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1. 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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2. Platelet function is modified by common sequence variation in megakaryocyte super enhancers

Author

Petersen, Romina, Lambourne, John J., Javierre, Biola M., Grassi, Luigi, Kreuzhuber, Roman, Ruklisa, Dace, Rosa, Isabel M., Tomé, Ana R., Elding, Heather, van Geffen, Johanna P., Jiang, Tao, Farrow, Samantha, Cairns, Jonathan, Al-Subaie, Abeer M., Ashford, Sofie, Attwood, Antony, Batista, Joana, Bouman, Heleen, Burden, Frances, Choudry, Fizzah A., Clarke, Laura, Flicek, Paul, Garner, Stephen F., Haimel, Matthias, Kempster, Carly, Ladopoulos, Vasileios, Lenaerts, An-Sofie, Materek, Paulina M., McKinney, Harriet, Meacham, Stuart, Mead, Daniel, Nagy, Magdolna, Penkett, Christopher J., Rendon, Augusto, Seyres, Denis, Sun, Benjamin, Tuna, Salih, van der Weide, Marie-Elise, Wingett, Steven W., Martens, Joost H., Stegle, Oliver, Richardson, Sylvia, Vallier, Ludovic, Roberts, David J., Freson, Kathleen, Wernisch, Lorenz, Stunnenberg, Hendrik G., Danesh, John, Fraser, Peter, Soranzo, Nicole, Butterworth, Adam S., Heemskerk, Johan W., Turro, Ernest, Spivakov, Mikhail, Ouwehand, Willem H., Astle, William J., Downes, Kate, Kostadima, Myrto, Frontini, Mattia, Lambourne, John [0000-0003-2460-0759], Grassi, Luigi [0000-0002-6308-7540], Haimel, Matthias [0000-0002-0320-0214], Rendon Restrepo, Augusto [0000-0001-8994-0039], Seyres, Denis [0000-0002-2066-6980], Sun, Ben [0000-0001-6347-2281], Tuna, Salih [0000-0003-3606-4367], Richardson, Sylvia [0000-0003-1998-492X], Vallier, Ludovic [0000-0002-3848-2602], Danesh, John [0000-0003-1158-6791], Soranzo, Nicole [0000-0003-1095-3852], Butterworth, Adam [0000-0002-6915-9015], Turro Bassols, Ernest [0000-0002-1820-6563], Ouwehand, Willem [0000-0002-7744-1790], Astle, William [0000-0001-8866-6672], Downes, Kate [0000-0003-0366-1579], Frontini, Mattia [0000-0001-8074-6299], Apollo - University of Cambridge Repository, MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, and Biochemie

Subjects
Blood Platelets, GENE-REGULATION, BLOOD, Erythroblasts, Science, Genetic Variation, OPEN CHROMATIN, DISEASE, Article, Chromatin, DNA-BINDING PROTEINS, THROMBUS FORMATION, GENOME, HUMAN CELL-TYPES, SEQ, Enhancer Elements, Genetic, TRAIT LOCI, Humans, Promoter Regions, Genetic, Megakaryocytes
Abstract

Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data and promoter long-range interactions. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions., 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

3. 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

4. Germline selection shapes human mitochondrial DNA diversity

Author

Wei, W, Tuna, S, Keogh, MJ, Smith, KR, Aitman, TJ, Beales, PL, Bennett, DL, Gale, DP, Bitner-Glindzicz, MAK, Black, GC, Brennan, P, Elliott, P, Flinter, FA, Floto, RA, Houlden, H, Irving, M, Koziell, A, Maher, ER, Markus, HS, Morrell, NW, Newman, WG, Roberts, I, Sayer, JA, Smith, KGC, Taylor, JC, Watkins, H, Webster, AR, Wilkie, AOM, Williamson, C, Attwood, A, Brown, M, Brod, NC, Crisp-Hihn, A, Davis, J, Deevi, SVV, Dewhurst, EF, Edwards, K, Erwood, M, Fox, J, Frary, AJ, Hu, F, Jolley, J, Kingston, N, Linger, R, Mapeta, R, Martin, J, Meacham, S, Papadia, S, Rayner-Matthews, PJ, Samarghitean, C, Shamardina, O, Simeoni, I, Staines, S, Staples, E, Stark, H, Stephens, J, Titterton, C, Von Ziegenweidt, J, Watt, C, Whitehorn, D, Wood, Y, Yates, K, Yu, P, James, R, Ashford, S, Penkett, CJ, Stirrups, KE, Bariana, T, Lentaigne, C, Sivapalaratnam, S, Westbury, SK, Allsup, DJ, Bakchoul, T, Biss, T, Boyce, S, Collins, J, Collins, PW, Curry, NS, Downes, K, Dutt, T, Erber, WN, Evans, G, Everington, T, Favier, R, Gomez, K, Greene, D, Gresele, P, Hart, D, Kazmi, R, Kelly, AM, Lambert, M, Madan, B, Mangles, S, Mathias, M, Millar, C, Obaji, S, Peerlinck, K, Roughley, C, Schulman, S, Scully, M, Shapiro, SE, Sibson, K, Sims, MC, Tait, RC, Talks, K, Thys, C, Toh, C-H, Van Geet, C, Westwood, J-P, Mumford, AD, Ouwehand, WH, Freson, K, Laffan, MA, Tan, RYY, Harkness, K, Mehta, S, Muir, KW, Hassan, A, Traylor, M, Drazyk, AM, Parry, D, Ahmed, M, Kazkaz, H, Vandersteen, AM, Ormondroyd, E, Thomson, K, Dent, T, Buchan, RJ, Bueser, T, Carr-White, G, Cook, S, Daniels, MJ, Harper, AR, Ware, JS, Dixon, PH, Chambers, J, Cheng, F, Estiu, MC, Hague, WM, Marschall, H-U, Vazquez-Lopez, M, Arno, G, French, CE, Michaelides, M, Moore, AT, Sanchis-Juan, A, Carss, K, Raymond, FL, Chinnery, PF, Griffiths, P, Horvath, R, Hudson, G, Jurkute, N, Pyle, A, Yu-Wai-Man, P, Whitworth, J, Adlard, J, Armstrong, R, Brewer, C, Casey, R, Cole, TRP, Evans, DG, Greenhalgh, L, Hanson, HL, Hoffman, J, Izatt, L, Kumar, A, Lalloo, F, Ong, KR, Park, S-M, Searle, C, Side, L, Snape, K, Woodward, E, Tischkowitz, M, Grozeva, D, Kurian, MA, Themistocleous, AC, Gosal, D, Marshall, A, Matthews, E, McCarthy, MI, Renton, T, Rice, ASC, Vale, T, Walker, SM, Woods, CG, Thaventhiran, JE, Allen, HL, Savic, S, Alachkar, H, Antrobus, R, Baxendale, HE, Browning, MJ, Buckland, MS, Cooper, N, Edgar, JDM, Egner, W, Gilmour, KC, Goddard, S, Gordins, P, Grigoriadou, S, Hackett, S, Hague, R, Hayman, G, Herwadkar, A, Huissoon, AP, Jolles, S, Kelleher, P, Kumararatne, D, Longhurst, H, Lorenzo, LE, Lyons, PA, Maimaris, J, Noorani, S, Richter, A, Sargur, RB, Sewell, WAC, Thomas, D, Thomas, MJ, Worth, A, Yong, PFK, Kuijpers, TW, Thrasher, AJ, Levine, AP, Sadeghi-Alavijeh, O, Wong, EKS, Cook, HT, Chan, MMY, Hall, M, Harris, C, McAlinden, P, Marchbank, KJ, Marks, S, Maxwell, H, Mozere, M, Wessels, J, Johnson, SA, Bleda, M, Hadinnapola, C, Haimel, M, Swietlik, E, Bogaard, H, Church, C, Coghlan, G, Condliffe, R, Corris, P, Danesino, C, Eyries, M, Gall, H, Ghofrani, H-A, Gibbs, JSR, Girerd, B, Holden, S, Houweling, A, Howard, LS, Humbert, M, Kiely, DG, Kovacs, G, Lawrie, A, Ross, RVM, Moledina, S, Montani, D, Newnham, M, Olschewski, A, Olschewski, H, Peacock, A, Pepke-Zaba, J, Scelsi, L, Seeger, W, Soubrier, F, Suntharalingam, J, Toshner, M, Treacy, C, Trembath, R, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Wilkins, MR, Wort, SJ, Graf, S, Louka, E, Roy, NB, Rao, A, Ancliff, P, Babbs, C, Layton, DM, Mead, AJ, O'Sullivan, J, Okoli, S, Saleem, M, Bierzynska, A, Diz, CB, Colby, E, Ekani, MN, Satchell, S, Fowler, T, Rendon, A, Scott, R, Smedley, D, Thomas, E, Caulfield, M, Abbs, S, Burrows, N, Chitre, M, Gattens, M, Gurnell, M, Kelsall, W, Poole, KES, Ross-Russell, R, Spasic-Boskovic, O, Twiss, P, Wagner, A, Banka, S, Clayton-Smith, J, Douzgou, S, Abulhoul, L, Aurora, P, Bockenhauer, D, Cleary, M, Dattani, M, Ganesan, V, Pilkington, C, Rahman, S, Shah, N, Wedderburn, L, Compton, CJ, Deshpande, C, Fassihi, H, Haque, E, Josifova, D, Mohammed, SN, Robert, L, Rose, SJ, Ruddy, DM, Sarkany, RN, Sayer, G, Shaw, AC, Campbell, C, Gibson, K, Koelling, N, Lester, T, Nemeth, AH, Palles, C, Patel, S, Sen, A, Taylor, J, Tomlinson, IP, Malka, S, Browning, AC, Burn, J, De Soyza, A, Graham, J, Pearce, S, Quinton, R, Schaefer, AM, Wilson, BT, Wright, M, Simpson, M, Syrris, P, Bradley, JR, Turro, E, ARD - Amsterdam Reproduction and Development, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Medical Research Council (MRC), Wellcome Trust, Wei, Wei [0000-0002-2945-3543], Tuna, Salih [0000-0003-3606-4367], Smith, Katherine R [0000-0002-0329-5938], Beales, Phil L [0000-0002-9164-9782], Bennett, David L [0000-0002-7996-2696], Gale, Daniel P [0000-0002-9170-1579], Brennan, Paul [0000-0003-1128-6254], Elliott, Perry [0000-0003-3383-3984], Floto, R Andres [0000-0002-2188-5659], Houlden, Henry [0000-0002-2866-7777], Koziell, Ania [0000-0003-4882-0246], Maher, Eamonn R [0000-0002-6226-6918], Markus, Hugh S [0000-0002-9794-5996], Morrell, Nicholas W [0000-0001-5700-9792], Newman, William G [0000-0002-6382-4678], Sayer, John A [0000-0003-1881-3782], Smith, Kenneth GC [0000-0003-3829-4326], Taylor, Jenny C [0000-0003-3602-5704], Watkins, Hugh [0000-0002-5287-9016], Webster, Andrew R [0000-0001-6915-9560], Wilkie, Andrew OM [0000-0002-2972-5481], Penkett, Christopher J [0000-0003-4006-7261], Stirrups, Kathleen E [0000-0002-6823-3252], Rendon, Augusto [0000-0001-8994-0039], Bradley, John R [0000-0002-7774-8805], Turro, Ernest [0000-0002-1820-6563], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Non-Mendelian inheritance, Genome, Mitochondrial/genetics, DNA, Mitochondrial/genetics, 0302 clinical medicine, Ovum/growth & development, MTDNA, TRANSCRIPTION, Genetics, education.field_of_study, Multidisciplinary, NIHR BioResource–Rare Diseases, ASSOCIATION, Heteroplasmy, Mitochondrial, Multidisciplinary Sciences, GENOME, REPLACEMENT, Science & Technology - Other Topics, Female, Maternal Inheritance, Mitochondrial DNA, General Science & Technology, Genetic genealogy, Population, Biology, Human mitochondrial genetics, SEQUENCE, DNA, Mitochondrial, 03 medical and health sciences, Genetic, 100,000 Genomes Project–Rare Diseases Pilot, Genetic variation, MD Multidisciplinary, Humans, Selection, Genetic, education, Selection, Ovum, Science & Technology, MUTATIONS, Genetic Variation, DNA, LEIGH-DISEASE, 030104 developmental biology, REPLICATION, Genome, Mitochondrial, HETEROPLASMY, 030217 neurology & neurosurgery
Abstract

INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.

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

Author

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

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

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

Published
2017

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

Author

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

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

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

Published
2016

7. A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss

Author

Simon Stritt, Michael Laffan, Salih Tuna, Sylvia Richardson, David J. Perry, F. Lucy Raymond, Sjoert B. G. Jansen, Myrto Kostadima, Tadbir K. Bariana, Ilenia Simeoni, Steve Austin, Andrew D Mumford, Carolyn M. Millar, Christopher J. Penkett, Sandrine Marlin, Wendy N. Erber, Sol Schulman, William J. Astle, Keith Gomez, Bernhard Nieswandt, Rémi Favier, Sofia Papadia, Claire Lentaigne, Augusto Rendon, Sofie Ashford, Michele P. Lambert, Stephanie Maiwald, Tamam Bakchoul, Peter William Collins, Chris Van Geet, Ernest Turro, Paquita Nurden, Anne M. Kelly, Mary Mathias, Romina Petersen, Rutendo Mapeta, Jonathan Stephens, Daniel Greene, Sarah K Westbury, Chantal Thys, Kathleen Freson, Willem H. Ouwehand, Alan T. Nurden, Kathleen Stirrups, John Bradley, Turro Bassols, Ernest [0000-0002-1820-6563], Astle, William [0000-0001-8866-6672], Papadia, Sofia [0000-0002-9222-3812], Stephens, Jonathan [0000-0003-2020-9330], Tuna, Salih [0000-0003-3606-4367], Simeoni, Ilenia [0000-0001-5039-2194], Johnson, Kathleen [0000-0002-6823-3252], Rendon Restrepo, Augusto [0000-0001-8994-0039], Bradley, John [0000-0002-7774-8805], Raymond, Lucy [0000-0003-2652-3355], Richardson, Sylvia [0000-0003-1998-492X], Ouwehand, Willem [0000-0002-7744-1790], Apollo - University of Cambridge Repository, Medical Research Council (MRC), and Medical Research Council

Subjects
0301 basic medicine, Male, Candidate gene, 030204 cardiovascular system & hematology, Biochemistry, 0302 clinical medicine, Inside BLOOD Commentary, Platelet, DIAPH1, Cytoskeleton, Child, