotype, Prognosis, Penetrance, Immunohistochemistry, Magnetic Resonance Imaging, 3. Good health, Phenotype, NFKB1 variant, Female, Haploinsufficiency, NFKB1 mutation, Adult, Heterozygote, Immunology, HAPLOINSUFFICIENCY, Article, 03 medical and health sciences, autosomal dominant, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged, business.industry, Common variable immunodeficiency, NF-kappa B p50 Subunit, NF-KAPPA-B1, Immune dysregulation, medicine.disease, 030104 developmental biology, Biological Variation, Population, CELLS, Mutation, Primary immunodeficiency, 3111 Biomedicine, business, Tomography, X-Ray Computed, Biomarkers, 030215 immunology
Abstract: Contains fulltext : 229571.pdf (Publisher’s version ) (Closed access) BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.
Published: 2020

19. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author: Nicholas A. Watkins, Julian C. Knight, William J. Astle, Stephan B. Felix, Petra Schubert, Andreas Greinacher, Laura M. Raffield, Guillaume Lettre, Leslie A. Lange, Erwin P. Bottinger, Jonathan D. Rosen, Frank J. A. van Rooij, Tim Kacprowski, Hua Tang, Regina Manansala, Manuel Tardaguila, Mohsen Ghanbari, Tao Jiang, Torben Hansen, Abdou Mousas, Adam S. Butterworth, Yoav Ben-Shlomo, Praveen Surendran, Terho Lehtimäki, Peter W.F. Wilson, Parsa Akbari, Hélène Choquet, Niels Grarup, Girish N. Nadkarni, Jean-Claude Tardif, Jennifer E. Huffman, Dragana Vuckovic, Ruth J. F. Loos, Karyn Megy, Emilie M. Wigdor, Michael Preuss, Alan B. Zonderman, Yukinori Okada, Oluf Pedersen, Arden Moscati, Leo-Pekka Lyytikäinen, Masahiro Kanai, Wei Huang, Andrew D Beswick, Stephen B. Watt, Erik L. Bao, Allan Linneberg, Paul Elliott, Eric Jorgenson, Tõnu Esko, Michael H. Guo, VA Million Veteran Program, Saori Sakaue, Mika Kähönen, Olli T. Raitakari, Stefan Weiss, Traci M. Bartz, Nina Mononen, Jette Bork-Jensen, Willem H. Ouwehand, Linda Broer, John Danesh, Masato Akiyama, James S. Floyd, Scott C. Ritchie, Kjell Nikus, Paul L. Auer, Emanuele Di Angelantonio, Ken Sin Lo, Kelly Cho, Uwe Völker, Ming-Huei Chen, Evangelos Evangelou, David J. Roberts, Na Cai, Benjamin Rodriguez, Savita Karthikeyan, Yoichiro Kamatani, Michael Inouye, Yoshinori Murakami, Yongmei Liu, Alexander P. Reiner, Koichi Matsuda, Jingzhong Ding, Kumaraswamy Naidu Chitrala, Niki Dimou, Andrew D. Johnson, Nathan Pankratz, Jeffrey Haessler, Vijay G. Sankaran, Oliver Stegle, Qi Guo, Karen L. Mohlke, Jennifer A. Brody, Michele K. Evans, Fotios Koskeridis, Cassandra N. Spracklen, Jerome I. Rotter, Ani Manichaikul, Patrick K. Albers, Caleb A. Lareau, Michel Georges, Hannes Ponstingl, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Yun Li, Klaudia Walter, Huijun Qian, Henry Völzke, Christopher J. Penkett, J. M. M. Howson, Kousik Kundu, Epidemiology, and Internal Medicine
Subjects: Gene regulatory network, LOCI, EFFICIENT, Genome-wide association study, VARIANTS, Blood cell, 0302 clinical medicine, RARE, genetics, 11 Medical and Health Sciences, 0303 health sciences, rare diseases, Biobank, ddc, medicine.anatomical_structure, fine-mapping, VA Million Veteran Program, symbols, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, UK Biobank, polygenic risk, rare disease, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, GENETIC ARCHITECTURE, 03 medical and health sciences, symbols.namesake, splicing, blood, medicine, CELL, Allele, GENOME-WIDE ASSOCIATION, COMMON, 030304 developmental biology, Science & Technology, COMPLEX, Oxygen transport, Cell Biology, 06 Biological Sciences, Genetic architecture, hematopoiesis, INTERROGATION, Mendelian inheritance, chromatin, omnigenic, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Summary Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation., Graphical Abstract, Highlights • Largest genome-wide association study of blood cell traits to date • Empiric assessments of omnigenic and infinitesimal models of polygenic variation • Functional insights into how genetic variants impact human hematopoiesis • Assessment of the effect of polygenic trait scores upon blood diseases, Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases.
Published: 2020
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20. Next-generation sequencing for the diagnosis of MYH9-RD: Predicting pathogenic variants

Author: Daniel Duarte, Mariana Bonduel, Sri V V Deevi, Kathleen Stirrups, Paolo Gresele, David Allsup, Rutendo Mapeta, Jonathan Stephens, Tadbir K. Bariana, Kathleen Freson, Nihr BioResource, Ernest Turro, Kim Elliott, Nicola Curry, David Keeling, D. J. Perry, Kate Downes, Carolyn M. Millar, Luigi Grassi, Keith Gomez, Nora Butta, Ilenia Simeoni, Emanuela Falcinelli, Peter William Collins, Michele P. Lambert, Christopher J. Penkett, Loredana Bury, John K. Wu, Nick Gleadall, Karina Althaus, Daniel Greene, Bruce Furie, Willem H. Ouwehand, Rachel Linger, Sarah K Westbury, Karyn Megy, Sarah Mangles, Megy, Karyn [0000-0002-2826-3879], Stephens, Jonathan [0000-0003-2020-9330], Downes, Kate [0000-0003-0366-1579], Johnson, Kathleen [0000-0002-6823-3252], Turro Bassols, Ernest [0000-0002-1820-6563], Ouwehand, Willem [0000-0002-7744-1790], Simeoni, Ilenia [0000-0001-5039-2194], and Apollo - University of Cambridge Repository
Subjects: Male, Variable severity, Fluorescent Antibody Technique, Gene Expression, high throughput next generation sequencing, Child, Genetics (clinical), Research Articles, 0303 health sciences, Kidney, 030305 genetics & heredity, Chromosome Mapping, High-Throughput Nucleotide Sequencing, Middle Aged, Macrothrombocytes, MYH9‐related disorders, ACMG guidelines, 3. Good health, Clinical Practice, medicine.anatomical_structure, Phenotype, clinical diagnosis, Child, Preschool, Female, ACMG Guidelines, Research Article, Adult, medicine.medical_specialty, Adolescent, Genotype, Platelet disorder, genomics, high throughput sequencing, MYH9-related disorders, variant classification, Biology, DNA sequencing, Evolution, Molecular, 03 medical and health sciences, Young Adult, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Alleles, Genetic Association Studies, 030304 developmental biology, Aged, Myosin Heavy Chains, Genetic variants, Genetic Variation, Infant, medicine.disease, Bleeding diathesis, Mutation
Abstract: The heterogeneous manifestations of MYH9‐related disorder (MYH9‐RD), characterized by macrothrombocytopenia, Döhle‐like inclusion bodies in leukocytes, bleeding of variable severity with, in some cases, ear, eye, kidney, and liver involvement, make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE‐BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 of the 50 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental in diagnosing 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9‐RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9‐RD should always be considered. A HTS‐based strategy is a reliable method to reach a conclusive diagnosis of MYH9‐RD in clinical practice., MYH9‐related disorder diagnosis is still challenging in clinical practice. We analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder and identified 50 patients with a rare variant in MYH9. In the presence of an unclassified platelet disorder with macrothrombocytes, MYH9‐RD should always be considered.
Published: 2020

21. Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension

Author: Karyn Megy, William C. Nichols, Chung K. Wendy, Jonathan Stephens, Nicholas W. Morrell, Christopher J. Penkett, Stefan Gräf, Tobias Tilly, Richard C. Trembath, Michael W. Pauciulo, Divya Pandya, Carrie L. Welch, Carmen M. Treacy, Allan Lawrie, Smitha Rajaram, Martin R. Wilkins, Yufeng Shen, Emilia M. Swietlik, Andrew J. Swift, Laura Southgate, Marcella Cogliano, Na Zhu, Heritable Pah, Katie A. Lutz, Daniel Greene, US Pah Biobank Enrolling Centers' Investigators, and Jennifer M. Martin
Subjects: Genetics, 0303 health sciences, Candidate gene, Kinase insert domain receptor, Biology, Bayesian inference, medicine.disease, Phenotype, Pulmonary hypertension, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, 030220 oncology & carcinogenesis, Rare mutations, medicine, Gene, 030304 developmental biology
Abstract: BackgroundApproximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics.MethodsWe analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed.ResultsHeterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics.ConclusionsThe Bayesian inference approach allowed us to independently validate KDR, which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
Published: 2019

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

Author: Minka J A Vries, Alexander Tolios, Johanna Gebhart, Ilenia Simeoni, Will Thomas, Stefanie Hofer, Matthias Haimel, Sofia Papadia, Keith Gomez, Daniel Greene, Rutendo Mapeta, Christopher J. Penkett, Willem H. Ouwehand, Michael Laffan, Kate Downes, Ernest Turro, Suthesh Sivapalaratnam, Louise C. Daugherty, Yvonne M. C. Henskens, Karyn Megy, Nick Gleadall, Howard Martin, Ingrid Pabinger, Martin Besser, Stephen Abbs, Andrew D Mumford, Daniel Duarte, Jonathan Stephens, Shoshana Revel-Vilk, Namir Al Hasso, Salih Tuna, Olga Shamardina, Sri V V Deevi, Chantal Thys, Emily Symington, Kathleen Freson, Nichola Cooper, Imperial College Healthcare NHS Trust- BRC Funding, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, RS: CARIM - R1 - Thrombosis and haemostasis, Promovendi CD, Biochemie, Faculteit FHML Centraal, MUMC+: DA CDL Algemeen (9), and RS: Carim - B04 Clinical thrombosis and Haemostasis
Subjects: Male, 0301 basic medicine, Platelet disorder, Immunology, Gene Dosage, Hemorrhage, Context (language use), VARIANTS, 030204 cardiovascular system & hematology, BIOBANK, Bioinformatics, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Copy-number variation, Hemostatic function, 1102 Cardiorespiratory Medicine and Haematology, MUTATION, GENETIC DIAGNOSIS, Blood Platelet Disorders, INHERITED THROMBOCYTOPENIA, Hemostasis, business.industry, High-Throughput Nucleotide Sequencing, 1103 Clinical Sciences, Thrombosis, Oligogenic Inheritance, NIHR BioResource, Cell Biology, Hematology, medicine.disease, DYSFUNCTION, Bleeding diathesis, 030104 developmental biology, 1114 Paediatrics and Reproductive Medicine, Female, business
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. ispartof: BLOOD vol:134 issue:23 pages:2082-2091 ispartof: location:United States status: published
Published: 2019

23. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Author: Gavin Arno, Keren J. Carss, Sarah Hull, Ceniz Zihni, Anthony G. Robson, Alessia Fiorentino, Alison J. Hardcastle, Graham E. Holder, Michael E. Cheetham, Vincent Plagnol, Anthony T. Moore, F. Lucy Raymond, Karl Matter, Maria S. Balda, Andrew R. Webster, Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Forbes Manson, Panagiotis Sergouniotis, Chris Inglehearn, Carmel Toomes, Manir Ali, Martin McKibbin, James Poulter, Kamron Khan, Emma Lord, Andrea Nemeth, Susan Downes, Stephanie Halford, Jing Yu, Stefano Lise, Nikos Ponitkos, Michel Michaelides, Veronica van Heyningen, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Ruth Armstrong, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Maria Bitner-Glindzicz, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Jenny Carmichael, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Detelina Grozeva, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Jane Hurst, Roger James, Stephen Jolles, Dragana Josifova, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Joan Paterson, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Elisabeth Rosser, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Alba Sanchis-Juan, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Emma Wakeling, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), and Med Microbiol, Infect Dis & Infect Prev
Subjects: Male, 0301 basic medicine, Retinal degeneration, Biallelic Mutation, RHOA, PROTEIN, Eye, Medical and Health Sciences, ACTIVATION, chemistry.chemical_compound, 0302 clinical medicine, 2.1 Biological and endogenous factors, Missense mutation, Exome, Aetiology, Genetics (clinical), Genetics & Heredity, Genetics, biology, Retinal Degeneration, Cell Polarity, MOSAIC EYES, Biological Sciences, Middle Aged, Phenotype, inherited retinal dystrophy, Pedigree, UK Inherited Retinal Disease Consortium, Female, apicobasal polarity, Retinal Dystrophies, Adult, NIHR Bioresource - Rare Diseases Consortium, ARHGEF18, Genotype, Mutation, Missense, Nerve Tissue Proteins, Retina, 03 medical and health sciences, Rare Diseases, retinitis pigmentosa, Report, CRB1, Retinitis pigmentosa, medicine, Humans, Amino Acid Sequence, Eye Proteins, Eye Disease and Disorders of Vision, Alleles, Human Genome, Neurosciences, Genetic Variation, Membrane Proteins, Epithelial Cells, Retinal, CELL FEATURES, medicine.disease, NUCLEOTIDE EXCHANGE FACTOR, p114RhoGEF, 030104 developmental biology, INTEGRATIVE GENOMICS VIEWER, OKO-MEDUZY, chemistry, Mutation, MORPHOGENESIS, 030221 ophthalmology & optometry, biology.protein, Missense, rhoA GTP-Binding Protein, Rho Guanine Nucleotide Exchange Factors, Genome-Wide Association Study
Abstract: Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs ∗ 63), c.1996C>T (p.Arg666 ∗ ), c.2632G>T (p.Glu878 ∗ ), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.
Published: 2017

24. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Author: Keren J. Carss, Gavin Arno, Marie Erwood, Jonathan Stephens, Alba Sanchis-Juan, Sarah Hull, Karyn Megy, Detelina Grozeva, Eleanor Dewhurst, Samantha Malka, Vincent Plagnol, Christopher Penkett, Kathleen Stirrups, Roberta Rizzo, Genevieve Wright, Dragana Josifova, Maria Bitner-Glindzicz, Richard H. Scott, Emma Clement, Louise Allen, Ruth Armstrong, Angela F. Brady, Jenny Carmichael, Manali Chitre, Robert H.H. Henderson, Jane Hurst, Robert E. MacLaren, Elaine Murphy, Joan Paterson, Elisabeth Rosser, Dorothy A. Thompson, Emma Wakeling, Willem H. Ouwehand, Michel Michaelides, Anthony T. Moore, Andrew R. Webster, F. Lucy Raymond, Timothy Aitman, Hana Alachkar, Sonia Ali, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Colin Church, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), Rue-Albrecht, K, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Biochemie, Raymond, Lucy [0000-0003-2652-3355], Apollo - University of Cambridge Repository, Vascular Medicine, and Paediatric Infectious Diseases / Rheumatology / Immunology
Subjects: 0301 basic medicine, Male, DNA Mutational Analysis, EXOME, PROTEIN, Eye, whole-genome sequence, NIHR-BioResource Rare Diseases Consortium, Medical and Health Sciences, Choroideremia, ACTIVATION, 0302 clinical medicine, Ethnicity, 2.1 Biological and endogenous factors, Exome, rare sequence variant, Copy-number variation, Aetiology, MUTATION, Genetics (clinical), Exome sequencing, Genetics & Heredity, Genetics, Genome, Adaptor Proteins, Biological Sciences, DYSTROPHY, copy-number variants, Female, Human, Common disease-common variant, LEBER CONGENITAL AMAUROSIS, Ethnic Groups, Genes, Recessive, Biology, DIAGNOSIS, Article, 03 medical and health sciences, Rare Diseases, Retinal Diseases, STARGARDT DISEASE, Clinical Research, REVEALS, Journal Article, medicine, Recessive, Humans, retinal dystrophy, Eye Disease and Disorders of Vision, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, Base Sequence, Genome, Human, Human Genome, Signal Transducing, Neurosciences, Genetic Variation, medicine.disease, GENE, Introns, Stargardt disease, Good Health and Well Being, 030104 developmental biology, Genes, Mutation, 030221 ophthalmology & optometry, Human genome
Abstract: Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.
Published: 2017

25. Comprehensive Description of Monoallelic GP1BA Variants Associated with Thrombocytopenia

Author: Nihr BioResource, Lucy FitzGibbon, Ernest Turro, Neil V. Morgan, Rachel C Peck, Sarah K Westbury, Karyn Megy, Andrew D Mumford, José Rivera, Daniel Greene, Walter H. Kahr, and Kate Downes
Subjects: Genetics, GP1BA, business.industry, Immunology, Medicine, Cell Biology, Hematology, business, Biochemistry
Abstract: GP1BA encodes the glycoprotein (GP) 1bα subunit of the GP1b/IX/V complex, the platelet receptor for von Willebrand factor (VWF) and a mediator of outside-in signalling that contributes to platelet activation. Biallelic variants in GPIBA that prevent surface expression of GPIB/IX/V cause the recessive disorder Bernard Soulier Syndrome (BSS; OMIM #23100) in which there is often severe bleeding caused by thrombocytopenia and platelet dysfunction. Thrombocytopenia has also been associated with monoallelic missense variants in the GP1bα R loop (residues 227-242) which enhance VWF binding (platelet-type von Willebrand disease (pVWD); OMIM #177820). Other monoallelic GPIBA missense variants such as the Bolzano variant (p.Ala172Val; OMIM #153670) have been associated with dominant thrombocytopenia without altered VWF levels. In order to better describe the relationship between monoallelic GPIBA variants and thrombocytopenia we evaluated data from the NIHR BioResource for Rare Diseases, (NBR-RD) and the Inherited Platelet Disorders programmes at the Universities of Birmingham (UK), Murcia (Spain) and Toronto (Canada) in which patients with unexplained platelet disorders underwent diagnostic next generation sequencing. Using the BeviMed method for genetic association we compared the genotypes at rare nonsynoymous variants of 105 unrelated thrombocytopenia cases (platelet count (PLT) 15. These were present in 29 index cases (18 females, median age 37 years) with unexplained thrombocytopenia and included the variant predicting the p.Asn150Ser substitution which was identified in seven independent index cases. The variants comprised 18 missense, two inframe insertions (one with an additional missense change) and one insertion resulting in a frame shift. Seven had been previously associated with thrombocytopenia. Sixteen of the variants predicted amino acid substitutions or single residue insertions within the GP1bα leucine rich repeat region (LRR; residues 48-200) or in adjacent regions of the LRR N- and C-terminal caps. Cases with variants in the LRR region typically displayed mild mucocutaneous bleeding, abnormal bleeding after minor trauma or surgery and heavy menstrual bleeding. The platelet count was typically 60-100 x109/L and mean platelet volume greater than 11 fL. There were two missense variants in the GP1bα R loop that have been previously associated with pVWD and two further previously unreported missense variants in the cytoplasmic domain. The final variant was a monoallelic single nucleotide insertion predicted to cause a frame shift and absent expression of GP1bα and has been previously reported as a biallelic variant associated with BSS. These data indicate that in a multicentre cross-sectional cohort of cases with otherwise unexplained thrombocytopenia, monoallelic missense GPIBA variants affecting the LRR or adjacent regions were more prevalent than R loop variants associated with pVWD or variants causing absent GP1bα expression associated with biallelic BSS. The LRR region contains the GP1bα-VWF binding site which is predicted to be disrupted by the missense variants observed in this study. The LRR region is also the location of the GP1bα Bolzano variant and six other monoallelic variants previously associated with thrombocytopenia in previous single case reports. These observations extend the repertoire of GPIBA variants associated with thrombocytopenia and although requiring experimental confirmation of pathogenicity, suggest a common molecular pathogenesis for dominant GPIBA-associated thrombocytopenia in which reduced circulating platelet numbers arises from defective GP1bα-VWF interactions. Figure Disclosures Turro: Tachyon Ventures: Other: Partner & Scientific Director.
Published: 2020

26. Curated disease-causing genes for bleeding, thrombotic, and platelet disorders: Communication from the SSC of the ISTH

Author: Karyn Megy, Michele P. Lambert, Anne Goodeve, Willem H. Ouwehand, Paolo Gresele, Loredana Bury, Kathleen Freson, Rutendo Mapeta, Paul F. Bray, Ilenia Simeoni, Daniel B. Bellissimo, Joannella Morales, Kate Downes, Pieter H. Reitsma, Freson, Kathleen [0000-0002-4381-2442], and Apollo - University of Cambridge Repository
Subjects: Platelet disorder, MEDLINE, Hemorrhage, Disease, Bioinformatics, Text mining, Predictive Value of Tests, Risk Factors, Genetic variation, Medicine, Humans, Genetic Predisposition to Disease, Gene, Hemostasis, business.industry, Genetic Variation, Thrombosis, Recommendations and Guidelines, Hematology, Phenotype, Blood Coagulation Factors, Molecular Diagnostic Techniques, Predictive value of tests, Blood Platelet Disorders, business, Subcommittee on Genomics in Thrombosis and Hemostasis
Abstract: ispartof: JOURNAL OF THROMBOSIS AND HAEMOSTASIS vol:17 issue:8 pages:1253-1260 ispartof: location:England status: published
Published: 2019

27. De novo variant in tyrosine kinase SRC causes thrombocytopenia: case report of a second family

Author: Chantal Thys, Lore De Kock, Kathleen Freson, Karyn Megy, Daniel Duarte, Chris Van Geet, and Kate Downes
Subjects: 0301 basic medicine, 030204 cardiovascular system & hematology, Germline, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Biopsy, Medicine, Humans, Platelet, Myelofibrosis, medicine.diagnostic_test, business.industry, Tyrosine phosphorylation, Hematology, General Medicine, medicine.disease, Thrombocytopenia, 030104 developmental biology, medicine.anatomical_structure, src-Family Kinases, chemistry, Child, Preschool, Cancer research, Female, Bone marrow, business, Tyrosine kinase, Proto-oncogene tyrosine-protein kinase Src
Abstract: A germline heterozygous gain-of-function p.E527K variant in tyrosine kinase SRC was previously found to cause thrombocytopenia, myelofibrosis, bleeding, bone pathologies, premature edentulism and mild facial dysmorphia in nine patients of a single pedigree. Because of this variant, SRC loses its self-inhibitory capacity, causing constitutively active SRC expression in platelets. These patients have fewer and heterogeneous-sized platelets that are hyporeactive to collagen. We now report a 5-year-old girl with syndromic thrombocytopenia due to the same SRC-E527K variant that occurs de novo. A bone marrow biopsy, blood smear analysis, platelet aggregations, flow cytometric analysis of P-selectin, SRC expression and tyrosine phosphorylation studies were performed to confirm the similarities between the two families. This study strengthens our previous finding that hyperactive SRC kinase results in mild platelet dysfunction and thrombocytopenia with hypogranular platelets and further expands the clinical description of this syndrome to improve early recognition.
Published: 2019

28. Large-Scale Whole-Genome Sequencing Reveals the Genetic Architecture of Primary Membranoproliferative GN and C3 Glomerulopathy

