Author: "Ernest Turro" / Publication Year Range: Last 10 years - Searchworks@Jio Institute Digital Library Search Results

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78 results on '"Ernest Turro"'

1. Variants in LRRC7 lead to intellectual disability, autism, aggression and abnormal eating behaviors

Author: Jana Willim, Daniel Woike, Daniel Greene, Sarada Das, Kevin Pfeifer, Weimin Yuan, Anika Lindsey, Omar Itani, Amber L. Böhme, Debora Tibbe, Hans-Hinrich Hönck, Fatemeh Hassani Nia, Undiagnosed Diseases Network, Michael Zech, Theresa Brunet, Laurence Faivre, Arthur Sorlin, Antonio Vitobello, Thomas Smol, Cindy Colson, Kristin Baranano, Krista Schatz, Allan Bayat, Kelly Schoch, Rebecca Spillmann, Erica E. Davis, Erin Conboy, Francesco Vetrini, Konrad Platzer, Sonja Neuser, Janina Gburek-Augustat, Alexandra Noel Grace, Bailey Mitchell, Alexander Stegmann, Margje Sinnema, Naomi Meeks, Carol Saunders, Maxime Cadieux-Dion, Juliane Hoyer, Julien Van-Gils, Jean-Madeleine de Sainte-Agathe, Michelle L. Thompson, E. Martina Bebin, Monika Weisz-Hubshman, Anne-Claude Tabet, Alain Verloes, Jonathan Levy, Xenia Latypova, Sönke Harder, Gary A. Silverman, Stephen C. Pak, Tim Schedl, Kathleen Freson, Andrew Mumford, Ernest Turro, Christian Schlein, Vandana Shashi, and Hans-Jürgen Kreienkamp
Subjects: Science
Abstract: Abstract Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca2+/calmodulin-dependent protein kinase II. We have previously observed an association between high impact variants in LRRC7 and Intellectual Disability; also three individual cases with variants in LRRC7 had been described. We identify here 33 individuals (one of them previously described) with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in LRRC7. The clinical spectrum involves intellectual disability, autism, ADHD, aggression and, in several cases, hyperphagia-associated obesity. A PDZ domain variant interferes with synaptic targeting of Densin-180 in primary cultured neurons. Using in vitro systems (two hybrid, BioID, coimmunoprecipitation of tagged proteins from 293T cells) we identified new candidate interaction partners for the LRR domain, including protein phosphatase 1 (PP1), and observed that variants in the LRR reduced binding to these proteins. We conclude that LRRC7 encodes a major determinant of intellectual development and behaviour.
Published: 2024
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2. NRG1 fusions in breast cancer

Author: Karen D. Howarth, Tashfina Mirza, Susanna L. Cooke, Suet-Feung Chin, Jessica C. Pole, Ernest Turro, Matthew D. Eldridge, Raquel Manzano Garcia, Oscar M. Rueda, Chris Boursnell, Jean E. Abraham, Carlos Caldas, and Paul A. W. Edwards
Subjects: NRG1 fusions, Breast cancer, NRG1, Clinically actionable, MDA-MB-175, Whole-genome sequencing, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background NRG1 gene fusions may be clinically actionable, since cancers carrying the fusion transcripts can be sensitive to tyrosine kinase inhibitors. The NRG1 gene encodes ligands for the HER2(ERBB2)-ERBB3 heterodimeric receptor tyrosine kinase, and the gene fusions are thought to lead to autocrine stimulation of the receptor. The NRG1 fusion expressed in the breast cancer cell line MDA-MB-175 serves as a model example of such fusions, showing the proposed autocrine loop and exceptional drug sensitivity. However, its structure has not been properly characterised, its oncogenic activity has not been fully explained, and there is limited data on such fusions in breast cancer. Methods We analysed genomic rearrangements and transcripts of NRG1 in MDA-MB-175 and a panel of 571 breast cancers. Results We found that the MDA-MB-175 fusion—originally reported as a DOC4(TENM4)-NRG1 fusion, lacking the cytoplasmic tail of NRG1—is in reality a double fusion, PPP6R3-TENM4-NRG1, producing multiple transcripts, some of which include the cytoplasmic tail. We hypothesise that many NRG1 fusions may be oncogenic not for lacking the cytoplasmic domain but because they do not encode NRG1’s nuclear-localised form. The fusion in MDA-MB-175 is the result of a very complex genomic rearrangement, which we partially characterised, that creates additional expressed gene fusions, RSF1-TENM4, TPCN2-RSF1, and MRPL48-GAB2. We searched for NRG1 rearrangements in 571 breast cancers subjected to genome sequencing and transcriptome sequencing and found four cases (0.7%) with fusions, WRN-NRG1, FAM91A1-NRG1, ARHGEF39-NRG1, and ZNF704-NRG1, all splicing into NRG1 at the same exon as in MDA-MB-175. However, the WRN-NRG1 and ARHGEF39-NRG1 fusions were out of frame. We identified rearrangements of NRG1 in many more (8% of) cases that seemed more likely to inactivate than to create activating fusions, or whose outcome could not be predicted because they were complex, or both. This is not surprising because NRG1 can be pro-apoptotic and is inactivated in some breast cancers. Conclusions Our results highlight the complexity of rearrangements of NRG1 in breast cancers and confirm that some do not activate but inactivate. Careful interpretation of NRG1 rearrangements will therefore be necessary for appropriate patient management.
Published: 2021
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3. Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans

Author: Wei Wei, Alistair T. Pagnamenta, Nicholas Gleadall, Alba Sanchis-Juan, Jonathan Stephens, John Broxholme, Salih Tuna, Christopher A. Odhams, Genomics England Research Consortium, NIHR BioResource, Carl Fratter, Ernest Turro, Mark J. Caulfield, Jenny C. Taylor, Shamima Rahman, and Patrick F. Chinnery
Subjects: Science
Abstract: Recent evidence has questioned the dogma of strict maternal transmission of mitochondrial DNA (mtDNA) in humans. Wei et al. saw no evidence of paternal transmission of mtDNA in 11,035 human trios, and show that nuclear-mitochondrial segments (NUMTs) can give the impression of paternal mtDNA transmission, but are actually inherited through the nuclear genome.
Published: 2020
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4. mRNA structural elements immediately upstream of the start codon dictate dependence upon eIF4A helicase activity

Author: Joseph A. Waldron, David C. Tack, Laura E. Ritchey, Sarah L. Gillen, Ania Wilczynska, Ernest Turro, Philip C. Bevilacqua, Sarah M. Assmann, Martin Bushell, and John Le Quesne
Subjects: eIF4A, RNA structure, Hippuristanol, Translation, Translation initiation, Cancer, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract: Abstract Background The RNA helicase eIF4A1 is a key component of the translation initiation machinery and is required for the translation of many pro-oncogenic mRNAs. There is increasing interest in targeting eIF4A1 therapeutically in cancer, thus understanding how this protein leads to the selective re-programming of the translational landscape is critical. While it is known that eIF4A1-dependent mRNAs frequently have long GC-rich 5′UTRs, the details of how 5′UTR structure is resculptured by eIF4A1 to enhance the translation of specific mRNAs are unknown. Results Using Structure-seq2 and polysome profiling, we assess global mRNA structure and translational efficiency in MCF7 cells, with and without eIF4A inhibition with hippuristanol. We find that eIF4A inhibition does not lead to global increases in 5′UTR structure, but rather it leads to 5′UTR remodeling, with localized gains and losses of structure. The degree of these localized structural changes is associated with 5′UTR length, meaning that eIF4A-dependent mRNAs have greater localized gains of structure due to their increased 5′UTR length. However, it is not solely increased localized structure that causes eIF4A-dependency but the position of the structured regions, as these structured elements are located predominantly at the 3′ end of the 5′UTR. Conclusions By measuring changes in RNA structure following eIF4A inhibition, we show that eIF4A remodels local 5′UTR structures. The location of these structural elements ultimately determines the dependency on eIF4A, with increased structure just upstream of the CDS being the major limiting factor in translation, which is overcome by eIF4A activity.
Published: 2019
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5. A novel missense variant in SLC18A2 causes recessive brain monoamine vesicular transport disease and absent serotonin in platelets

Author: Manisha Padmakumar, Jaak Jaeken, Vincent Ramaekers, Lieven Lagae, Daniel Greene, Chantal Thys, Chris Van Geet, NIHR BioResource, Kathleen Stirrups, Kate Downes, Ernest Turro, and Kathleen Freson
Subjects: epilepsy, platelet dense granules, serotonin, vesicular monoamine transporter 2, whole genome sequencing, Diseases of the endocrine glands. Clinical endocrinology, RC648-665, Genetics, QH426-470
Abstract: Abstract Background Brain monoamine vesicular transport disease is an infantile onset neurodevelopmental disorder caused by variants in SLC18A2, which codes for the vesicular monoamine transporter 2 (VMAT2) protein, involved in the transport of monoamines into synaptic vesicles and of serotonin into platelet dense granules. Case presentation The presented case is of a child, born of healthy consanguineous parents, who exhibited hypotonia, mental disability, epilepsy, uncontrolled movements, and gastrointestinal problems. A trial treatment with L‐DOPA proved unsuccessful and the exact neurological involvement could not be discerned due to normal metabolic and brain magnetic resonance imaging results. Platelet studies and whole genome sequencing were performed. At age 4, the child's platelets showed a mild aggregation and adenosine triphosphate secretion defect that could be explained by dysmorphic dense granules observed by electron microscopy. Interestingly, the dense granules were almost completely depleted of serotonin. A novel homozygous p.P316A missense variant in VMAT2 was detected in the patient and the consanguineous parents were found to be heterozygous for this variant. Although the presence of VMAT2 on platelet dense granules has been demonstrated before, this is the first report of defective platelet dense granule function related to absent serotonin storage in a patient with VMAT2 deficiency but without obvious clinical bleeding problems. Conclusions This study illustrates the homology between serotonin metabolism in brain and platelets, suggesting that these blood cells can be model cells for some pathways relevant for neurological diseases. The literature on VMAT2 deficiency is reviewed.
Published: 2019
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6. Transcription Factor Levels after Forward Programming of Human Pluripotent Stem Cells with GATA1, FLI1, and TAL1 Determine Megakaryocyte versus Erythroid Cell Fate Decision

Author: Amanda Dalby, Jose Ballester-Beltrán, Chiara Lincetto, Annett Mueller, Nicola Foad, Amanda Evans, James Baye, Ernest Turro, Thomas Moreau, Marloes R. Tijssen, and Cedric Ghevaert
Subjects: Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract: Summary: The production of blood cells and their precursors from human pluripotent stem cells (hPSCs) in vitro has the potential to make a significant impact upon healthcare provision. We demonstrate that the forward programming of hPSCs through overexpression of GATA1, FLI1, and TAL1 leads to the production of a population of progenitors that can differentiate into megakaryocyte or erythroblasts. Using “rainbow” lentiviral vectors to quantify individual transgene expression in single cells, we demonstrate that the cell fate decision toward an erythroblast or megakaryocyte is dictated by the level of FLI1 expression and is independent of culture conditions. Early FLI1 expression is critical to confer proliferative potential to programmed cells while its subsequent silencing or maintenance dictates an erythroid or megakaryocytic fate, respectively. These committed progenitors subsequently expand and mature into megakaryocytes or erythroblasts in response to thrombopoietin or erythropoietin. Our results reveal molecular mechanisms underlying hPSC forward programming and novel opportunities for application to transfusion medicine. : The authors show that overexpression of GATA1, TAL1, and FLI1 in hPSCs leads to the formation of progenitors that are committed early during differentiation to either the megakaryocytic or erythroid lineage. The cell fate decision is independent of the cytokines used (TPO or EPO) but is dictated by the level of the FLI1 transgene. Keywords: pluripotent stem cells, forward programming, megakaryocyte, erythroblast, lineage fate decision
Published: 2018
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7. Cell type-specific novel long non-coding RNA and circular RNA in the BLUEPRINT hematopoietic transcriptomes atlas

Author: Luigi Grassi, Osagie G. Izuogu, Natasha A.N. Jorge, Denis Seyres, Mariona Bustamante, Frances Burden, Samantha Farrow, Neda Farahi, Fergal J. Martin, Adam Frankish, Jonathan M. Mudge, Myrto Kostadima, Romina Petersen, John J. Lambourne, Sophia Rowlston, Enca Martin-Rendon, Laura Clarke, Kate Downes, Xavier Estivill, Paul Flicek, Joost H.A. Martens, Marie-Laure Yaspo, Hendrik G. Stunnenberg, Willem H. Ouwehand, Fabio Passetti, Ernest Turro, and Mattia Frontini
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Transcriptional profiling of hematopoietic cell subpopulations has helped to characterize the developmental stages of the hematopoietic system and the molecular bases of malignant and non-malignant blood diseases. Previously, only the genes targeted by expression microarrays could be profiled genome-wide. High-throughput RNA sequencing, however, encompasses a broader repertoire of RNA molecules, without restriction to previously annotated genes. We analyzed the BLUEPRINT consortium RNA-sequencing data for mature hematopoietic cell types. The data comprised 90 total RNA-sequencing samples, each composed of one of 27 cell types, and 32 small RNA-sequencing samples, each composed of one of 11 cell types. We estimated gene and isoform expression levels for each cell type using existing annotations from Ensembl. We then used guided transcriptome assembly to discover unannotated transcripts. We identified hundreds of novel non-coding RNA genes and showed that the majority have cell type-dependent expression. We also characterized the expression of circular RNA and found that these are also cell type-specific. These analyses refine the active transcriptional landscape of mature hematopoietic cells, highlight abundant genes and transcriptional isoforms for each blood cell type, and provide a valuable resource for researchers of hematologic development and diseases. Finally, we made the data accessible via a web-based interface: https://blueprint.haem.cam.ac.uk/bloodatlas/.
Published: 2020
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8. Identification of a homozygous recessive variant in PTGS1 resulting in a congenital aspirin-like defect in platelet function

Author: Melissa V. Chan, Melissa A. Hayman, Suthesh Sivapalaratnam, Marilena Crescente, Harriet E. Allan, Matthew L. Edin, Darryl C. Zeldin, Ginger L. Milne, Jonathan Stephens, Daniel Greene, Moghees Hanif, Valerie B. O'Donnell, Liang Dong, Michael G. Malkowski, Claire Lentaigne, Katherine Wedderburn, Matthew Stubbs, Kate Downes, Willem H. Ouwehand, Ernest Turro, NIHR BioResource, Daniel P. Hart, Kathleen Freson, Michael A. Laffan, and Timothy D. Warner
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: We have identified a rare missense variant on chromosome 9, position 125145990 (GRCh37), in exon 8 in PTGS1 (the gene encoding cyclo-oxygenase 1, COX-1, the target of anti-thrombotic aspirin therapy). We report that in the homozygous state within a large consanguineous family this variant is associated with a bleeding phenotype and alterations in platelet reactivity and eicosanoid production. Western blotting and confocal imaging demonstrated that COX-1 was absent in the platelets of three family members homozygous for the PTGS1 variant but present in their leukocytes. Platelet reactivity, as assessed by aggregometry, lumi-aggregometry and flow cytometry, was impaired in homozygous family members, as were platelet adhesion and spreading. The productions of COX-derived eicosanoids by stimulated platelets were greatly reduced but there were no changes in the levels of urinary metabolites of COX-derived eicosanoids. The proband exhibited additional defects in platelet aggregation and spreading which may explain why her bleeding phenotype was slightly more severe than those of other homozygous affected relatives. This is the first demonstration in humans of the specific loss of platelet COX-1 activity and provides insight into its consequences for platelet function and eicosanoid metabolism. Notably despite the absence of thromboxane A2 (TXA2) formation by platelets, urinary TXA2 metabolites were in the normal range indicating these cannot be assumed as markers of in vivo platelet function. Results from this study are important benchmarks for the effects of aspirin upon platelet COX-1, platelet function and eicosanoid production as they define selective platelet COX-1 ablation within humans.
Published: 2020
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9. Platelet function is modified by common sequence variation in megakaryocyte super enhancers

Author: Romina Petersen, John J. Lambourne, Biola M. Javierre, Luigi Grassi, Roman Kreuzhuber, Dace Ruklisa, Isabel M. Rosa, Ana R. Tomé, Heather Elding, Johanna P. van Geffen, Tao Jiang, Samantha Farrow, Jonathan Cairns, Abeer M. Al-Subaie, Sofie Ashford, Antony Attwood, Joana Batista, Heleen Bouman, Frances Burden, Fizzah A. Choudry, Laura Clarke, Paul Flicek, Stephen F. Garner, Matthias Haimel, Carly Kempster, Vasileios Ladopoulos, An-Sofie Lenaerts, Paulina M. Materek, Harriet McKinney, Stuart Meacham, Daniel Mead, Magdolna Nagy, Christopher J. Penkett, Augusto Rendon, Denis Seyres, Benjamin Sun, Salih Tuna, Marie-Elise van der Weide, Steven W. Wingett, Joost H. Martens, Oliver Stegle, Sylvia Richardson, Ludovic Vallier, David J. Roberts, Kathleen Freson, Lorenz Wernisch, Hendrik G. Stunnenberg, John Danesh, Peter Fraser, Nicole Soranzo, Adam S. Butterworth, Johan W. Heemskerk, Ernest Turro, Mikhail Spivakov, Willem H. Ouwehand, William J. Astle, Kate Downes, Myrto Kostadima, and Mattia Frontini
Subjects: Science
Abstract: Numerous genetic variants, including those located in the non-coding regions of the genome, are known to be associated with blood cells traits. Here, Frontini and colleagues investigate their potential regulatory functions using epigenomic data and promoter long-range interactions.
Published: 2017
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10. PIGO deficiency: palmoplantar keratoderma and novel mutations

Author: Marie-Anne Morren, Jaak Jaeken, Gepke Visser, Isabelle Salles, Chris Van Geet, NIHR BioResource, Ilenia Simeoni, Ernest Turro, and Kathleen Freson
Subjects: CDG, Congenital disorder(s) of glycosylation, Glycosylphosphatidylinositol, GPI, Hyperkeratosis, Hyperphosphatasemia, Medicine
Abstract: Abstract Background Several genetic defects have been identified in the glycosylphosphatidylinositol (GPI) anchor synthesis, including mutations in PIGO encoding phosphatidylinositol glycan anchor biosynthesis class O protein. These defects constitute a subgroup of the congenital disorders of glycosylation (CDG). Seven patients from five families have been reported carrying variants in PIGO that cause an autosomal recessive syndrome characterised by dysmorphism, psychomotor disability, epilepsy and hyperphosphatasemia. Methods Whole exome sequencing was performed in a boy with dysmorphism, psychomotor disability, epilepsy, palmoplantar keratoderma, hyperphosphatasemia and platelet dysfunction without a clinical bleeding phenotype. Results Two novel variants in PIGO were detected. The missense variant encoding p. His871Pro was inherited from the boy’s father while the frameshift variant encoding p. Arg604ProfsTer40 was maternally inherited. Conclusion A boy with two novel PIGO variants is reported. The skin phenotype and platelet dysfunction in this patient have not been described in previously reported patients with PIGO deficiency but it is of course uncertain whether these are caused by this disorder. The literature on PIGO deficiency is reviewed.
Published: 2017
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11. Author Correction: Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans

Author: Wei Wei, Alistair T. Pagnamenta, Nicholas Gleadall, Alba Sanchis-Juan, Jonathan Stephens, John Broxholme, Salih Tuna, Christopher A. Odhams, Genomics England Research Consortium, NIHR BioResource, Carl Fratter, Ernest Turro, Mark J. Caulfield, Jenny C. Taylor, Shamima Rahman, and Patrick F. Chinnery
Subjects: Science
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2020
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12. Inherited missense variants that affect GFI1B function do not necessarily cause bleeding diatheses

Author: Rinske van Oorschot, Anna E. Marneth, Saskia M. Bergevoet, Maaike G.J.M. van Bergen, Kathelijne Peerlinck, Claire E. Lentaigne, Carolyn M. Millar, Sarah K. Westbury, Remi Favier, Wendy N. Erber, Ernest Turro, Joop H. Jansen, Willem H. Ouwehand, Harriet L. McKinney, NIHR BioResource Collaborative Group, Kate Downes, Kathleen Freson, and Bert A. van der Reijden
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2019
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13. Sphingolipid dysregulation due to lack of functional KDSR impairs proplatelet formation causing thrombocytopenia

Author: Tadbir K. Bariana, Veerle Labarque, Jessica Heremans, Chantal Thys, Mara De Reys, Daniel Greene, Benjamin Jenkins, Luigi Grassi, Denis Seyres, Frances Burden, Deborah Whitehorn, Olga Shamardina, Sofia Papadia, Keith Gomez, NIHR BioResource, Chris Van Geet, Albert Koulman, Willem H. Ouwehand, Cedric Ghevaert, Mattia Frontini, Ernest Turro, and Kathleen Freson
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Sphingolipids are fundamental to membrane trafficking, apoptosis, and cell differentiation and proliferation. KDSR or 3-keto-dihydrosphingosine reductase is an essential enzyme for de novo sphingolipid synthesis, and pathogenic mutations in KDSR result in the severe skin disorder erythrokeratodermia variabilis et progressiva-4. Four of the eight reported cases also had thrombocytopenia but the underlying mechanism has remained unexplored. Here we expand upon the phenotypic spectrum of KDSR deficiency with studies in two siblings with novel compound heterozygous variants associated with thrombocytopenia, anemia, and minimal skin involvement. We report a novel phenotype of progressive juvenile myelofibrosis in the propositus, with spontaneous recovery of anemia and thrombocytopenia in the first decade of life. Examination of bone marrow biopsies showed megakaryocyte hyperproliferation and dysplasia. Megakaryocytes obtained by culture of CD34+ stem cells confirmed hyperproliferation and showed reduced proplatelet formation. The effect of KDSR insufficiency on the sphingolipid profile was unknown, and was explored in vivo and in vitro by a broad metabolomics screen that indicated activation of an in vivo compensatory pathway that leads to normalization of downstream metabolites such as ceramide. Differentiation of propositus-derived induced pluripotent stem cells to megakaryocytes followed by expression of functional KDSR showed correction of the aberrant cellular and biochemical phenotypes, corroborating the critical role of KDSR in proplatelet formation. Finally, Kdsr depletion in zebrafish recapitulated the thrombocytopenia and showed biochemical changes similar to those observed in the affected siblings. These studies support an important role for sphingolipids as regulators of cytoskeletal organization during megakaryopoiesis and proplatelet formation.
Published: 2019
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14. Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg2+ homeostasis and cytoskeletal architecture

Author: Simon Stritt, Paquita Nurden, Remi Favier, Marie Favier, Silvia Ferioli, Sanjeev K. Gotru, Judith M M. van Eeuwijk, Harald Schulze, Alan T. Nurden, Michele P. Lambert, Ernest Turro, Stephanie Burger-Stritt, Masayuki Matsushita, Lorenz Mittermeier, Paola Ballerini, Susanna Zierler, Michael A. Laffan, Vladimir Chubanov, Thomas Gudermann, Bernhard Nieswandt, and Attila Braun
Subjects: Science
Abstract: Although Mg2+is vital for platelet activation and aggregation, its regulation in these cells is still largely unknown. Here, the authors show that TRPM7, a cation channel and a protein kinase, regulates thrombopoiesis and platelet size by affecting the cytoskeleton of these cells in mice and humans.
Published: 2016
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15. Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors

Author: Marjorie Poggi, Matthias Canault, Marie Favier, Ernest Turro, Paul Saultier, Dorsaf Ghalloussi, Veronique Baccini, Lea Vidal, Anna Mezzapesa, Nadjim Chelghoum, Badreddine Mohand-Oumoussa, Céline Falaise, Rémi Favier, Willem H. Ouwehand, Mathieu Fiore, Franck Peiretti, Pierre Emmanuel Morange, Noémie Saut, Denis Bernot, Andreas Greinacher, NIHR BioResource, Alan T. Nurden, Paquita Nurden, Kathleen Freson, David-Alexandre Trégouët, Hana Raslova, and Marie-Christine Alessi
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Variants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants, and variants located in the E26 transformation-specific binding domain (encoding p.A377T, p.Y401N) led to reduced binding to corepressors. We also observed a large expansion of megakaryocyte colony-forming units derived from variant carriers and reduced proplatelet formation with abnormal cytoskeletal organization. The defect in proplatelet formation was also observed in control CD34+ cell-derived megakaryocytes transduced with lentiviral particles encoding mutant ETV6. Reduced expression levels of key regulators of the actin cytoskeleton CDC42 and RHOA were measured. Moreover, changes in the actin structures are typically accompanied by a rounder platelet shape with a highly heterogeneous size, decreased platelet arachidonic response, and spreading and retarded clot retraction in ETV6 deficient platelets. Elevated numbers of circulating CD34+ cells were found in p.P214L and p.Y401N carriers, and two patients from different families suffered from refractory anemia with excess blasts, while one patient from a third family was successfully treated for acute myeloid leukemia. Overall, our study provides novel insights into the role of ETV6 as a driver of cytoskeletal regulatory gene expression during platelet production, and the impact of variants resulting in platelets with altered size, shape and function and potentially also in changes in circulating progenitor levels.
Published: 2017
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16. MitoPhen database: a human phenotype ontology-based approach to identify mitochondrial DNA diseases

Author: Alba Sanchis-Juan, Ernest Turro, Katherine Schon, Patrick F. Chinnery, Daniel Greene, Rita Horvath, Wei Wei, Lucy Raymond, Jelle van den Ameele, Thiloka Ratnaike, Horvath, Rita [0000-0002-9841-170X], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository
Subjects: Mitochondrial DNA, Mitochondrial Diseases, Databases, Factual, AcademicSubjects/SCI00010, Mitochondrial disease, Data Resources and Analyses, Biology, computer.software_genre, Heteroplasmy, DNA, Mitochondrial, Human Phenotype Ontology, Genetics, medicine, Humans, Genetic testing, Database, medicine.diagnostic_test, Genetic heterogeneity, medicine.disease, Phenotype, Biological Ontologies, Mutation, computer, Rare disease
Abstract: Diagnosing mitochondrial disorders remains challenging. This is partly because the clinical phenotypes of patients overlap with those of other sporadic and inherited disorders. Although the widespread availability of genetic testing has increased the rate of diagnosis, the combination of phenotypic and genetic heterogeneity still makes it difficult to reach a timely molecular diagnosis with confidence. An objective, systematic method for describing the phenotypic spectra for each variant provides a potential solution to this problem. We curated the clinical phenotypes of 6688 published individuals with 89 pathogenic mitochondrial DNA (mtDNA) mutations, collating 26 348 human phenotype ontology (HPO) terms to establish the MitoPhen database. This enabled a hypothesis-free definition of mtDNA clinical syndromes, an overview of heteroplasmy-phenotype relationships, the identification of under-recognized phenotypes, and provides a publicly available reference dataset for objective clinical comparison with new patients using the HPO. Studying 77 patients with independently confirmed positive mtDNA diagnoses and 1083 confirmed rare disease cases with a non-mitochondrial nuclear genetic diagnosis, we show that HPO-based phenotype similarity scores can distinguish these two classes of rare disease patients with a false discovery rate
Published: 2021

17. 580 MitoPhen: A human phenotype ontology-based tool to identify mitochondrial DNA disease

Author: Thiloka Ratnaike, Daniel Greene, Ida Paramanov, Leslie Matalonga, Katherine Schon, Jelle van den Ameele, Rita Horvath, Ernest Turro, and Patrick Chinnery
Published: 2022

18. Identification of a homozygous recessive variant in PTGS1 resulting in a congenital aspirin-like defect in platelet function

Author: Michael G. Malkowski, Michael Laffan, Nihr BioResource, Melissa A. Hayman, Darryl C. Zeldin, Liang Dong, Valerie B. O'Donnell, Melissa V. Chan, Daniel Greene, Kathleen Freson, Harriet E. Allan, Ginger L. Milne, Daniel P. Hart, Timothy D. Warner, Moghees Hanif, Suthesh Sivapalaratnam, Claire Lentaigne, Ernest Turro, Kate Downes, Marilena Crescente, Matthew L. Edin, Jonathan Stephens, Willem H. Ouwehand, Matthew Stubbs, and Katherine Wedderburn
Subjects: 0301 basic medicine, Proband, medicine.medical_specialty, Aspirin, Eicosanoid metabolism, business.industry, PTGS1, Hematology, 030204 cardiovascular system & hematology, 03 medical and health sciences, Thromboxane A2, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Endocrinology, chemistry, Internal medicine, Medicine, Missense mutation, Platelet, business, Eicosanoid Production, medicine.drug
Abstract: We have identified a rare missense variant on chromosome 9, position 125145990 (GRCh37), in exon 8 in PTGS1 (the gene encoding cyclo-oxygenase 1, COX-1, the target of anti-thrombotic aspirin therapy). We report that in the homozygous state within a large consanguineous family this variant is associated with a bleeding phenotype and alterations in platelet reactivity and eicosanoid production. Western blotting and confocal imaging demonstrated that COX-1 was absent in the platelets of three family members homozygous for the PTGS1 variant but present in their leukocytes. Platelet reactivity, as assessed by aggregometry, lumi-aggregometry and flow cytometry, was impaired in homozygous family members, as were platelet adhesion and spreading. The productions of COX-derived eicosanoids by stimulated platelets were greatly reduced but there were no changes in the levels of urinary metabolites of COX-derived eicosanoids. The proband exhibited additional defects in platelet aggregation and spreading which may explain why her bleeding phenotype was slightly more severe than those of other homozygous affected relatives. This is the first demonstration in humans of the specific loss of platelet COX-1 activity and provides insight into its consequences for platelet function and eicosanoid metabolism. Notably despite the absence of thromboxane A2 (TXA2) formation by platelets, urinary TXA2 metabolites were in the normal range indicating these cannot be assumed as markers of in vivo platelet function. Results from this study are important benchmarks for the effects of aspirin upon platelet COX-1, platelet function and eicosanoid production as they define selective platelet COX-1 ablation within humans.
Published: 2020

19. A novel missense variant in SLC18A2 causes recessive brain monoamine vesicular transport disease and absent serotonin in platelets

Author: Nihr BioResource, Jaak Jaeken, Lieven Lagae, Ernest Turro, Kate Downes, Kathleen Stirrups, Daniel Greene, Manisha Padmakumar, Chantal Thys, Kathleen Freson, Vincent Ramaekers, and Chris Van Geet
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Case Report, Case Reports, QH426-470, Vesicular monoamine transporter 2, Biochemistry, Genetics and Molecular Biology (miscellaneous), Diseases of the endocrine glands. Clinical endocrinology, vesicular monoamine transporter 2, Neurodevelopmental disorder, Internal medicine, Internal Medicine, medicine, Genetics, Missense mutation, Platelet, whole genome sequencing, biology, platelet dense granules, business.industry, medicine.disease, RC648-665, Hypotonia, serotonin, Vesicular transport protein, Monoamine neurotransmitter, Endocrinology, biology.protein, epilepsy, Serotonin, medicine.symptom, business
Abstract: BACKGROUND: Brain monoamine vesicular transport disease is an infantile onset neurodevelopmental disorder caused by variants in SLC18A2, which codes for the vesicular monoamine transporter 2 (VMAT2) protein, involved in the transport of monoamines into synaptic vesicles and of serotonin into platelet dense granules. CASE PRESENTATION: The presented case is of a child, born of healthy consanguineous parents, who exhibited hypotonia, mental disability, epilepsy, uncontrolled movements, and gastrointestinal problems. A trial treatment with L-DOPA proved unsuccessful and the exact neurological involvement could not be discerned due to normal metabolic and brain magnetic resonance imaging results.Platelet studies and whole genome sequencing were performed. At age 4, the child's platelets showed a mild aggregation and adenosine triphosphate secretion defect that could be explained by dysmorphic dense granules observed by electron microscopy. Interestingly, the dense granules were almost completely depleted of serotonin. A novel homozygous p.P316A missense variant in VMAT2 was detected in the patient and the consanguineous parents were found to be heterozygous for this variant. Although the presence of VMAT2 on platelet dense granules has been demonstrated before, this is the first report of defective platelet dense granule function related to absent serotonin storage in a patient with VMAT2 deficiency but without obvious clinical bleeding problems. CONCLUSIONS: This study illustrates the homology between serotonin metabolism in brain and platelets, suggesting that these blood cells can be model cells for some pathways relevant for neurological diseases. The literature on VMAT2 deficiency is reviewed. ispartof: JIMD Rep vol:47 issue:1 pages:9-16 ispartof: location:United States status: Published online
Published: 2019

20. NRG1 fusions in breast cancer

Author: Matthew D. Eldridge, Karen Howarth, Oscar M. Rueda, Jean Abraham, Jessica C.M. Pole, Ernest Turro, Carlos Caldas, Paul A.W. Edwards, Tashfina Mirza, Suet-Feung Chin, Chris Boursnell, Raquel Manzano Garcia, Susanna L. Cooke, Howarth, Karen D. [0000-0002-1124-4583], Mirza, Tashfina [0000-0002-5780-9789], Cooke, Susanna L. [0000-0002-0955-0346], Chin, Suet-Feung [0000-0001-5697-1082], Pole, Jessica C. [0000-0002-5651-302X], Turro, Ernest [0000-0002-1820-6563], Eldridge, Matthew D. [0000-0002-5799-8911], Garcia, Raquel Manzano [0000-0002-5124-8992], Rueda, Oscar M. [0000-0003-0008-4884], Boursnell, Chris [0000-0002-3494-4451], Abraham, Jean E. [0000-0003-0688-4807], Caldas, Carlos [0000-0003-3547-1489], Edwards, Paul A. W. [0000-0002-4789-3374], Apollo - University of Cambridge Repository, Howarth, Karen D [0000-0002-1124-4583], Cooke, Susanna L [0000-0002-0955-0346], Pole, Jessica C [0000-0002-5651-302X], Eldridge, Matthew D [0000-0002-5799-8911], Rueda, Oscar M [0000-0003-0008-4884], Abraham, Jean E [0000-0003-0688-4807], and Edwards, Paul AW [0000-0002-4789-3374]
Subjects: MDA-MB-175, Oncogene Proteins, Fusion, Neuregulin-1, Breast Neoplasms, Biology, lcsh:RC254-282, Clinically actionable, Translocation, Genetic, Receptor tyrosine kinase, 03 medical and health sciences, Exon, 0302 clinical medicine, Breast cancer, Cell Line, Tumor, mental disorders, Biomarkers, Tumor, medicine, Humans, Transcriptome sequencing, Autocrine signalling, Gene, 030304 developmental biology, NRG1 fusions, Gene Rearrangement, Whole genome sequencing, 0303 health sciences, NRG1, Whole-genome sequencing, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Gene Expression Regulation, Neoplastic, Alternative Splicing, Genetic Loci, 030220 oncology & carcinogenesis, RNA splicing, Cancer research, biology.protein, Female, Tyrosine kinase, Signal Transduction, Research Article
Abstract: Funder: Cancer Research UK, Funder: Breast Cancer Now, Funder: Addenbrookes Charitable Trust, Funder: Mark Foundation For Cancer Research; doi: http://dx.doi.org/10.13039/100014599, Funder: Addenbrooke's Charitable Trust, Cambridge University Hospitals (GB), Background: NRG1 gene fusions may be clinically actionable, since cancers carrying the fusion transcripts can be sensitive to tyrosine kinase inhibitors. The NRG1 gene encodes ligands for the HER2(ERBB2)-ERBB3 heterodimeric receptor tyrosine kinase, and the gene fusions are thought to lead to autocrine stimulation of the receptor. The NRG1 fusion expressed in the breast cancer cell line MDA-MB-175 serves as a model example of such fusions, showing the proposed autocrine loop and exceptional drug sensitivity. However, its structure has not been properly characterised, its oncogenic activity has not been fully explained, and there is limited data on such fusions in breast cancer. Methods: We analysed genomic rearrangements and transcripts of NRG1 in MDA-MB-175 and a panel of 571 breast cancers. Results: We found that the MDA-MB-175 fusion—originally reported as a DOC4(TENM4)-NRG1 fusion, lacking the cytoplasmic tail of NRG1—is in reality a double fusion, PPP6R3-TENM4-NRG1, producing multiple transcripts, some of which include the cytoplasmic tail. We hypothesise that many NRG1 fusions may be oncogenic not for lacking the cytoplasmic domain but because they do not encode NRG1’s nuclear-localised form. The fusion in MDA-MB-175 is the result of a very complex genomic rearrangement, which we partially characterised, that creates additional expressed gene fusions, RSF1-TENM4, TPCN2-RSF1, and MRPL48-GAB2. We searched for NRG1 rearrangements in 571 breast cancers subjected to genome sequencing and transcriptome sequencing and found four cases (0.7%) with fusions, WRN-NRG1, FAM91A1-NRG1, ARHGEF39-NRG1, and ZNF704-NRG1, all splicing into NRG1 at the same exon as in MDA-MB-175. However, the WRN-NRG1 and ARHGEF39-NRG1 fusions were out of frame. We identified rearrangements of NRG1 in many more (8% of) cases that seemed more likely to inactivate than to create activating fusions, or whose outcome could not be predicted because they were complex, or both. This is not surprising because NRG1 can be pro-apoptotic and is inactivated in some breast cancers. Conclusions: Our results highlight the complexity of rearrangements of NRG1 in breast cancers and confirm that some do not activate but inactivate. Careful interpretation of NRG1 rearrangements will therefore be necessary for appropriate patient management.
Published: 2021

21. 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

22. 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

23. Cell type-specific novel long non-coding RNA and circular RNA in the BLUEPRINT hematopoietic transcriptomes atlas

Author: Natasha Andressa Nogueira Jorge, Jonathan M. Mudge, Mattia Frontini, Myrto Kostadima, Osagie G. Izuogu, Enca Martin-Rendon, Hendrik G. Stunnenberg, Romina Petersen, Denis Seyres, Xavier Estivill, Paul Flicek, Luigi Grassi, Samantha Farrow, Fabio Passetti, John J. Lambourne, Willem H. Ouwehand, Neda Farahi, Frances Burden, Adam Frankish, Sophia Rowlston, Joost H.A. Martens, Marie-Laure Yaspo, Kate Downes, Mariona Bustamante, Laura Clarke, Ernest Turro, Fergal J. Martin, Ouwehand, Willem [0000-0002-7744-1790], and Apollo - University of Cambridge Repository
Subjects: Cell type, Cell, Sang -- Malalties, Computational biology, Biology, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Circular RNA, medicine, Gene, Sequence Analysis, RNA, Gene Expression Profiling, RNA, High-Throughput Nucleotide Sequencing, Hematology, RNA, Circular, Long non-coding RNA, medicine.anatomical_structure, RNA, Long Noncoding, DNA microarray, Genètica, 030215 immunology
Abstract: Transcriptional profiling of hematopoietic cell subpopulations has helped to characterize the developmental stages of the hematopoietic system and the molecular bases of malignant and non-malignant blood diseases. Previously, only the genes targeted by expression microarrays could be profiled genome-wide. High-throughput RNA sequencing, however, encompasses a broader repertoire of RNA molecules, without restriction to previously annotated genes. We analyzed the BLUEPRINT consortium RNA-sequencing data for mature hematopoietic cell types. The data comprised 90 total RNA-sequencing samples, each composed of one of 27 cell types, and 32 small RNA-sequencing samples, each composed of one of 11 cell types. We estimated gene and isoform expression levels for each cell type using existing annotations from Ensembl. We then used guided transcriptome assembly to discover unannotated transcripts. We identified hundreds of novel non-coding RNA genes and showed that the majority have cell type-dependent expression. We also characterized the expression of circular RNA and found that these are also cell type-specific. These analyses refine the active transcriptional landscape of mature hematopoietic cells, highlight abundant genes and transcriptional isoforms for each blood cell type, and provide a valuable resource for researchers of hematologic development and diseases. Finally, we made the data accessible via a web-based interface: https://blueprint.haem.cam.ac.uk/bloodatlas/. The work was funded by a grant from the European Commission 7th Framework Program (FP7/2007–2013, grant 282510, BLUEPRINT) to XE, PF, JHAM, MY, HGS and WHO. WHO is an NIHR senior investigator and receives funding from Bristol-Myers Squibb, the British Heart Foundation, the Medical Research Council and the NIHR. OGI, FJM, AF, JMM, LC and PF are funded by the Wellcome Trust (WT108749/Z/15/Z) with additional funding for specific project components such as GENCODE from the National Human Genome Research Institute of the National Institutes of Health (2U41HG007234). FP is supported by the Fundação Carlos Chagas Filho de Amparo à Pesquisado Estado do Rio de Janeiro (FAPERJ; E-26/203.229/2016). NANJ is a recipient of a scholarship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES; Finance Code 001). MF is supported by the British Heart Foundation (FS/18/53/33863)
Published: 2020
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24. A new pedigree with thrombomodulin-associated coagulopathy in which delayed fibrinolysis is partially attenuated by co-inherited TAFI deficiency

Author: R. Campbell Tait, Sarah K Westbury, Dirk Hendriks, Kate Downes, Claire S. Whyte, Andrew D Mumford, Nicola J. Mutch, Jonathan Stephens, Karen Claesen, Nihr BioResource, Ernest Turro, Joachim C. Mertens, Emma J Leishman, and Anne-Louise Latif
Subjects: medicine.medical_specialty, Carboxypeptidase B2, medicine.medical_treatment, Thrombomodulin, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genetic model, Fibrinolysis, Coagulopathy, genomics, Medicine, Humans, Gene, Hematology, business.industry, Abnormal bleeding, Thrombin, thrombomodulin, Blood Coagulation Disorders, medicine.disease, bleeding, Pedigree, Hemostasis, Immunology, fibrinolysis, Human medicine, business, TAFI (carboxypeptidase B2 (CPB2)/procarboxypeptidase U (proCPU))
Abstract: Background: Thrombomodulin-associated coagulopathy (TM-AC) is a rare bleeding disorder in which a single reported p.Cys537* variant in the thrombomodulin gene THBD causes high plasma thrombomodulin (TM) levels. High TM levels attenuate thrombin generation and delay fibrinolysis. Objectives: To report the characteristics of pedigree with a novel THBD variant causing TM-AC, and co-inherited deficiency of thrombin-activatable fibrinolysis inhibitor (TAFI).Patients/methods: Identification of pathogenic variants in haemostasis genes by next-generation sequencing and case recall for deep phenotyping.Results: Pedigree members with a previously reported THBD variant predicting p.Pro496Argfs*10 and chain truncation in TM transmembrane domain had abnormal bleeding and greatly increased plasma TM levels. Affected cases had attenuated thrombin generation and delayed fibrinolysis similar to previous reported TM_AC cases with THBD p.Cys537*. Coincidentally, some pedigree members also harboured a stop-gain variant in CPB2 encoding TAFI. This reduced plasma TAFI levels but was asymptomatic. Pedigree members with TM-AC caused by the p.Pro496Argfs*10 THBD variant and also TAFI deficiency had a partially attenuated delay in fibrinolysis, but no change in the defective thrombin generation.Conclusions: These data extend the reported genetic repertoire of TM-AC and establish a common molecular pathogenesis arising from high plasma levels of TM extra-cellular domain. The data further confirm that the delay in fibrinolysis associated with TM-AC is directly linked to increased TAFI activation. The combination of the rare variants in the pedigree members provides a unique genetic model to develop understanding of the thrombin-TM system and its regulation of TAFI.
Published: 2020

25. Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans

Author: Ernest Turro, Alistair T. Pagnamenta, Jonathan Stephens, Shamima Rahman, Jenny C. Taylor, John Broxholme, Mark J. Caulfield, Patrick F. Chinnery, Christopher A. Odhams, Wei Wei, Salih Tuna, Alba Sanchis-Juan, Carl Fratter, Nicholas Gleadall, Wei, Wei [0000-0002-2945-3543], Pagnamenta, Alistair T [0000-0001-7334-0602], Tuna, Salih [0000-0003-3606-4367], Fratter, Carl [0000-0001-7125-5391], Turro, Ernest [0000-0002-1820-6563], Caulfield, Mark J [0000-0001-9295-3594], Rahman, Shamima [0000-0003-2088-730X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, Mitochondrial DNA, Nuclear gene, Science, General Physics and Astronomy, Biology, Human mitochondrial genetics, DNA, Mitochondrial, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Mitochondrial genome, Humans, Family, Genetic variation, Allele, Author Correction, lcsh:Science, Whole genome sequencing, Genetics, Cell Nucleus, Multidisciplinary, Models, Genetic, Eukaryote, Haplotype, Reproducibility of Results, General Chemistry, Heteroplasmy, Pedigree, 030104 developmental biology, chemistry, Haplotypes, Paternal Inheritance, lcsh:Q, Female, 030217 neurology & neurosurgery, DNA
Abstract: Several strands of evidence question the dogma that human mitochondrial DNA (mtDNA) is inherited exclusively down the maternal line, most recently in three families where several individuals harbored a ‘heteroplasmic haplotype’ consistent with biparental transmission. Here we report a similar genetic signature in 7 of 11,035 trios, with allelic fractions of 5–25%, implying biparental inheritance of mtDNA in 0.06% of offspring. However, analysing the nuclear whole genome sequence, we observe likely large rare or unique nuclear-mitochondrial DNA segments (mega-NUMTs) transmitted from the father in all 7 families. Independently detecting mega-NUMTs in 0.13% of fathers, we see autosomal transmission of the haplotype. Finally, we show the haplotype allele fraction can be explained by complex concatenated mtDNA-derived sequences rearranged within the nuclear genome. We conclude that rare cryptic mega-NUMTs can resemble paternally mtDNA heteroplasmy, but find no evidence of paternal transmission of mtDNA in humans., Recent evidence has questioned the dogma of strict maternal transmission of mitochondrial DNA (mtDNA) in humans. Wei et al. saw no evidence of paternal transmission of mtDNA in 11,035 human trios, and show that nuclear-mitochondrial segments (NUMTs) can give the impression of paternal mtDNA transmission, but are actually inherited through the nuclear genome.
Published: 2020
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26. 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

27. mRNA structural elements immediately upstream of the start codon dictate dependence upon eIF4A helicase activity

Author: Philip C. Bevilacqua, Sarah M. Assmann, Ernest Turro, Ania Wilczynska, David C. Tack, Laura E. Ritchey, Joseph A. Waldron, Sarah L. Gillen, Martin Bushell, John Le Quesne, Turro Bassols, Ernest [0000-0002-1820-6563], and Apollo - University of Cambridge Repository
Subjects: Hippuristanol, Translation, Translational efficiency, lcsh:QH426-470, education, Codon, Initiator, Biology, Eif4a, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Eukaryotic translation, Translation initiation, Humans, RNA, Messenger, Nucleic acid structure, RNA structure, lcsh:QH301-705.5, health care economics and organizations, 030304 developmental biology, Cancer, 0303 health sciences, Messenger RNA, Research, DMS, Translation (biology), RNA Helicase A, G-quadruplexes, humanities, Cell biology, 3. Good health, lcsh:Genetics, Sterols, chemistry, lcsh:Biology (General), 030220 oncology & carcinogenesis, eIF4A, Polysome Profiling, Eukaryotic Initiation Factor-4A, MCF-7 Cells, Structure-seq, 5' Untranslated Regions
Abstract: Funder: Medical Research Council, BACKGROUND:The RNA helicase eIF4A1 is a key component of the translation initiation machinery and is required for the translation of many pro-oncogenic mRNAs. There is increasing interest in targeting eIF4A1 therapeutically in cancer, thus understanding how this protein leads to the selective re-programming of the translational landscape is critical. While it is known that eIF4A1-dependent mRNAs frequently have long GC-rich 5'UTRs, the details of how 5'UTR structure is resculptured by eIF4A1 to enhance the translation of specific mRNAs are unknown. RESULTS:Using Structure-seq2 and polysome profiling, we assess global mRNA structure and translational efficiency in MCF7 cells, with and without eIF4A inhibition with hippuristanol. We find that eIF4A inhibition does not lead to global increases in 5'UTR structure, but rather it leads to 5'UTR remodeling, with localized gains and losses of structure. The degree of these localized structural changes is associated with 5'UTR length, meaning that eIF4A-dependent mRNAs have greater localized gains of structure due to their increased 5'UTR length. However, it is not solely increased localized structure that causes eIF4A-dependency but the position of the structured regions, as these structured elements are located predominantly at the 3' end of the 5'UTR. CONCLUSIONS:By measuring changes in RNA structure following eIF4A inhibition, we show that eIF4A remodels local 5'UTR structures. The location of these structural elements ultimately determines the dependency on eIF4A, with increased structure just upstream of the CDS being the major limiting factor in translation, which is overcome by eIF4A activity.
Published: 2020
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28. 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

29. 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

30. 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

31. 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

32. Monoallelic loss-of-function THPO variants cause heritable thrombocytopenia

Author: Kate Downes, Kate Burley, Nihr BioResource, Andrew D Mumford, Janine Collins, Sarah K Westbury, Naomi Cornish, Daniel Greene, Lucy FitzGibbon, M Riyaad Aungraheeta, Dominic Alibhai, and Ernest Turro
Subjects: business.industry, Hematology, Isoxazoles, Biology, Bioinformatics, Thrombocytopenia, Stimulus Report, Text mining, Thrombopoietin, hemic and lymphatic diseases, Journal Article, Humans, Secretion, business, Loss function, Intracellular
Abstract: Thrombopoietin (TPO) is a lineage-specific cytokine that is synthesized predominantly in hepatocytes and is an essential regulator of self-renewal of hematopoietic stem cells and their differentiation into platelet-forming megakaryocytes. The major TPO isoform is a 353-aa peptide containing a highly glycosylated C-terminal domain and an amino-terminal receptor binding domain (RBD) that mediates interaction with the TPO receptor (c-mpl) on hematopoietic cells. TPO is encoded by the THPO gene, which maps to 3q27.1 and contains up to 6 coding exons.Increased TPO production caused by gain-of-function THPO variants results in the myeloproliferative disorder thrombocythemia-1 (Online Mendelian Inheritance in Man #187950), in which the circulating platelet count is elevated, sometimes causing bleeding or thrombosis. In contrast, biallelic loss-of-function THPO variants result in a severe reduction in the platelet count and multilineage bone marrow failure. Here, we present genetic and functional evidence that monoallelic loss-of-function THPO variants also result in reduced platelet count but do not affect other circulating blood cells.
Published: 2019

33. Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome

Author: Kathleen Stirrups, Chris Van Geet, Stephanie Humblet-Baron, Ernest Turro, Daniel Greene, Isabelle Meyts, Erika Van Nieuwenhove, Roxanne Collin, Patrick Matthys, Karen Put, Sylvie Lesage, Jessica Heremans, Adrian Liston, Josselyn E. Garcia-Perez, Christopher J. Penkett, Ingele Casteels, Francis de Zegher, Chantal Thys, Kathleen Freson, Susan M. Schlenner, and Carine Wouters
Subjects: Blood Platelets, 0301 basic medicine, Adolescent, Primary Immunodeficiency Diseases, Megakaryocyte differentiation, Immunology, Biology, Osteochondrodysplasias, Compound heterozygosity, 03 medical and health sciences, Retinal Diseases, Megakaryocyte, RNA, Small Nuclear, Exome Sequencing, medicine, Humans, Protein Splicing, Immunology and Allergy, Cell Lineage, Child, MAPK1, Cells, Cultured, Thrombopoietin, Cell Proliferation, Mitogen-Activated Protein Kinase 1, B-Lymphocytes, Precursor Cells, B-Lymphoid, Immunologic Deficiency Syndromes, Intron, Infant, Cell Differentiation, Pedigree, 030104 developmental biology, medicine.anatomical_structure, Child, Preschool, RNA splicing, Mental Retardation, X-Linked, Cancer research, Dense granule, Cardiomyopathies, Megakaryocytes, Signal Transduction
Abstract: BACKGROUND: Roifman syndrome is a rare inherited disorder characterized by spondyloepiphyseal dysplasia, growth retardation, cognitive delay, hypogammaglobulinemia, and, in some patients, thrombocytopenia. Compound heterozygous variants in the small nuclear RNA gene RNU4ATAC, which is necessary for U12-type intron splicing, were identified recently as driving Roifman syndrome. OBJECTIVE: We studied 3 patients from 2 unrelated kindreds harboring compound heterozygous or homozygous stem II variants in RNU4ATAC to gain insight into the mechanisms behind this disorder. METHODS: We systematically profiled the immunologic and hematologic compartments of the 3 patients with Roifman syndrome and performed RNA sequencing to unravel important splicing defects in both cell lineages. RESULTS: The patients exhibited a dramatic reduction in B-cell numbers, with differentiation halted at the transitional B-cell stage. Despite abundant B-cell activating factor availability, development past this B-cell activating factor-dependent stage was crippled, with disturbed minor splicing of the critical mitogen-activated protein kinase 1 signaling component. In the hematologic compartment patients with Roifman syndrome demonstrated defects in megakaryocyte differentiation, with inadequate generation of proplatelets. Platelets from patients with Roifman syndrome were rounder, with increased tubulin and actin levels, and contained increased α-granule and dense granule markers. Significant minor intron retention in 354 megakaryocyte genes was observed, including DIAPH1 and HPS1, genes known to regulate platelet and dense granule formation, respectively. CONCLUSION: Together, our results provide novel molecular and cellular data toward understanding the immunologic and hematologic features of Roifman syndrome. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:142 issue:2 pages:630-646 ispartof: location:United States status: published
Published: 2018

34. High‐throughput sequencing approaches for diagnosing hereditary bleeding and platelet disorders

Author: Kathleen Freson and Ernest Turro
Subjects: Blood Platelets, Male, 0301 basic medicine, Platelet disorder, Hemorrhage, 030204 cardiovascular system & hematology, Biology, Hemophilia A, Bioinformatics, DNA sequencing, 03 medical and health sciences, Blood Coagulation Disorders, Inherited, 0302 clinical medicine, Humans, Genetic Predisposition to Disease, Gene, Blood Platelet Disorders, Genome, Genetic heterogeneity, Genetic Variation, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Hematology, Phenotype, Digenic inheritance, 030104 developmental biology, Etiology
Abstract: Hereditary bleeding and platelet disorders (BPDs) are characterized by marked genetic heterogeneity, far greater than previously appreciated. The list of genes involved in the regulation of megakaryopoiesis, platelet formation, platelet function and bleeding has been growing rapidly since the introduction of high-throughput sequencing (HTS) approaches in research. Thanks to the gradual adoption of HTS in diagnostic practice, these discoveries are improving the diagnostic yield for BPD patients, who may or may not present with bleeding problems and often have other clinical symptoms unrelated to the blood system. However, it was previously found that screening for all known etiologies gives a diagnostic yield of over 90% when the phenotype closely matches a known BPD but drops to 10% when the phenotype is indicative of a novel disorder. Thus, further research is needed to identify currently unknown etiologies for BPDs. Novel genes are likely to be found to be implicated in BPDs. New modes of inheritance, including digenic inheritance, are likely to play a role in some cases. Additionally, identifying and interpreting pathogenic variants outside exons is a looming challenge that can only be tackled with an improved understanding of the regulatory landscape of relevant cell types and with the transition from targeted sequencing to whole-genome sequencing in the clinic.
Published: 2017

35. 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

36. 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

37. 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

38. Author Correction: Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans

Author: Jenny C. Taylor, Patrick F. Chinnery, John Broxholme, Nicholas Gleadall, Jonathan Stephens, Christopher A. Odhams, Ernest Turro, Shamima Rahman, Alistair T. Pagnamenta, Carl Fratter, Wei Wei, Salih Tuna, Alba Sanchis-Juan, and Mark J. Caulfield
Subjects: Genetics, Mitochondrial DNA, Multidisciplinary, Science, General Physics and Astronomy, General Chemistry, Biology, biology.organism_classification, General Biochemistry, Genetics and Molecular Biology, Genetic variation, Eukaryote, lcsh:Q, lcsh:Science
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2020

39. A coagulation defect arising from heterozygous premature termination of tissue factor

Author: Sol Schulman, Emale El-Darzi, Kathelijne Peerlinck, Chad A. Cowan, Calvin R. Schuster, Marisa A Brake, Mary H.C. Florido, Robert Flaumenhaft, Ernest Turro, Max Friesen, Nihr BioResource, Kathleen Freson, Willem H. Ouwehand, Glenn Merrill-Skoloff, Bruce Furie, Randal J. Westrick, and Lin Lin
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Heterozygote, Vascular smooth muscle, Induced Pluripotent Stem Cells, Haploinsufficiency, Frameshift mutation, Thromboplastin, 03 medical and health sciences, Tissue factor, Mice, 0302 clinical medicine, Blood Coagulation Disorders, Inherited, Internal medicine, medicine, Animals, Humans, Thrombus, Frameshift Mutation, Gene Editing, Mice, Knockout, Hematology, Base Sequence, business.industry, Abnormal bleeding, General Medicine, Peptide Chain Termination, Translational, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Phenotype, Coagulation, Codon, Nonsense, 030220 oncology & carcinogenesis, Cancer research, Female, business, Research Article
Abstract: Tissue factor (TF) is the primary initiator of blood coagulation in vivo and the only blood coagulation factor for which a human genetic defect has not been described. As there are no routine clinical assays that capture the contribution of endogenous TF to coagulation initiation, the extent to which reduced TF activity contributes to unexplained bleeding is unknown. Using whole genome sequencing, we identified a heterozygous frameshift variant (p.Ser117HisfsTer10) in F3, the gene encoding TF, causing premature termination of TF ("TFshort") in a woman with unexplained bleeding. Routine hematological laboratory evaluation of the proposita was normal. CRISPR-edited human induced pluripotent stem cells recapitulating the variant were differentiated into vascular smooth muscle and endothelial cells that demonstrated haploinsufficiency of TF. The variant F3 transcript is eliminated by nonsense-mediated decay. Neither overexpression nor addition of exogenous recombinant TFshort inhibited factor Xa or thrombin generation, excluding a dominant negative mechanism. F3+/- mice provide an animal model of TF haploinsufficiency and exhibited prolonged bleeding times, impaired thrombus formation, and reduced survival following major injury. Heterozygous TF deficiency is present in at least 1 in 25,000 individuals and could limit coagulation initiation in undiagnosed individuals with abnormal bleeding but a normal routine laboratory evaluation.
Published: 2019

40. Identification of a homozygous recessive variant in

Author: Melissa V, Chan, Melissa A, Hayman, Suthesh, Sivapalaratnam, Marilena, Crescente, Harriet E, Allan, Matthew L, Edin, Darryl C, Zeldin, Ginger L, Milne, Jonathan, Stephens, Daniel, Greene, Moghees, Hanif, Valerie B, O'Donnell, Liang, Dong, Michael G, Malkowski, Claire, Lentaigne, Katherine, Wedderburn, Matthew, Stubbs, Kate, Downes, Willem H, Ouwehand, Ernest, Turro, Nihr, BioResource, Daniel P, Hart, Kathleen, Freson, Michael A, Laffan, and Timothy D, Warner
Subjects: Blood Platelets, Thromboxane A2, Aspirin, Platelet Aggregation, Platelet Function Tests, Cyclooxygenase 1, Humans, Female, Article
Abstract: We have identified a rare missense variant on chromosome 9, position 125145990 (GRCh37), in exon 8 in prostaglandin endoperoxide synthase 1 (PTGS1) (the gene encoding cyclo-oxygenase 1 [COX-1], the target of anti-thrombotic aspirin therapy). We report that in the homozygous state within a large consanguineous family this variant is associated with a bleeding phenotype and alterations in platelet reactivity and eicosanoid production. Western blotting and confocal imaging demonstrated that COX-1 was absent in the platelets of three family members homozygous for the PTGS1 variant but present in their leukocytes. Platelet reactivity, as assessed by aggregometry, lumi-aggregometry and flow cytometry, was impaired in homozygous family members, as were platelet adhesion and spreading. The productions of COXderived eicosanoids by stimulated platelets were greatly reduced but there were no changes in the levels of urinary metabolites of COX-derived eicosanoids. The proband exhibited additional defects in platelet aggregation and spreading which may explain why her bleeding phenotype was slightly more severe than those of other homozygous affected relatives. This is the first demonstration in humans of the specific loss of platelet COX-1 activity and provides insight into its consequences for platelet function and eicosanoid metabolism. Notably despite the absence of thromboxane A2 formation by platelets, urinary thromboxane A2 metabolites were in the normal range indicating these cannot be assumed as markers of in vivo platelet function. Results from this study are important benchmarks for the effects of aspirin upon platelet COX-1, platelet function and eicosanoid production as they define selective platelet COX-1 ablation within humans.
Published: 2019

41. Cell type specific novel lincRNAs and circRNAs in the BLUEPRINT haematopoietic transcriptomes atlas

Author: Luigi Grassi, N. A. Jeorge, Kate Downes, Frances Burden, Paul Flicek, Xavier Estivill, John J. Lambourne, Neda Farahi, Henk Stunnenberg, Willem H. Ouwehand, Romina Petersen, Denis Seyres, Fergal J. Martin, Fabio Passetti, Adam Frankish, Sophia Rowlston, Laura Clarke, Joost H.A. Martens, S. Farrow, Myrto Kostadima, Osagie G. Izuogu, Ernest Turro, Marie-Laure Yaspo, Jonathan M. Mudge, Mariona Bustamante, Mattia Frontini, and Enca Martin-Rendon
Subjects: 0303 health sciences, Small RNA, Cell type, RNA, Computational biology, Gene Annotation, Biology, Genome, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Transcriptional profiling of hematopoietic cell subpopulations has helped characterize the developmental stages of the hematopoietic system and the molecular basis of malignant and non-malignant blood diseases for the past three decades. The introduction of high-throughput RNA sequencing has increased knowledge of the full repertoire of RNA molecules in hematopoietic cells of different types, without relying on prior gene annotation. Here, we introduce the analysis of the BLUEPRINT consortium gene expression data for mature hematopoietic cells, comprising 90 total RNA and 32 small RNA sequencing experiments, from 27 different cell types. We used these data to describe the transcriptional profile of each we used guided transcriptome assembly to extend the annotation of the transcribed genome, which led to the identification of hundreds of novel non-coding RNA genes, which display a high degree of cell type specificity. We also characterized the expression of circular RNAs and found that these are also highly cell type specific. This resource refines the active transcriptional landscape of mature hematopoietic cells, highlights abundant genes and transcriptional isoforms for each cell type, and provides valuable data and visualisation tools for the scientific community working on hematological development and diseases.
Published: 2019
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42. Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses

Author: James Thaventhiran, Duncan I. Jodrell, Fiona Shackley, Chi Ma, Joshua D. Milner, Daniel Greene, Alison M. Condliffe, Ruth A. Sabroe, Meltem Gürel, Guangping Sun, Sarah Spencer, William Rae, Katarzyna D. Kania, William Egner, Jonathan Stephens, Emily Staples, Adrian J. Thrasher, Ernest Turro, Hana Lango Allen, Diarmuid Kerrin, Yuan Zhang, Ravishankar Sargur, Hye Sun Kuehn, Sevgi Köstel Bal, Salih Tuna, Melanie York, Rico Chandra Ardy, Kenneth G. C. Smith, Sergio D. Rosenzweig, Tala Shahin, Annika Pecchia-Bekkum, Marini Thian, William P.M. Worrall, Simon Tavaré, Syed Irfan Raza, Hamid Nawaz Tipu, Matthew A. Brown, Kaan Boztug, Thaventhiran, James [0000-0001-8616-074X], Lango Allen, Hana [0000-0002-7803-8688], Rae, William [0000-0003-0095-2514], Stephens, Jonathan [0000-0003-2020-9330], Tuna, Salih [0000-0003-3606-4367], Turro Bassols, Ernest [0000-0002-1820-6563], Tavare, Simon [0000-0002-3716-4952], Jodrell, Duncan [0000-0001-9360-1670], Smith, Kenneth [0000-0003-3829-4326], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Adult, Male, Adolescent, Immunology, education, Immunoglobulin E, Pathogenesis, Atopy, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, Eosinophilia, Humans, Interleukin 6, Child, Immunodeficiency, Research Articles, health care economics and organizations, Inflammation, biology, business.industry, Interleukin-6, Brief Definitive Report, Immunologic Deficiency Syndromes, Infant, Newborn, medicine.disease, Receptors, Interleukin-6, 3. Good health, 030104 developmental biology, HEK293 Cells, Child, Preschool, Interleukin-6 receptor, biology.protein, Primary immunodeficiency, Female, medicine.symptom, business, 030215 immunology
Abstract: Spencer et al. report the first description of human IL-6R deficiency in two patients presenting with recurrent infections, atopy, elevated IgE, and abnormal acute-phase responses., IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R. We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.
Published: 2019

43. Sphingolipid dysregulation due to lack of functional KDSR impairs proplatelet formation causing thrombocytopenia

Author: Deborah Whitehorn, Mattia Frontini, Ernest Turro, Luigi Grassi, Cedric Ghevaert, Albert Koulman, Tadbir K. Bariana, Veerle Labarque, Keith Gomez, Willem H. Ouwehand, Benjamin Jenkins, Jessica Heremans, Olga Shamardina, Mara De Reys, Chris Van Geet, Sofia Papadia, Denis Seyres, Frances Burden, Daniel Greene, Nihr BioResource, Chantal Thys, Kathleen Freson, Seyres, Denis [0000-0002-2066-6980], Shamardina, Olga [0000-0003-4994-2157], Papadia, Sofia [0000-0002-9222-3812], Koulman, Albert [0000-0001-9998-051X], Ouwehand, Willem [0000-0002-7744-1790], Ghevaert, Cedric [0000-0002-9251-0934], Frontini, Mattia [0000-0001-8074-6299], Turro Bassols, Ernest [0000-0002-1820-6563], and Apollo - University of Cambridge Repository
Subjects: Platelets, Blood Platelets, Male, induced pluripotent stem cell, Ceramide, Cellular differentiation, Induced Pluripotent Stem Cells, Biology, Article, megakaryocyte, Platelet Biology & its Disorders, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Erythrokeratodermia variabilis, Megakaryocyte, medicine, Animals, Humans, Metabolomics, Myelofibrosis, Induced pluripotent stem cell, Child, Cells, Cultured, Zebrafish, Sphingolipids, proplatelet, Cell Differentiation, Hematology, medicine.disease, Prognosis, Sphingolipid, Thrombocytopenia, Pedigree, Alcohol Oxidoreductases, medicine.anatomical_structure, chemistry, Mutation, Cancer research, Female, sphingolipid, Stem cell, Megakaryocytes, 030215 immunology
Abstract: Sphingolipids are fundamental to membrane trafficking, apoptosis, and cell differentiation and proliferation. KDSR or 3-keto-dihydrosphingosine reductase is an essential enzyme for de novo sphingolipid synthesis, and pathogenic mutations in KDSR result in the severe skin disorder erythrokeratodermia variabilis et progressiva-4 Four of the eight reported cases also had thrombocytopenia but the underlying mechanism has remained unexplored. Here we expand upon the phenotypic spectrum of KDSR deficiency with studies in two siblings with novel compound heterozygous variants associated with thrombocytopenia, anemia, and minimal skin involvement. We report a novel phenotype of progressive juvenile myelofibrosis in the propositus, with spontaneous recovery of anemia and thrombocytopenia in the first decade of life. Examination of bone marrow biopsies showed megakaryocyte hyperproliferation and dysplasia. Megakaryocytes obtained by culture of CD34+ stem cells confirmed hyperproliferation and showed reduced proplatelet formation. The effect of KDSR insufficiency on the sphingolipid profile was unknown, and was explored in vivo and in vitro by a broad metabolomics screen that indicated activation of an in vivo compensatory pathway that leads to normalization of downstream metabolites such as ceramide. Differentiation of propositus-derived induced pluripotent stem cells to megakaryocytes followed by expression of functional KDSR showed correction of the aberrant cellular and biochemical phenotypes, corroborating the critical role of KDSR in proplatelet formation. Finally, Kdsr depletion in zebrafish recapitulated the thrombocytopenia and showed biochemical changes similar to those observed in the affected siblings. These studies support an important role for sphingolipids as regulators of cytoskeletal organization during megakaryopoiesis and proplatelet formation. ispartof: HAEMATOLOGICA vol:104 issue:5 pages:1036-1045 ispartof: location:Italy status: published
Published: 2019

44. 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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45. 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

46. 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

47. The Human Phenotype Ontology in 2017

Author: Rachel Thompson, Stanley J. F. Laulederkind, Richard H. Scott, Panagiotis I. Sergouniotis, Ada Hamosh, Mark Engelstad, Hanns Lochmüller, Gareth Baynam, Richard Sever, Roger James, Hugh Dawkins, Laureen E. Connell, C. Turner, Andrew D. Devereau, Susan M. Bello, Michael Brudno, Courtney Hum, Cynthia L. Smith, Julie A. McMurry, Michael M. Segal, Damian Smedley, Gholson J. Lyon, Helen V. Firth, Ingo Helbig, Tom Vulliamy, Roland Krause, Patrick F. Chinnery, Franz Schaefer, Ernest Turro, Melissa A. Haendel, Cornelius F. Boerkoel, Peter N. Robinson, Willem H. Ouwehand, Orion J. Buske, Kym M. Boycott, Volker Straub, Bert B.A. de Vries, Daniel Greene, Valentina Cipriani, Erin D. Foster, Annie Olry, Julius O.B. Jacobsen, Laura E. DeMare, Marijcke W. M. Veltman, Nikolas Pontikos, Andreas Zankl, Tudor Groza, Kathleen Freson, Sebastian Köhler, Ana Rath, Nicole Vasilevsky, Julie von Ziegenweidt, Ségolène Aymé, Soichi Ogishima, Johanna A. Jähn, Jing Yu, Tomasz Zemojtel, Stephan Züchner, and Christopher J. Mungall
Subjects: 0301 basic medicine, Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine], Genomics, Translational research, Computational biology, Biology, Ontology (information science), Terminology, Translational Research, Biomedical, 03 medical and health sciences, Rare Diseases, Human Phenotype Ontology, Genetics, Database Issue, Humans, Precision Medicine, Multidisciplinary, general & others [D99] [Human health sciences], Genetic Association Studies, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Computational Biology, Biological Ontologies, Precision medicine, Phenotype, 3. Good health, 030104 developmental biology, Algorithms, Software
Abstract: Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology. ispartof: Nucleic Acids Research vol:45 issue:D1 pages:D865-D876 ispartof: location:England status: published
Published: 2016

48. Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy

Author: Claire S. Whyte, Christopher Reilly-Stitt, Sarah K Westbury, Kathleen Stirrups, Oliver Chapman, Mary E. Walker, Andrew D Mumford, Ernest Turro, Kate Burley, Nihr BioResource, Nicola J. Mutch, Stirrups, Kathleen [0000-0002-6823-3252], Turro Bassols, Ernest [0000-0002-1820-6563], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Thrombomodulin, medicine.medical_treatment, Immunology, Factor VIIa, 030204 cardiovascular system & hematology, 1102 Cardiovascular Medicine And Haematology, Biochemistry, Thrombosis and Hemostasis, law.invention, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Thrombin, law, Internal medicine, Fibrinolysis, 1114 Paediatrics And Reproductive Medicine, Coagulopathy, Humans, Medicine, Thromboplastin, Genes, Dominant, business.industry, 1103 Clinical Sciences, Cell Biology, Hematology, Blood Coagulation Disorders, Middle Aged, medicine.disease, Recombinant Proteins, Pedigree, Phenotype, 030104 developmental biology, Endocrinology, Hemostasis, Recombinant DNA, Female, Prothrombin, business, circulatory and respiratory physiology, medicine.drug
Abstract: Thrombomodulin-associated coagulopathy (TM-AC) is a newly recognized dominant bleeding disorder in which a p.Cys537Stop variant in the thrombomodulin (TM) gene THBD, results in high plasma TM levels and protein C-mediated suppression of thrombin generation. Thrombin in complex with TM also activates thrombin-activatable fibrinolysis inhibitor (TAFI). However, the effect of the high plasma TM on fibrinolysis in TM-AC is unknown. Plasma from TM-AC cases and high-TM model control samples spiked with recombinant soluble TM showed reduced tissue factor-induced thrombin generation. Lysis of plasma clots from TM-AC cases was significantly delayed compared with controls but was completely restored when TM/thrombin-mediated TAFI activation was inhibited. Clots formed in blood from TM-AC cases had the same viscoelastic strength as controls but also showed a TAFI-dependent delay in fibrinolysis. Delayed fibrinolysis was reproduced in high-TM model plasma and blood samples. Partial restoration of thrombin generation with recombinant activated factor VII or activated prothrombin complex concentrate did not alter the delayed fibrinolysis in high-TM model blood. Our finding of a previously unrecognized fibrinolytic phenotype indicates that bleeding in TM-AC has a complex pathogenesis and highlights the pivotal role of TM as a regulator of hemostasis.
Published: 2016

49. 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

50. 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

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