Author: Daniel P. Gale, Keren J. Carss, Omid Sadeghi-Alavijeh, Salih Tuna, Monika Mozere, Mmy Chan, Deborah Whitehorn, Eks Wong, H Maxwell, MT Christian, Claire L. Harris, Sally Johnson, Sofie Ashford, Adam P. Levine, H.T. Cook, P McAlinden, Christopher J. Penkett, Kevin J. Marchbank, Karyn Megy, Stephen D. Marks, Kathleen Stirrups, Matthew Hall, J Wessels, and National Institute for Health Research
Subjects: Male, Candidate gene, Glomerulonephritis, Membranoproliferative, Locus (genetics), Genome-wide association study, Human leukocyte antigen, Biology, Gene mutation, Serogroup, Glomerulopathy, HLA-DQ Antigens, Atypical hemolytic uremic syndrome, medicine, Humans, Genetics, Complement C3 Nephritic Factor, Whole Genome Sequencing, 1103 Clinical Sciences, General Medicine, Complement C3, HLA-DR Antigens, Urology & Nephrology, medicine.disease, Basic Research, Nephrology, Alternative complement pathway, Kidney Diseases, Female
Abstract: BACKGROUND: Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN. METHODS: We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource–Rare Diseases Study. We examined copy number, rare, and common variants. RESULTS: Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (P=3.29×10−8; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 (P=1.21×10−8; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure. CONCLUSIONS: We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.
Published: 2019

29. How common are single gene mutations as a cause for lacunar stroke? A targeted gene panel study

Author: Hugh S. Markus, Daniel Duarte, Olga Shamardina, Sri V V Deevi, Karyn Megy, Willem H. Ouwehand, Rutendo Mapeta, Rhea Y. Y. Tan, Kate Downes, Matthew Traylor, and Stefan Gräf
Subjects: 0301 basic medicine, Male, Lacunar stroke, Population, Migraine with Aura, CADASIL, DNA sequencing, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Missense mutation, Humans, Age of Onset, education, Connective Tissue Diseases, Genotyping, Aged, Genetics, Whole genome sequencing, education.field_of_study, business.industry, High-Throughput Nucleotide Sequencing, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, Cerebral Small Vessel Diseases, Mutation, Stroke, Lacunar, Female, Neurology (clinical), Age of onset, business, 030217 neurology & neurosurgery, Cerebral Amyloid Angiopathy, Familial
Abstract: ObjectivesTo determine the frequency of rare and pertinent disease-causing variants in small vessel disease (SVD)-associated genes (such as NOTCH3, HTRA1, COL4A1, COL4A2, FOXC1, TREX1, and GLA) in cerebral SVD, we performed targeted gene sequencing in 950 patients with younger-onset apparently sporadic SVD stroke using a targeted sequencing panel.MethodsWe designed a high-throughput sequencing panel to identify variants in 15 genes (7 known SVD genes, 8 SVD-related disorder genes). The panel was used to screen a population of 950 patients with younger-onset (≤70 years) MRI-confirmed SVD stroke, recruited from stroke centers across the United Kingdom. Variants were filtered according to their frequency in control databases, predicted effect, presence in curated variant lists, and combined annotation dependent depletion scores. Whole genome sequencing and genotyping were performed on a subset of patients to provide a direct comparison of techniques. The frequency of known disease-causing and pertinent variants of uncertain significance was calculated.ResultsWe identified previously reported variants in 14 patients (8 cysteine-changing NOTCH3 variants in 11 patients, 2 HTRA1 variants in 2 patients, and 1 missense COL4A1 variant in 1 patient). In addition, we identified 29 variants of uncertain significance in 32 patients.ConclusionRare monogenic variants account for about 1.5% of younger onset lacunar stroke. Most are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy variants, but the second most common gene affected is HTRA1. A high-throughput sequencing technology platform is an efficient, reliable method to screen for such mutations.
Published: 2019

30. Whole-genome sequencing of rare disease patients in a national healthcare system

Author: William J. Astle, F. Lucy Raymond, Kathleen Freson, Willem H. Ouwehand, Karyn Megy, Kathleen Stirrups, and Ernest Turro
Subjects: Whole genome sequencing, Genetics, 0303 health sciences, Disease, Biology, Genome, 3. Good health, LRBA, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, 030220 oncology & carcinogenesis, Mendelian inheritance, symbols, Allele, Gene, 030304 developmental biology, Rare disease
Abstract: Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and mediating genes for more than half such disorders remain to be discovered. We implemented whole-genome sequencing (WGS) in a national healthcare system to streamline diagnosis and to discover unknown aetiological variants, in the coding and non-coding regions of the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 patients with detailed phenotypic data. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed aetiological. Using WGS of UK Biobank1, we showed that rare alleles can explain the presence of some individuals in the tails of a quantitative red blood cell (RBC) trait. Finally, we reported 4 novel non-coding variants which cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
Published: 2019
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31. Diagnostic high-throughput sequencing of 2,390 patients with bleeding, thrombotic and platelet disorders

Author: Olga Shamardina, Chantal Thys, Michael Laffan, Stephen Abbs, Suthesh Sivapalaratnam, Alexander Tolios, S. V. Deevil, Sofia Papadia, Matthias Haimel, Ilenia Simeoni, N. Al Hasso, Ernest Turro, S. Revel-Vilk, Karyn Megy, Stefanie Hofer, Johanna Gebhart, Minka J A Vries, Daniel Greene, Kathleen Freson, Louise C. Daugherty, Yvonne M. C. Henskens, Rutendo Mapeta, Howard Martin, Daniel Duarte, J. Stephens, Emily Symington, Nick Gleadall, Willem H. Ouwehand, Nihr BioResource, Christopher J. Penkett, Ingrid Pabinger, Nichola Cooper, Salih Tuna, Martin Besser, Kate Downes, Andrew D Mumford, Will Thomas, and Keith Gomez
Subjects: business.industry, Hemostasis, Platelet disorder, Medicine, Oligogenic Inheritance, Platelet, Context (language use), Bioinformatics, business, Gene, Uncertain significance, DNA sequencing
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 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.
Published: 2018

32. Whole genome sequencing of a sporadic primary immunodeficiency cohort

Author: Andy G. Lynch, Jonathan Stephens, Sinisa Savic, Kenneth G. C. Smith, Silje F. Jørgensen, Emily Staples, Ernest Turro, David Ellinghaus, Siobhan O. Burns, Rachel Linger, Christopher J. Penkett, Zinan Zhang, Ravishankar Sargur, A Worth, Karyn Megy, Nicholas Gleadall, Oliver S. Burren, William Rae, Steven Hanson, Paula Rayner-Matthews, Matthew Buckland, Kathleen Stirrups, David M. Sansom, Adrian J. Thrasher, Daniel Greene, James Thaventhiran, Sri V V Deevi, Willem H. Ouwehand, Crina Samarghitean, Hana Lango Allen, Pavels Gordins, Dinakantha S. Kumararatne, Antony J. Cutler, Helen Baxendale, Paul A. Lyons, Taco W. Kuijpers, Moira Thomas, Suranjith L. Seneviratne, Jesmeen Maimaris, Alba Sanchis-Juan, Matthew A. Brown, Paul Tuijnenburg, Eva Ellinghaus, James H.R. Farmery, Kimberly Gilmour, Ilenia Simeoni, and Tom H. Karlsen
Subjects: Whole genome sequencing, Genetics, 0303 health sciences, Genome-wide association study, Biology, Immune dysregulation, medicine.disease, medicine.disease_cause, Phenotype, Penetrance, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Primary immunodeficiency, medicine, Coding region, Gene, 030304 developmental biology
Abstract: Primary immunodeficiency (PID) is characterised by recurrent and often life-threatening infections, autoimmunity and cancer, and it presents major diagnostic and therapeutic challenges. Although the most severe forms present in early childhood, the majority of patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent, and up to 10% develop lymphoid malignancies1–3. Consequently, in sporadic PID genetic diagnosis is difficult and the role of genetics is not well defined. We addressed these challenges by performing whole genome sequencing (WGS) of a large PID cohort of 1,318 participants. Analysis of coding regions of 886 index cases found disease-causing mutations in known monogenic PID genes in 10.3%, while a Bayesian approach (BeviMed4) identified multiple potential new candidate genes, including IVNS1ABP. Exploration of the non-coding genome revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to variable penetrance and phenotypic complexity in PID. Thus, a cohort-based WGS approach to PID diagnosis can increase diagnostic yield while deepening our understanding of the key pathways influencing human immune responsiveness.
Published: 2018

33. Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing

Author: Karyn Megy, Nicholas Gleadall, Christopher E. French, Ricardo Garcia Branco, Marie Erwood, Topun Austin, Olga Shamardina, Willem H. Ouwehand, Helen Dolling, F Lucy Raymond, Alba Sanchis-Juan, Luca Stefanucci, Keren J. Carss, Jonathan Stephens, Eleanor Dewhurst, Trevor Cole, Christopher J. Penkett, Isabelle Delon, Detelina Grozeva, Kathleen Stirrups, Andrew R. Webster, Gavin Arno, Stephens, Jonathan [0000-0003-2020-9330], French, Courtney [0000-0001-7620-1544], Shamardina, Olga [0000-0003-4994-2157], Johnson, Kathleen [0000-0002-6823-3252], Dolling, Helen [0000-0001-6279-3622], Stefanucci, Luca [0000-0002-4352-1151], Austin, Topun [0000-0002-8428-8624], Ouwehand, Willem [0000-0002-7744-1790], Raymond, Lucy [0000-0003-2652-3355], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Nanopore, Male, lcsh:QH426-470, Systems biology, CDKL5, lcsh:Medicine, Cell Cycle Proteins, Heterogeneous-Nuclear Ribonucleoprotein U, Biology, Protein Serine-Threonine Kinases, Genome sequencing, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Genetics, CEP78, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, Genetics (clinical), Genome, Human, Research, Breakpoint, lcsh:R, Complex structural variant, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Human genetics, ARID1B, DNA-Binding Proteins, lcsh:Genetics, 030104 developmental biology, HNRNPU, Genomic Structural Variation, Mutation, Next-generation sequencing, Molecular Medicine, Identification (biology), Female, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Background Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation. Methods We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case. Results We identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements. Conclusions Our results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation. Electronic supplementary material The online version of this article (10.1186/s13073-018-0606-6) contains supplementary material, which is available to authorized users.
Published: 2018

34. Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort

Author: Karyn Megy, William Rae, Thaventhiran Jed., A Herwadkar, Paul Tuijnenburg, S Grigoriadou, Oliver S. Burren, Christopher J. Penkett, Zinan Zhang, Daniel Greene, Sinisa Savic, Willem H. Ouwehand, Matthew E. Hurles, Deevi Svv., Edgar Jdm., Crina Samarghitean, A Worth, Nicholas Gleadall, David Ellinghaus, Taco W. Kuijpers, Tom H. Karlsen, H Lango Allen, Catharina Schuetz, Pavels Gordins, Antony J. Cutler, Jesmeen Maimaris, Smith Kgc., David M. Sansom, Steven Hanson, Jonathan Stephens, Paul A. Lyons, Paula Rayner-Matthews, Kathleen Stirrups, Alba Sanchis-Juan, Adrian J. Thrasher, Anita Chandra, Andy G. Lynch, E Rivers, Siobhan O. Burns, Matthew A. Brown, Rachel Linger, Ilenia Simeoni, Eva Ellinghaus, Kimberly Gilmour, Ravishankar Sargur, Farmery Jhr., Matthew Buckland, Aarnoud Huissoon, Sarah Goddard, Dinakantha S. Kumararatne, Emily Staples, Ernest Turro, Helen Baxendale, Moira Thomas, Silje F. Jørgensen, Stephen Jolles, Suranjith L. Seneviratne, F Boschann, and Neill S. Cooper
Subjects: Whole genome sequencing, Multidisciplinary, business.industry, Cohort, MEDLINE, Primary immunodeficiency, Medicine, Genomics, Computational biology, business, medicine.disease
Published: 2020

35. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author: Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care
Subjects: 0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: © 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
Published: 2018

36. GRID – Genomics of Rare Immune Disorders: a highly sensitive and specific diagnostic gene panel for patients with primary immunodeficiencies

Author: Sinisa Savic, Hannah Stark, Ilenia Simeoni, Olga Shamardina, Rutendo Mapeta, Deborah Whitehorn, Kathleen Stirrups, Willem H. Ouwehand, Daniel Duarte, Paula Rayner-Matthews, Moira Thomas, Adrian J. Thrasher, Taco W. Kuijpers, Karyn Megy, Kenneth G. C. Smith, Christopher J. Penkett, Jonathan Stephens, Nihr BioResource, Emily Staples, Ernest Turro, Hana Lango Allen, Siobhan O. Burns, James Thaventhiran, and Sri V V Deevi
Subjects: 0303 health sciences, biology, business.industry, Genomics, Computational biology, Compound heterozygosity, Phenotype, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Immune system, biology.protein, Medicine, Bruton's tyrosine kinase, Missense mutation, Copy-number variation, business, Gene, 030304 developmental biology, 030215 immunology
Abstract: Primary Immune disorders affect 15,000 new patients every year in Europe. Genetic tests are usually performed on a single or very limited number of genes leaving the majority of patients without a genetic diagnosis. We designed, optimised and validated a new clinical diagnostic platform called GRID, Genomics of Rare Immune Disorders, to screen in parallel 279 genes, including 2015 IUIS genes, known to be causative of Primary Immune disorders (PID). Validation to clinical standard using more than 58,000 variants in 176 PID patients shows an excellent sensitivity, specificity. The customised and automated bioinformatics pipeline prioritises and reports pertinent Single Nucleotide Variants (SNVs), INsertions and DELetions (INDELs) as well as Copy Number Variants (CNVs). An example of the clinical utility of the GRID panel, is represented by a patient initially diagnosed with X-linked agammaglobulinemia due to a missense variant in the BTK gene with severe inflammatory bowel disease. GRID results identified two additional compound heterozygous variants in IL17RC, potentially driving the altered phenotype.
Published: 2018
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37. De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Author: Yoko Ito, Keren J. Carss, Sofia T. Duarte, Taila Hartley, Boris Keren, Manju A. Kurian, Isabelle Marey, Perinne Charles, Carla Mendonça, Caroline Nava, Rolph Pfundt, Alba Sanchis-Juan, Hans van Bokhoven, Anthony van Essen, Conny van Ravenswaaij-Arts, Kym M. Boycott, Kristin D. Kernohan, Sarah Dyack, F. Lucy Raymond, Timothy Aitman, David Bennett, Mark Caulfield, Patrick Chinnery, Daniel Gale, Ania Koziell, Taco W. Kuijpers, Michael A. Laffan, Eamonn Maher, Hugh S. Markus, Nicholas W. Morrell, Willem H. Ouwehand, David J. Perry, Irene Roberts, Kenneth G.C. Smith, Adrian Thrasher, Hugh Watkins, Catherine Williamson, Geoffrey Woods, Sofie Ashford, John R. Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Christopher J. Penkett, Kathleen Stirrups, Marijke Veltman, Tim Young, Matthew Brown, Naomi Clements-Brod, John Davis, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Amy Frary, Rachel Linger, Jennifer M. Martin, Sofia Papadia, Karola Rehnstrom, Hannah Stark, David Allsup, Steve Austin, Tamam Bakchoul, Tadbir K. Bariana, Paula Bolton-Maggs, Elizabeth Chalmers, Janine Collins, Peter Collins, Wendy N. Erber, Tamara Everington, Remi Favier, Kathleen Freson, Bruce Furie, Michael Gattens, Johanna Gebhart, Keith Gomez, Daniel Greene, Andreas Greinacher, Paolo Gresele, Daniel Hart, Johan W.M. Heemskerk, Yvonne Henskens, Rashid Kazmi, David Keeling, Anne M. Kelly, Michele P. Lambert, Claire Lentaigne, Ri Liesner, Mike Makris, Sarah Mangles, Mary Mathias, Carolyn M. Millar, Andrew Mumford, Paquita Nurden, Jeanette Payne, John Pasi, Kathelijne Peerlinck, Shoshana Revel-Vilk, Michael Richards, Matthew Rondina, Catherine Roughley, Sol Schulman, Harald Schulze, Marie Scully, Suthesh Sivapalaratnam, Matthew Stubbs, R. Campbell Tait, Kate Talks, Jecko Thachil, Cheng-Hock Toh, Ernest Turro, Chris Van Geet, Minka De Vries, Timothy Q. Warner, Henry Watson, Sarah Westbury, Abigail Furnell, Rutendo Mapeta, Paula Rayner-Matthews, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Christopher Watt, Deborah Whitehorn, Antony Attwood, Louise Daugherty, Sri V.V. Deevi, Csaba Halmagyi, Fengyuan Hu, Vera Matser, Stuart Meacham, Karyn Megy, Olga Shamardina, Catherine Titterton, Salih Tuna, Ping Yu, Julie von Ziegenweldt, William Astle, Marta Bleda, Stefan Gräf, Matthias Haimel, Hana Lango-Allen, Sylvia Richardson, Paul Calleja, Stuart Rankin, Wojciech Turek, Julie Anderson, Christine Bryson, Jenny Carmichael, Coleen McJannet, Sophie Stock, Louise Allen, Gautum Ambegaonkar, Ruth Armstrong, Gavin Arno, Maria Bitner-Glindzicz, Angie Brady, Natalie Canham, Manali Chitre, Emma Clement, Virginia Clowes, Patrick Deegan, Charu Deshpande, Rainer Doffinger, Helen Firth, Frances Flinter, Courtney French, Alice Gardham, Neeti Ghali, Paul Gissen, Detelina Grozeva, Robert Henderson, Anke Hensiek, Simon Holden, Muriel Holder, Susan Holder, Jane Hurst, Dragana Josifova, Deepa Krishnakumar, Melissa Lees, Robert MacLaren, Anna Maw, Sarju Mehta, Michel Michaelides, Anthony Moore, Elaine Murphy, Soo-Mi Park, Alasdair Parker, Chris Patch, Joan Paterson, Julia Rankin, Evan Reid, Elisabeth Rosser, Richard Sandford, Saikat Santra, Richard Scott, Aman Sohal, Penelope Stein, Ellen Thomas, Dorothy Thompson, Marc Tischkowitz, Julie Vogt, Emma Wakeling, Evangeline Wassmer, Andrew Webster, Sonia Ali, Souad Ali, Harm J. Boggard, Colin Church, Gerry Coghlan, Victoria Cookson, Paul A. Corris, Amanda Creaser-Myers, Rosa DaCosta, Natalie Dormand, Mélanie Eyries, Henning Gall, Pavandeep K. Ghataorhe, Stefano Ghio, Ardi Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Alan Greenhalgh, Charaka Hadinnapola, Arjan C. Houweling, Marc Humbert, Anna Huis in’t Veld, Fiona Kennedy, David G. Kiely, Gabor Kovacs, Allan Lawrie, Rob V. Mackenzie Ross, Rajiv Machado, Larahmie Masati, Sharon Meehan, Shahin Moledina, David Montani, Shokri Othman, Andrew J. Peacock, Joanna Pepke-Zaba, Val Pollock, Gary Polwarth, Lavanya Ranganathan, Christopher J. Rhodes, Kevin Rue-Albrecht, Gwen Schotte, Debbie Shipley, Florent Soubrier, Laura Southgate, Laura Scelsi, Jay Suntharalingam, Yvonne Tan, Mark Toshner, Carmen M. Treacy, Richard Trembath, Anton Vonk Noordegraaf, Sara Walker, Ivy Wanjiku, John Wharton, Martin Wilkins, Stephen J. Wort, Katherine Yates, Hana Alachkar, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Claire Booth, Michael Browning, Siobhan Burns, Anita Chandra, Nichola Cooper, Sophie Davies, Lisa Devlin, Elizabeth Drewe, David Edgar, William Egner, Rohit Ghurye, Kimberley Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Aarnoud Huissoon, Stephen Jolles, Peter Kelleher, Dinakantha Kumararatne, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Sai Murng, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith Seneviratne, Carrock Sewell, Emily Staples, Hans Stauss, James Thaventhiran, Moira Thomas, Steve Welch, Lisa Willcocks, Nigel Yeatman, Patrick Yong, Phil Ancliff, Christian Babbs, Mark Layton, Eleni Louka, Simon McGowan, Adam Mead, Noémi Roy, Jenny Chambers, Peter Dixon, Cecelia Estiu, Bill Hague, Hanns-Ulrich Marschall, Michael Simpson, Sam Chong, Ingrid Emmerson, Lionel Ginsberg, David Gosal, Rob Hadden, Rita Horvath, Mohamed Mahdi-Rogers, Adnan Manzur, Andrew Marshall, Emma Matthews, Mark McCarthy, Mary Reilly, Tara Renton, Andrew Rice, Andreas Themistocleous, Tom Vale, Natalie Van Zuydam, Suellen Walker, Liz Ormondroyd, Gavin Hudson, Wei Wei, Patrick Yu Wai Man, James Whitworth, Maryam Afzal, Elizabeth Colby, Moin Saleem, Omid S. Alavijeh, H. Terry Cook, Sally Johnson, Adam P. Levine, Edwin K.S. Wong, Rhea Tan, Alex MacKenzie, Jacek Majewski, Michael Brudno, Dennis Bulman, David Dyment, Freson, Kathleen, Peerlinck, Kathelijne, Van Geet, Christel, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, Medical Research Council (MRC), Clinical Cognitive Neuropsychiatry Research Program (CCNP), APH - Aging & Later Life, Pediatric surgery, Human genetics, ACS - Atherosclerosis & ischemic syndromes, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, and Molecular cell biology and Immunology
Subjects: 0301 basic medicine, Male, Care4Rare Canada Consortium, WAVE FAMILY PROTEINS, actin cytoskeleton, PROTEIN, HDE NEU PED, medicine.disease_cause, Whole Exome Sequencing, 0302 clinical medicine, Neurodevelopmental disorder, SYNAPTIC PLASTICITY, Intellectual disability, WAVE1 complex, PLASTICITY, EXCHANGE, 11 Medical and Health Sciences, Exome sequencing, Genetics (clinical), seizures, Genetics & Heredity, Genetics, Mutation, WASF1, DENDRITIC SPINES, developmental delay, Female, DISEASE GENE-DISCOVERY, Adult, Heterozygote, GENES, DISORDERS, autism, Biology, ACTIN, 03 medical and health sciences, Young Adult, Seizures, Report, Intellectual Disability, Exome Sequencing, medicine, Humans, PROTRUSIONS, recurrent de novo truncating mutations, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, lamellipodia, neurodevelopmental disorder, Actin remodeling, Heterozygote advantage, NIHR BioResource, 06 Biological Sciences, medicine.disease, Actin cytoskeleton, Wiskott-Aldrich Syndrome Protein Family, 030104 developmental biology, WAVE, RETARDATION, 030217 neurology & neurosurgery
Abstract: Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:1 pages:144-153 ispartof: location:United States status: published
Published: 2018

38. Expression Atlas update—an integrated database of gene and protein expression in humans, animals and plants

Author: Anja Füllgrabe, James C. Wright, Robert Petryszak, Satu Koskinen, Alvis Brazma, Pankaj Jaiswal, Laura Huerta, Elisabet Barrera, Mitra Barzine, Tony Burdett, Jyoti S. Choudhary, Catherine Snow, Emma Hastings, Oliver Mannion, Simon Jupp, Y. Amy Tang, Wolfgang Huber, Eleanor Williams, Nuno A. Fonseca, Maria Keays, Karyn Megy, Hendrik Weisser, Helen Parkinson, and Alfonso Muñoz-Pomer Fuentes
Subjects: Proteomics, 0301 basic medicine, InterPro, Gene Expression Profiling, Human Protein Atlas, Proteins, Computational biology, Plants, Biology, ENCODE, Bioinformatics, Hierarchical clustering, Gene expression profiling, Transcriptome, User-Computer Interface, 03 medical and health sciences, 030104 developmental biology, Cell Line, Tumor, Databases, Genetic, Genetics, Database Issue, Animals, Humans, Gene
Abstract: Expression Atlas (http://www.ebi.ac.uk/gxa) provides information about gene and protein expression in animal and plant samples of different cell types, organism parts, developmental stages, diseases and other conditions. It consists of selected microarray and RNA-sequencing studies from ArrayExpress, which have been manually curated, annotated with ontology terms, checked for high quality and processed using standardised analysis methods. Since the last update, Atlas has grown seven-fold (1572 studies as of August 2015), and incorporates baseline expression profiles of tissues from Human Protein Atlas, GTEx and FANTOM5, and of cancer cell lines from ENCODE, CCLE and Genentech projects. Plant studies constitute a quarter of Atlas data. For genes of interest, the user can view baseline expression in tissues, and differential expression for biologically meaningful pairwise comparisons-estimated using consistent methodology across all of Atlas. Our first proteomics study in human tissues is now displayed alongside transcriptomics data in the same tissues. Novel analyses and visualisations include: 'enrichment' in each differential comparison of GO terms, Reactome, Plant Reactome pathways and InterPro domains; hierarchical clustering (by baseline expression) of most variable genes and experimental conditions; and, for a given gene-condition, distribution of baseline expression across biological replicates.
Published: 2015

39. ArrayExpress update—simplifying data submissions

Author: Robert Petryszak, Ekaterina Pilicheva, Karyn Megy, Alvis Brazma, Tony Burdett, Gabriella Rustici, Olga Melnichuk, Emma Hastings, Ugis Sarkans, Helen Parkinson, Marco Brandizi, Natalja Kurbatova, Andrew Tikhonov, Eleanor Williams, Miroslaw Dylag, Nikolay Kolesnikov, Maria Keays, and Y. Amy Tang
Subjects: Internet, business.industry, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Genomics, Biology, Data submission, Bioinformatics, World Wide Web, Databases, Genetic, Genetics, Database Issue, The Internet, business, Software, Oligonucleotide Array Sequence Analysis
Abstract: The ArrayExpress Archive of Functional Genomics Data (http://www.ebi.ac.uk/arrayexpress) is an international functional genomics database at the European Bioinformatics Institute (EMBL-EBI) recommended by most journals as a repository for data supporting peer-reviewed publications. It contains data from over 7000 public sequencing and 42 000 array-based studies comprising over 1.5 million assays in total. The proportion of sequencing-based submissions has grown significantly over the last few years and has doubled in the last 18 months, whilst the rate of microarray submissions is growing slightly. All data in ArrayExpress are available in the MAGE-TAB format, which allows robust linking to data analysis and visualization tools and standardized analysis. The main development over the last two years has been the release of a new data submission tool Annotare, which has reduced the average submission time almost 3-fold. In the near future, Annotare will become the only submission route into ArrayExpress, alongside MAGE-TAB format-based pipelines. ArrayExpress is a stable and highly accessed resource. Our future tasks include automation of data flows and further integration with other EMBL-EBI resources for the representation of multi-omics data.
Published: 2014

40. Genome sequence of Aedes aegypti, a major arbovirus vector

Author: Sergio Verjovski-Almeida, James E. Galagan, Ryan C. Kennedy, Zhiyong Xi, Jason R. Miller, Eric Eisenstadt, Kyanne R. Reidenbach, Robert V. Bruggner, Yu-Hui Rogers, Hadi Quesneville, Doreen Werner, Owen White, Alexander S. Raikhel, Mario Stanke, J. Spencer Johnston, Diane D. Lovin, Evgenia V. Kriventseva, Ian T. Paulsen, Kathryn S. Campbell, Norman H. Lee, Ewan Birney, Karyn Megy, Hean Koo, David Kulp, Shelby L. Bidwell, Jingsong Zhu, Philip Montgomery, Paolo Amedeo, Yongmei Zhao, Chinnappa D. Kodira, Javier Costas, Michael C. Schatz, Steven P. Sinkins, Claire M. Fraser-Liggett, Martin Shumway, Kurt LaButti, Akio Mori, Brendan J. Loftus, Manfred Grabherr, Eric O. Stinson, Frank H. Collins, Zhijian Jake Tu, Monique R. Coy, Matt Crawford, Janice P. Vanzee, William M. Gelbart, Joshua Orvis, Peter Arensburger, Chunhong Mao, Evgeny M. Zdobnov, Saul A. Kravitz, Suely Lopes Gomes, David DeCaprio, David G. Hogenkamp, Daniel Lawson, Dennis L. Knudson, David W. Severson, George Dimopoulos, Marcelo B. Soares, Sinéad B. O'Leary, Peter W. Atkinson, David M. Jaffe, Becky deBruyn, Martin Hammond, Ana L. T. O. Nascimento, Jim Biedler, Stefan Wyder, Jose M. C. Tubio, Bruce W. Birren, Catherine A. Hill, Chad Nusbaum, Eduardo Lee, Song Li, Susan E. Brown, Jennifer R. Wortman, James R. Hogan, Hamza El-Dorry, Qi Zhao, Linda Hannick, Carlos Frederico Martins Menck, Vishvanath Nene, Jonathan Crabtree, Steven L. Salzberg, Michael H. Holmes, Maria de Fatima Bonaldo, Quinghu Ren, Mihaela Pertea, Charles Roth, Evan Mauceli, Karin Eiglmeier, Horacio Naveira, Brian J. Haas, Qiandong Zeng, Neil F. Lobo, Jennifer R. Schneider, The Institute for Genomic Research, The Institute for Genomic Research, Rockville, European Bioinformatics Institute [Hinxton] ( EMBL-EBI ), European Molecular Biology Laboratory [Hinxton], Broad Institute of MIT and Harvard ( BROAD INSTITUTE ), Broad Institute of MIT and Harvard, Virginia Polytechnic Institute and State University [Blacksburg], University College Dublin [Dublin] ( UCD ), Bloomberg School of Public Health, Johns Hopkins University ( JHU ) -Bloomberg School of Public Health, University of Geneva Medical School, Swiss Institute of Bioinformatics-University of Geneva Medical School, University of Notre Dame ( UND ), Harvard University [Cambridge], College of Agricultural Sciences Colorado State University, Colorado State University [Fort Collins] ( CSU ) -College of Agricultural Sciences, Northwestern University [Evanston], University of California [Riverside] ( UCR ), Department of Atmospheric, Oceanic and Planetary Physics [Oxford] ( AOPP ), University of Oxford [Oxford], Purdue University [West Lafayette], Centro Nacional de Genotipado Fundación Pública Galega de Medicina Xenómica Hospital Clínico Universitario de Santiago, Centro Nacional de Genotipado-Fundación Pública Galega de Medicina Xenómica-Hospital Clínico Universitario de Santiago, Institut Pasteur [Paris], Universidade de Sao Paulo Instituto de Quimica, Universidade de São Paulo ( USP ) -Instituto de Quimica, Texas A&M University [College Station], Joint Technology Center, University of Massachusetts [Amherst] ( UMass Amherst ), Universidade de Sao Paulo, Institute of Biomedical Sciences, Universidade de São Paulo ( USP ) -Institute of Biomedical Sciences, Instituto Butantan [São Paulo], Universidade da Coruña, University of Maryland [College Park], Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), University of California [Santa Cruz] ( UCSC ), Complexo Hospitalario Universitario de Santiago, Universität Göttingen, Georg-August-Universität Göttingen, George Washington University Medical Center, George Washington University ( GW ), The Institute for Genomic Research (TIGR), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University College Dublin [Dublin] (UCD), Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL)-University of Geneva Medical School, University of Notre Dame [Indiana] (UND), Colorado State University [Fort Collins] (CSU)-College of Agricultural Sciences, University of California [Riverside] (UCR), University of California, Department of Atmospheric, Oceanic and Planetary Physics [Oxford] (AOPP), Universidade de São Paulo (USP)-Instituto de Quimica, University of Massachusetts [Amherst] (UMass Amherst), University of Massachusetts System (UMASS), Universidade de São Paulo (USP)-Institute of Biomedical Sciences (ICB/USP), Universidade de São Paulo (USP), University of Maryland System, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), University of California [Santa Cruz] (UCSC), Georg-August-University [Göttingen], The George Washington University (GW), George Washington University (GW), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL)-University of Geneva Medical School, Harvard University, University of California [Riverside] (UC Riverside), University of California (UC), University of Oxford, Institut Pasteur [Paris] (IP), Universidade de São Paulo = University of São Paulo (USP)-Instituto de Quimica, Universidade de São Paulo = University of São Paulo (USP)-Institute of Biomedical Sciences (ICB/USP), Universidade de São Paulo = University of São Paulo (USP), University of California [Santa Cruz] (UC Santa Cruz), Georg-August-University = Georg-August-Universität Göttingen, Zdobnov, Evgeny, and Wyder, Stefan
Subjects: 0106 biological sciences, Male, Transcription, Genetic, Genome, Insect, transposons, receptors, Genes, Insect, Aedes/ genetics/metabolism, MESH: Genes, Insect, Yellow Fever/prevention & control/transmission, MESH: Base Sequence, 01 natural sciences, Dengue/prevention & control/transmission, MESH: Protein Structure, Tertiary, MESH: Arboviruses, MESH : Insect Vectors, MESH: Insect Proteins, MESH : Anopheles gambiae, MESH: Animals, MESH : Arboviruses, insects, MESH: Yellow Fever, superfamily, ddc:616, 0303 health sciences, Anopheles, MESH : Genes, Insect, 3. Good health, yellow-fever mosquito, anopheles-gambiae, drosophila-melanogaster, expression, evolution, organization, Drosophila melanogaster, MESH: DNA Transposable Elements, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Multigene Family, Public Health, MESH : Protein Structure, Tertiary, MESH: Sex Characteristics, Molecular Sequence Data, MESH : Multigene Family, MESH: Sex Determination (Genetics), MESH : Sex Determination (Genetics), Arbovirus, Article, 03 medical and health sciences, Species Specificity, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Anopheles gambiae, Yellow Fever, MESH: Species Specificity, Humans, MESH: Humans, MESH: Molecular Sequence Data, fungi, MESH : Humans, MESH : Sex Characteristics, Membrane Transport Proteins, Sex Determination Processes, medicine.disease, Insect Vectors, Protein Structure, Tertiary, Sex Determination (Genetics), MESH: Multigene Family, MESH: Female, MESH : Sequence Analysis, DNA, MESH: Sequence Analysis, DNA, Drosophila melanogaster/genetics, MESH : Molecular Sequence Data, Odorant binding, Insect Proteins/genetics, Anopheles gambiae, MESH: Dengue, Genome, MESH: Membrane Transport Proteins, Dengue, MESH : Membrane Transport Proteins, Aedes, Insect Vectors/ genetics/metabolism, MESH : Drosophila melanogaster, MESH : Female, Membrane Transport Proteins/genetics, Genetics, MESH : Insect Proteins, Sex Characteristics, Multidisciplinary, MESH: Synteny, MESH: Aedes, MESH : Genome, Insect, MESH : DNA Transposable Elements, Insect Proteins, Female, Orthologous Gene, MESH : Male, MESH : Dengue, Aedes aegypti, MESH: Insect Vectors, Biology, 010603 evolutionary biology, Synteny, MESH: Drosophila melanogaster, Protein Structure, Tertiary/genetics, MESH : Yellow Fever, parasitic diseases, medicine, MESH : Species Specificity, Animals, 030304 developmental biology, MESH : Aedes, Base Sequence, MESH: Genome, Insect, MESH: Transcription, Genetic, MESH : Synteny, MESH : Transcription, Genetic, Sequence Analysis, DNA, biology.organism_classification, MESH: Male, DNA Transposable Elements, MESH : Base Sequence, MESH : Animals, Arboviruses, Anopheles gambiae/genetics/metabolism
Abstract: We present a draft sequence of the genome of Aedes aegypti , the primary vector for yellow fever and dengue fever, which at ∼1376 million base pairs is about 5 times the size of the genome of the malaria vector Anopheles gambiae . Nearly 50% of the Ae. aegypti genome consists of transposable elements. These contribute to a factor of ∼4 to 6 increase in average gene length and in sizes of intergenic regions relative to An. gambiae and Drosophila melanogaster . Nonetheless, chromosomal synteny is generally maintained among all three insects, although conservation of orthologous gene order is higher (by a factor of ∼2) between the mosquito species than between either of them and the fruit fly. An increase in genes encoding odorant binding, cytochrome P450, and cuticle domains relative to An. gambiae suggests that members of these protein families underpin some of the biological differences between the two mosquito species.
Published: 2016

41. 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

42. Nature Communications

Author: Adam R. Wespiser, Don Gilbert, Vincent Croset, Joseph J. Gillespie, Renfu Shao, Timothy J. Kurtti, Julio Rozas, Hugh M. Robertson, Stephen C. Barker, Karen E. Nelson, Ketaki Bhide, Yoonseong Park, Brooke W. Bissinger, Patricia V. Pietrantonio, Joao H. F. Pedra, Janice P. Van Zee, Peter Arensburger, Hyeogsun Kwon, Timothy P. Driscoll, Daniel Lawson, Ryan C. Kennedy, Emma G. Lang, David Jiang, Jessica B. Hostetler, Jesús Vázquez, Zhijian Jake Tu, José de la Fuente, Bruce W. Birren, Juraj Koči, David R. Nelson, Catherine A. Hill, Brian P. Walenz, Frank Hauser, Cornelis J. P. Grimmelikhuijzen, Mathangi Thiagarajan, Andrew B. Nuss, Richard Benton, Linda Hannick, Kristin Lees, Stephen K. Wikel, Daniel R. Caffrey, Evgeny M. Zdobnov, Jason R. Miller, Elisabet Caler, Melissa J. Caimano, José M. C. Ribeiro, Jeffrey M. Grabowski, Elena Bonzón-Kulichenko, Monika Gulia-Nuss, Marta Tojo, Daniel E. Sonenshine, Joyce M. Sakamoto, Rushika Perera, Sergey Koren, R. Michael Roe, Nieves Ayllón, Qiandong Zeng, Jyothi Thimmapuram, Katherine M. Kocan, Jenica L. Abrudan, Gloria I. Giraldo-Calderón, Margarita Villar, David B. Sattelle, Alejandro Sánchez-Gracia, Francisca C. Almeida, Donghun Kim, Granger G. Sutton, Richard J. Kuhn, Maiara S. Severo, Sayed M.S. Khalil, Jiwei Zhu, Cristian Tornador, Shelby L. Bidwell, Vinita Joardar, Jose M. C. Tubio, Robert M. Waterhouse, Justin D. Radolf, Martin Hammond, Sarah Young, Steven D. Buckingham, Frank H. Collins, Yumin Qi, Ladislav Šimo, Maria F. Unger, Jason M. Meyer, Karyn Megy, Neal S. Silverman, Filipe G. Vieira, Martin Shumway, Jennifer R. Wortman, Claire M. Fraser, Yunlong Yang, Vishvanath Nene, Waterhouse, Robert, Zdobnov, Evgeny, University of Nevada, Partenaires INRAE, Department of Entomology, Michigan State University [East Lansing], Michigan State University System-Michigan State University System, Department Biotechnology, University of São Paulo (USP), Department of Biological Sciences, The Open University [Milton Keynes] (OU), North Carolina State University, Center for High Performance Simulation and Department of Chemical and Biomolecular Engineering, Department of Genetic Medicine and Development, Université de Genève (UNIGE), Broad Institute of Harvard and MIT, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Massachusetts Institute of Technology (MIT), University College of London [London] (UCL), SaBio, Instituto de Investigación en Recursos Cinegéticos (IREC), Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University [Stillwater], National Institute of Allergy and Infectious Deseases (NIAID), University of Cambridge [UK] (CAM), VectorBase, Purdue University, J. Craig Venter Institute [La Jolla, USA] (JCVI), University of Notre Dame [Indiana] (UND), Universitat Autònoma de Barcelona (UAB), Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), University of Connecticut (UCONN), Virginia Polytechnic Institute and State University [Blacksburg], Department of Biology, Indiana University [Bloomington], Indiana University System-Indiana University System, Department of Biochemistry [Blacksburg], Virginia Tech [Blacksburg], Agricultural Research Center, Texas A&M University System, Minnesota State University, University of Manchester [Manchester], Department of Bioengineering and Therapeutic Sciences, University of California [San Francisco] (UCSF), University of California-University of California, Pennsylvania State University (Penn State), Penn State System-Penn State System, University of California [Riverside] (UCR), University of California, Universidade de Santiago de Compostela [Spain] (USC ), Department of Experimental and Health Sciences, Universitat Pompeu Fabra [Barcelona] (UPF), University of Barcelona, California State Polytechnic University [Pomona] (CAL POLY POMONA), University of Queensland [Brisbane], University of the Sunshine Coast (USC), University of Copenhagen = Københavns Universitet (KU), University of Tennessee, Universidade de Vigo, Cancer Genome Project, The Wellcome Trust Sanger Institute [Cambridge], University of Illinois, University of Illinois System, Quinnipiac University, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services (NIAID, NIH, DHHS) [N01-AI30071, HHSN272200900007C, HHSN266200400001C, 5R01GM77117-5], NIH-NIAID [HHSN266200400039C, HHSN272200900039C], Australian Research Council [DP120100240], Ministerio de Ciencia e Innovacion of Spain [BFU2007-6292, BFU2010-15484, BIO2009-07990, BIO2012-37926], NIH [1R01AI090062, 1R21AI096268, HHSN272200900040C, R01AI017828, R01AI043006], NSF [IOS-0949194], Xunta de Galicia of Spain [10PXIB918057PR], EU FP7 ANTIGONE [278976], USDA-NRI/CREES [2008-35302-18820], Texas AgriLife Research Vector Biology grant, European Research Council Starting Independent, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Biochemistry, Fralin Life Sciences Institute, NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos), National Institutes of Health (Estados Unidos), Australian Research Council, Ministerio de Ciencia e Innovación (España), United States of Department of Health & Human Services, National Science Foundation (Estados Unidos), Xunta de Galicia (España), Unión Europea. Comisión Europea, United States Department of Agriculture. National Institute of Food and Agriculture, Texas AgriLife Research, European Research Council, Swiss National Science Foundation, Fundação para a Ciência e a Tecnologia (Portugal), Lundbeck Foundation, Broad Genomics Platform, National Institute of Allergy and Infectious Diseases (US), National Institutes of Health (US), Department of Health and Human Services (US), National Science Foundation (US), Xunta de Galicia, European Commission, Department of Agriculture (US), Boehringer Ingelheim Fonds, Gulia-Nuss, Monika, and Fundação para a Ciência e Tecnologia (Portugal)
Subjects: 0301 basic medicine, beetle tribolium-castaneum, Langat virus, [SDV]Life Sciences [q-bio], General Physics and Astronomy, PROTEIN, CATTLE TICK, Xenopus laevis, Lyme disease, anaplasma-phagocytophilum infection, Lyme Disease/transmission, ddc:576.5, BEETLE TRIBOLIUM-CASTANEUM, Genetics, Lyme Disease, Genome, Multidisciplinary, biology, Ecology, cattle tick, evolutionary analyses, CHEMOSENSORY RECEPTORS, Babesiosis, Genomics, drosophila, 3. Good health, Ixodes/genetics, DROSOPHILA, Ixodes scapularis, LIFE-STYLE, chemosensory receptors, Anaplasma phagocytophilum, life-style, Human granulocytic anaplasmosis, boophilus-microplus, united-states, protein, Science, Ligand-Gated Ion Channels/genetics, UNITED-STATES, Tick, ANAPLASMA-PHAGOCYTOPHILUM INFECTION, Article, General Biochemistry, Genetics and Molecular Biology, Arachnid Vectors/genetics, 03 medical and health sciences, BOOPHILUS-MICROPLUS, parasitic diseases, medicine, Animals, Ixodes, Gene Expression Profiling, General Chemistry, Ligand-Gated Ion Channels, Genome/genetics, Oocytes, biology.organism_classification, medicine.disease, bacterial infections and mycoses, EVOLUTIONARY ANALYSES, 030104 developmental biology, Arachnid Vectors
Abstract: Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing ∼57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick–host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host ‘questing’, prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent., This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services (NIAID, NIH, DHHS) under contract numbers N01-AI30071, HHSN272200900007C, HHSN266200400001C and 5R01GM77117-5. Its contents are solely the responsibility of the authors and do not represent the official views of the NIH. Additional grants and contracts supporting work described in this manuscript were from the NIH-NIAID (HHSN266200400039C and HHSN272200900039C) to F.H.C., and a subcontract under HHSN272200900039C to C.A.H. and J.M.M., the Australian Research Council Discovery Project (DP120100240) to S.C.B. and R.S., the Ministerio de Ciencia e Innovación of Spain (BFU2007–6292; BFU2010–15484) to J.R., BIO2009–07990 and BIO2012–37926 to J.V. NIH-1R01AI090062 to Y.P., L.S., and J.K., NIH 1R21AI096268 and NSF IOS-0949194 to R.M.R., the Xunta de Galicia of Spain (10PXIB918057PR) to J.M.C.T. and M.T., BFU2011–23896 and EU FP7 ANTIGONE (278976) to J.F., the USDA-NRI/CREES (2008-35302-18820) and Texas AgriLife Research Vector Biology grant to P.V.P. and European Research Council Starting Independent Researcher Grant (205202) to R.B., J.M.R was supported by the intramural program of the NIAID, R.M.W. by a Marie Curie International Outgoing Fellowship PIOF-GA-2011–303312, E.M.Z. by Swiss National Science Foundation awards 31003A-125350 and 31003A-143936, J.M.G. by an NIH-NCATS award TL1 TR000162 and NSF Graduate Research Fellowship (DGE 1333468), V.C. by a Boehringer Ingelheim Ph.D. Fellowship, F.G.V. by a Fundação para a Ciência e a Tecnologia, Portugal fellowship (SFRH/BD/22360/2005), C.J.P.G. and F.H. by The Lundbeck Foundation (Denmark), and J.J.G. by NIH awards HHSN272200900040C, R01AI017828 and R01AI043006. Support from the Broad Genomics Platform is gratefully acknowledged.
Published: 2016

43. Ensembl Genomes: Extending Ensembl across the taxonomic space

Author: Eugene Kulesha, Uma Maheswari, Paul J. Kersey, Daniel M. Staines, Daniel Lawson, Karyn Megy, Franck Valentin, Andrew D. Yates, Gautier Koscielny, Rhoda Kinsella, Paul S. Derwent, Albert J. Vilella, Arnaud Kerhornou, Matthias Haimel, Andreas Kähäri, Stephen Keenan, Michael Nuhn, Ewan Birney, Glenn Proctor, and Javier Herrero
Subjects: 0106 biological sciences, Gene Expression, Information Storage and Retrieval, Genome browser, Computational biology, Biology, Vertebrate and Genome Annotation Project, 01 natural sciences, Genome, 03 medical and health sciences, Annotation, Ensembl Genomes, Databases, Genetic, Genetics, Animals, Ensembl, 030304 developmental biology, computer.programming_language, Internet, 0303 health sciences, Polymorphism, Genetic, Computational Biology, Articles, Genome project, Invertebrates, Protein Structure, Tertiary, ComputingMethodologies_PATTERNRECOGNITION, Genome, Fungal, Perl, Databases, Nucleic Acid, computer, Genome, Bacterial, Genome, Plant, Software, 010606 plant biology & botany
Abstract: Ensembl Genomes (http://www.ensemblgenomes.org) is a new portal offering integrated access to genome-scale data from non-vertebrate species of scientific interest, developed using the Ensembl genome annotation and visualisation platform. Ensembl Genomes consists of five sub-portals (for bacteria, protists, fungi, plants and invertebrate metazoa) designed to complement the availability of vertebrate genomes in Ensembl. Many of the databases supporting the portal have been built in close collaboration with the scientific community, which we consider as essential for maintaining the accuracy and usefulness of the resource. A common set of user interfaces (which include a graphical genome browser, FTP, BLAST search, a query optimised data warehouse, programmatic access, and a Perl API) is provided for all domains. Data types incorporated include annotation of (protein and non-protein coding) genes, cross references to external resources, and high throughput experimental data (e.g. data from large scale studies of gene expression and polymorphism visualised in their genomic context). Additionally, extensive comparative analysis has been performed, both within defined clades and across the wider taxonomy, and sequence alignments and gene trees resulting from this can be accessed through the site.
Published: 2009

44. Genomic resources for invertebrate vectors of human pathogens, and the role of VectorBase

Author: Karyn Megy, Robert V. Bruggner, Daniel Lawson, Ewan Birney, Frank H. Collins, and Martin Hammond
Subjects: Microbiology (medical), Anopheles gambiae, Genome, Insect, Genomics, Computational biology, Aedes aegypti, Pediculus humanus, Microbiology, Article, Evolution, Molecular, parasitic diseases, Culex pipiens, Blood-Borne Pathogens, Genetics, Animals, Humans, Molecular Biology, Phylogeny, Ecology, Evolution, Behavior and Systematics, Expressed Sequence Tags, biology, Arthropod Vectors, Sequence Analysis, DNA, biology.organism_classification, Virology, Infectious Diseases, Ixodes scapularis, Vector (epidemiology), Databases, Nucleic Acid, Arthropod Vector
Abstract: High-throughput genome sequencing techniques have now reached vector biology with an emphasis on those species that are vectors of human pathogens. The first mosquito to be sequenced was Anopheles gambiae, the vector for Plasmodium parasites that cause malaria. Further mosquitoes have followed: Aedes aegypti (Yellow fever and Dengue fever vector) and Culex pipiens (lymphatic filariasis and West Nile fever). Species that are currently in sequencing include the body louse Pediculus humanus (Typhus vector), the triatomine Rhodnius prolixus (Chagas disease vector) and the tick Ixodes scapularis (Lyme disease vector). The motivations for sequencing vector genomes are to further understand vector biology, with an eye on developing new control strategies (for example novel chemical attractants or repellents) or understanding the limitations of current strategies (for example the mechanism of insecticide resistance); to analyse the mechanisms driving their evolution; and to perform an exhaustive analysis of the gene repertory. The proliferation of genomic data creates the need for efficient and accessible storage. We present VectorBase, a genomic resource centre that is both involved in the annotation of vector genomes and act as a portal for access to the genomic information (http://www.vectorbase.org).
Published: 2009

45. VectorBase: a data resource for invertebrate vector genomics

Author: William M. Gelbart, Fotis C. Kafatos, Robert V. Bruggner, Peter W. Atkinson, Ryan Butler, Nora J. Besansky, Karyn Megy, Scott Christley, Frank H. Collins, Peter Arensburger, Jason M. Meyer, Daniel Lawson, George K. Christophides, Robert M. MacCallum, Nathan Konopinski, Pantelis Topalis, Martin Hammond, Catherine A. Hill, Gregory R. Madey, Emmanuel Dialynas, Kathryn S. Campbell, Eric O. Stinson, David W. Severson, Christos Louis, Neil F. Lobo, Seth Redmond, and Ewan Birney
Subjects: Anopheles gambiae, 030231 tropical medicine, Genome, Insect, Genomics, Computational biology, Pediculus humanus, 03 medical and health sciences, 0302 clinical medicine, Aedes, parasitic diseases, Anopheles, Databases, Genetic, Genetics, Animals, 030304 developmental biology, 0303 health sciences, biology, Ixodes, Ecology, Gene Expression Profiling, Arthropod Vectors, Pediculus, Articles, biology.organism_classification, 3. Good health, Culex, Culicidae, Vocabulary, Controlled, Ixodes scapularis, Vector (epidemiology), Arthropod Vector
Abstract: VectorBase (http://www.vectorbase.org) is an NIAID-funded Bioinformatic Resource Center focused on invertebrate vectors of human pathogens. VectorBase annotates and curates vector genomes providing a web accessible integrated resource for the research community. Currently, VectorBase contains genome information for three mosquito species: Aedes aegypti, Anopheles gambiae and Culex quinquefasciatus, a body louse Pediculus humanus and a tick species Ixodes scapularis. Since our last report VectorBase has initiated a community annotation system, a microarray and gene expression repository and controlled vocabularies for anatomy and insecticide resistance. We have continued to develop both the software infrastructure and tools for interrogating the stored data.
Published: 2008

46. αIIbβ3 variants defined by next-generation sequencing: predicting variants likely to cause Glanzmann thrombasthenia

Author: Kathleen Freson, Cedric Ghevaert, Willem Ouwehand, Karyn Megy, Marguerite Neerman-Arbez, Sarah Westbury, Augusto Rendon, Marta Filizola, Johan Heemskerk, Biochemie, RS: CARIM - R1 - Thrombosis and haemostasis, and Neerman Arbez, Marguerite
Subjects: Exome/genetics, Models, Molecular, Thrombasthenia/genetics/metabolism, Protein Conformation, Gene Frequency, Models, hemic and lymphatic diseases, Fibrinogen/chemistry/metabolism, Missense mutation, ddc:576.5, Exome, single-nucleotide variants, Genetics, High-Throughput Nucleotide Sequencing/methods, Multidisciplinary, High-Throughput Nucleotide Sequencing, PNAS Plus, Databases, Nucleic Acid, Protein Binding, Thrombasthenia, Protein Structure, integrin, Platelet Glycoprotein GPIIb-IIIa Complex/chemistry/genetics/metabolism, Immunoblotting, Mutation, Missense, Platelet Glycoprotein GPIIb-IIIa Complex, Biology, DNA sequencing, Databases, Glanzmann, molecular modeling, next-generation sequencing, Alleles, Fibrinogen, HEK293 Cells, Humans, Protein Structure, Tertiary, Allele, Allele frequency, Gene, Nucleic Acid, Molecular, Fibrinogen binding, Minor allele frequency, Mutation, Missense, Tertiary
Abstract: Next-generation sequencing is transforming our understanding of human genetic variation but assessing the functional impact of novel variants presents challenges. We analyzed missense variants in the integrin αIIbβ3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the ThromboGenomics project, comprising ∼32,000 alleles from 16,108 individuals. We analyzed the results in comparison with 111 missense variants in these genes previously reported as being associated with Glanzmann thrombasthenia (GT), 20 associated with alloimmune thrombocytopenia, and 5 associated with aniso/macrothrombocytopenia. We identified 114 novel missense variants in ITGA2B (affecting ∼11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting ∼9% of the amino acids). Of the variants, 96% had minor allele frequencies (MAF) < 0.1%, indicating their rarity. Based on sequence conservation, MAF, and location on a complete model of αIIbβ3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. αIIb P176H and β3 C547G severely reduced αIIbβ3 expression, whereas αIIb P943A partially reduced αIIbβ3 expression and had no effect on fibrinogen binding. We used receiver operating characteristic curves of combined annotation-dependent depletion, Polyphen 2-HDIV, and sorting intolerant from tolerant to estimate the percentage of novel variants likely to be deleterious. At optimal cut-off values, which had 69-98% sensitivity in detecting GT mutations, between 27% and 71% of the novel αIIb or β3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on αIIbβ3 and highlight the challenges in predicting the clinical significance of novel missense variants. ispartof: Proceedings of the National Academy of Sciences of the United States of America vol:112 issue:15 pages:E1898-E1907 ispartof: location:United States status: published
Published: 2015

47. Genome of Rhodnius prolixus, an insect vector of Chagas disease, reveals unique adaptations to hematophagy and parasite infection

Author: Carla Polycarpo, Magda D. Lugon, Emmanuelle Jacquin-Joly, Francisco Prosdocimi, Katia C. Gondim, Daniel Lawson, Raquel J. Vionette-Amaral, Karyn Megy, Andrew Pike, Fernando A. Monteiro, David Majerowicz, Marco Mariotti, Gloria I. Giraldo-Calderón, Fernando G. Noriega, Ana Beatriz Walter-Nuno, M. Patricia Juárez, Leonardo Koerich, A. Bernardo Carvalho, Marcos Sterkel, Fernando Abad-Franch, Catrina Fronick, Samara G. da Costa, Eloy S. Seabra-Junior, Márcio G. Pavan, Pedro L. Oliveira, Willy Jablonka, Myriam Harry, Ana C.A. Melo, Rita D. Fernandez-Medina, George Dimopoulos, Igor Rodrigues da Costa, Cristiano Lazoski, Alessandra A. Guarneri, Paula L. Marcet, Lucinda Fulton, Gena G. Lawrence, Patrícia Azambuja, Gabriela O. Paiva-Silva, Adriana Granzotto, Francisco Panzera, Marcelo G. Lorenzo, Didac Santesmasses, Raquel L.L. Oliveira, Ricardo Nascimento Araújo, Hugh M. Robertson, Renata Schama, Matheus Souza-Gomes, Didier Salmon, Iron F. De-Paula, José M. C. Ribeiro, Roderic Guigó, Derek Wilson, Ana Caroline P. Gandara, Rolando Rivera-Pomar, André Q. Torres, Raul Ursic-Bedoya, Andrés Lavore, Scott J. Emrich, Marcio Fontenele, Laurence Rodrigues do Amaral, Felipe A. Dias, Mário A.C. Silva-Neto, Claudia M. A. Carareto, John Spieth, Nicolás Pedrini, Erwin Huebner, Claudio R. Lazzari, Rafael D. Mesquita, Helena Araujo, Ian Orchard, Fernando A. Genta, Daniel S.T. Hughes, Zhijian Jake Tu, Carl Lowenberger, Paula R. Bittencourt-Cunha, Marcos Henrique Ferreira Sorgine, Michael J. Montague, Rodrigo Nunes da Fonseca, Gustavo M. Calderón-Fernández, Alexandre A. Peixoto, Marcela Nouzova, Angela B. Lange, Gilbert Oliveira-Silveira, Eloi S. Garcia, L. Aravind, Ellen M. Dotson, Hatisaburo Masuda, Glória R.C. Braz, Bruno Gomes, Natalia Esponda-Behrens, Raphael R.S. Lopes, Marilvia Dansa, Sheila Ons, Patrícia Fampa, Rodrigo Dutra Nunes, Mikkel B. Christensen, Ana Paula Salerno, Mabel L. Taracena, Marta Tojo, Georgia C. Atella, Jose Manuel Latorre-Estivalis, Marcos H. Pereira, Agustina Pascual, Michele Alves-Bezerra, Robert M. Waterhouse, Theo Mota, Rodrigo Ribeiro-Rodrigues, Thiago M. Venancio, Lucia Pagola, Fanis Missirlis, Carlos R. O. Daumas-Filho, Jose M. C. Tubio, Lívia Silva-Cardoso, Wesley C. Warren, Richard K. Wilson, Patrick Minx, Mateus Berni, Mesquita, Rafael D., Vionette Amaral, Raquel J., Departamento de Bioquimica, UNICAMP, Institut de recherche sur la biologie de l'insecte UMR7261 (IRBI), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), National Institutes of Health Grant [NHGRI-HG003079], National Institutes of Health National Institute of Allergy and Infectious Diseases Grant [HHSN272200900039C], Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Fundacao de Amparo a Pesquisa do Estado de Minas Gerais, Consejo Nacional de Investigaciones Cientificas y Tecnicas de Argentina, Agencia Nacional de Promocion de Ciencia y Tecnologia, Fundacion Bunge y Born, Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior/FAPERJ, [PIOF-GA-2011-303312], and Université de Tours-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0106 biological sciences, Chagas disease, Biología, [SDV]Life Sciences [q-bio], ved/biology.organism_classification_rank.species, maladie de chagas, 01 natural sciences, Genome, purl.org/becyt/ford/1 [https], rhodnius prolixus, Putative gene, ddc:576.5, Genetics, 0303 health sciences, Multidisciplinary, Host-Parasite Interactions/genetics, RHODNIUS PROLIXUS, Ecology, Trypanosoma cruzi/physiology, Adaptation, Physiological/genetics, Biological Sciences, 3. Good health, GENOME, Wolbachia, Wolbachia/genetics, Gene Transfer, Horizontal, hematophagy, Hematophagy, Rhodnius, Molecular Sequence Data, Rhodnius prolixus, genome, immunity, Biology, IMMUNITY, 010603 evolutionary biology, 03 medical and health sciences, Animals, Humans, Model organism, purl.org/becyt/ford/1.6 [https], Gene, Rhodnius/genetics/parasitology, 030304 developmental biology, Base Sequence, ved/biology, CHAGAS DISEASE, biology.organism_classification, Insect Vectors/genetics/parasitology, HEMATOPHAGY
Abstract: Rhodnius prolixus not only has served as a model organism for the study of insect physiology, but also is a major vector of Chagas disease, an illness that affects approximately seven million people worldwide. We sequenced the genome of R. prolixus, generated assembled sequences covering 95% of the genome (∼702 Mb), including 15,456 putative protein-coding genes, and completed comprehensive genomic analyses of this obligate blood-feeding insect. Although immunedeficiency (IMD)-mediated immune responses were observed, R. prolixus putatively lacks key components of the IMD pathway, suggesting a reorganization of the canonical immune signaling network. Although both Toll and IMD effectors controlled intestinal microbiota, neither affected Trypanosoma cruzi, the causal agent of Chagas disease, implying the existence of evasion or tolerance mechanisms. R. prolixus has experienced an extensive loss of selenoprotein genes, with its repertoire reduced to only two proteins, one of which is a selenocysteine-based glutathione peroxidase, the first found in insects. The genome contained actively transcribed, horizontally transferred genes from Wolbachia sp., which showed evidence of codon use evolution toward the insect use pattern. Comparative protein analyses revealed many lineage-specific expansions and putative gene absences in R. prolixus, including tandem expansions of genes related to chemoreception, feeding, and digestion that possibly contributed to the evolution of a blood-feeding lifestyle. The genome assembly and these associated analyses provide critical information on the physiology and evolution of this important vector species and should be instrumental for the development of innovative disease control methods., La lista completa de autores que integran el documento puede consultarse en el archivo, Este documento tiene una corrección (ver documento relacionado)., Centro Regional de Estudios Genómicos, Instituto de Investigaciones Bioquímicas de La Plata
Published: 2015

48. Prospecting for pig single nucleotide polymorphisms in the human genome: have we struck gold?

Author: L. Grapes, S. Rudd, Rohan L. Fernando, Karyn Megy, Max F. Rothschild, and Dominique Rocha
Subjects: Expressed Sequence Tags, Genetics, Expressed sequence tag, dbSNP, Genome, Human, In silico, Statistics as Topic, Sus scrofa, Computational Biology, Single-nucleotide polymorphism, General Medicine, Putative snps, Biology, Polymorphism, Single Nucleotide, Mice, Open Reading Frames, Food Animals, Homologous chromosome, Animals, Cluster Analysis, Humans, Animal Science and Zoology, Human genome, Databases, Nucleic Acid, Gene
Abstract: Summary Gene-to-gene variation in the frequency of single nucleotide polymorphisms (SNPs) has been observed in humans, mice, rats, primates and pigs, but a relationship across species in this variation has not been described. Here, the frequency of porcine coding SNPs (cSNPs) identified by in silico methods, and the frequency of murine cSNPs, were compared with the frequency of human cSNPs across homologous genes. From 150 000 porcine expressed sequence tag (EST) sequences, a total of 452 SNP-containing sequence clusters were found, totalling 1394 putative SNPs. All the clustered porcine EST annotations and SNP data have been made publicly available at http://sputnik.btk.fi/project?name¼swine. Human and murine cSNPs were identified from dbSNP and were characterized as either validated or total number of cSNPs (validated plus nonvalidated) for comparison purposes. The correlation between in silico pig cSNP and validated human cSNP densities was found to be 0.77 (p < 0.00001) for a set of 25 homologous genes, while a correlation of 0.48 (p < 0.0005) was found for a primarily random sample of 50 homologous human and mouse genes. This is the first evidence of conserved gene-to-gene variability in cSNP frequency across species and indicates that site-directed screening of porcine genes that are homologous to cSNP-rich human genes may rapidly advance cSNP discovery in pigs. J. Anim. Breed. Genet. ISSN 0931-2668
Published: 2006

49. Analysis of public single nucleotide polymorphisms in commercial pig populations

Author: Dominique Rocha, Karyn Megy, and S. Kollers
Subjects: Genetics, Genetic diversity, Single-nucleotide polymorphism, General Medicine, Biology, law.invention, Nucleotide diversity, SNP genotyping, genomic DNA, law, Polymorphism (computer science), Animal Science and Zoology, Restriction fragment length polymorphism, Polymerase chain reaction
Abstract: Summary More than 5500 pig single nucleotide polymorphisms (SNPs) were recently identified and deposited in the public domain. To test the usefulness of these public SNPs, 109 SNPs were analysed for polymorphism within six commercial pig populations. A functional polymerase chain reaction (PCR) assay was obtained for 103 SNPs and it was possible to validate c. 59% by PCR-restriction fragment length polymorphism. Furthermore, polymorphism was found using a relatively limited number of genomic DNA samples, indicating that these polymorphisms are segregating at a useful frequency in these populations. The high percentage of validated markers demonstrates the utility of these public pig SNPs to identify loci responsible for economically important traits in commercial pig populations.
Published: 2005

50. Genome sequence of the tsetse fly (Glossina morsitans): vector of African trypanosomiasis

Author: George F. Obiero, Victor Chukwudi Osamor, Atsushi Toyoda, Apollo Simon Peter Balyeidhusa, Cheolho Sim, Paul O. Mireji, Jelle Caers, Serap Aksoy, Irene Omedo, Jan Van Den Abbeele, Lucien Manga, Wanqi Hu, Daniel Lawson, Tadashi Imanishi, Sing-Hoi Sze, Jeffery W. Jones, Sumir Panji, Erich Loza Telleria, Mandy Sanders, Joy J. Winzerling, Dawn L. Geiser, Atway R. Msangi, Joshua B. Benoit, Sandy J. Macdonald, Junichi Watanabe, James Cotton, Francesca Scolari, Steven G. Nyanjom, Linda M. Field, George Githinji, Vineet K. Sharma, José M. C. Ribeiro, Furaha Mramba, Stella Lehane, Shuhua Fu, Marco Falchetto, Imna I. Malele, Michael A. Riehle, Tulika P. Srivastava, Hugh M. Robertson, Immo A. Hansen, Mmule Makgamathe, Caleb K. Kibet, Philippe Solano, Alan Christoffels, Yoshihiro Kawahara, Megan E. Meuti, Nicola Mulder, Patrick Wincker, Gerd Gäde, Zahra Jalali Sefid Dashti, Heather G. Marco, Sheila C. Ommeh, Veronika Michalkova, Cher-Pheng Ooi, Geoffrey M. Attardo, Oliver Manangwa, David L. Denlinger, Alistair C. Darby, Todd D. Taylor, Daniel S.T. Hughes, Mark Wamalwa, Michael W. Gaunt, Daphne Q.-D. Pham, Rosaline W. Macharia, Chinyere K. Okoro, Lee R. Haines, Masahira Hattori, Markus Friedrich, Jingwen Wang, Aaron A. Baumann, Jing-Jiang Zhou, Martin Aslett, Judith H. Willis, Deirdre Walshe, Justin T. Peyton, Alvaro Acosta-Serrano, Loyce M. Okedi, Ludvik M. Gomulski, Johnson Kinyua, Daniel K. Masiga, Mathurin Koffi, J.J.O. Koekemoer, Corey L. Brelsfoard, Gordon William Harkins, Geoffrey H. Siwo, Guy Caljon, Michael A. Quail, Grace Murilla, Anna K. Snyder, Adele Kruger, Gavin H. Thomas, Anna R. Malacrida, Patrick P. Abila, Liliane Schoofs, Rosemary Bateta, Martin T. Swain, Michael J. Lehane, Richard Gregory, Kostas Bourtzis, Brian L. Weiss, Eleanor J Stanley, Zhijian Tu, Matthew Berriman, Winston Hide, David P. Price, Yutaka Suzuki, Maxwell J. Scott, Aaron M. Tarone, Joanna E. Auma, Johnson O. Ouma, Christiane Hertz-Fowler, Alia Benkahla, Karyn Megy, Sophie Ravel, Noboru Inoue, Feziwe Mpondo, Sarah Mwangi, Yeya T. Touré, Florence N. Wamwiri, Clair Rose, Neil D. Rawlings, George Tsiamis, Thiago Luiz, Peter Arensburger, Mario Jonas, Wesley C. Warren, Rita V. M. Rio, Richard K. Wilson, Heikki Lehväslaiho, Denis M. Larkin, Urvashi N. Ramphul, Qirui Zhang, Dawn Stephens, Neil Hall, Kevin K. Marucha, Ryuichi Sakate, Institut de Recherche pour le Développement (IRD [France-Sud]), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Parasitologie Médicale, Biotechnologies et Biomolécules (LR11IPT06), Institut Pasteur de Tunis, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
Subjects: MESH: Sequence Analysis, DNA, MESH: Insect Vectors/physiology, Genome, Insect, MESH: Insect Vectors/genetics, Genes, Insect, MESH: Genes, Insect, Genome, MESH: Insect Vectors/microbiology, Salivary Glands, MESH: Genome, Insect, 0302 clinical medicine, African trypanosomiasis, MESH: Animals, Genetics, MESH: Salivary Glands/physiology, 0303 health sciences, Multidisciplinary, MESH: Symbiosis, biology, Microbiota, Reproduction, MESH: Tsetse Flies/genetics, MESH: Tsetse Flies/parasitology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Blood, MESH: Feeding Behavior, MESH: Insect Proteins/physiology, Insect Proteins, Wolbachia, MESH: Trypanosoma/physiology, Female, Trypanosoma, Tsetse Flies, MESH: Tsetse Flies/microbiology, MESH: Trypanosomiasis, African/transmission, 030231 tropical medicine, Molecular Sequence Data, Sensation, MESH: Wolbachia/physiology, MESH: Molecular Sequence Annotation, Article, MESH: Sensation/genetics, 03 medical and health sciences, medicine, MESH: Blood, MESH: Microbiota, Animals, MESH: Reproduction/genetics, Symbiosis, Gene, 030304 developmental biology, Whole genome sequencing, MESH: Insect Vectors/parasitology, MESH: Molecular Sequence Data, MESH: Insect Proteins/genetics, MESH: Salivary Glands/parasitology, Tsetse fly, Molecular Sequence Annotation, Feeding Behavior, Sequence Analysis, DNA, biology.organism_classification, medicine.disease, Insect Vectors, Trypanosomiasis, African, Vector (epidemiology), MESH: Tsetse Flies/physiology, MESH: Wolbachia/genetics, Trypanosomiasis, MESH: Female
Abstract: Africa's Bane Tsetse are blood-feeding, fast-flying flies that transmit a range of Trypanosoma spp. protozoan pathogens, which cause sleeping sickness in humans and their nagana in their livestock. The International Glossina Genome Initiative (p. 380 ) sequenced the genome of Glossina morsitans and identified the genes for many attributes of the tsetse's remarkable biology, including viviparity and the expression of analogs of mammalian milk proteins. Tsetse are host to several specific symbionts that appear to synthesize essential nutrients for the fly and also to hitherto undiscovered parasitoid-derived viruses. Deeper exploration of this genome will reveal what makes these fly species so host- and trypanosome specific.
Published: 2014

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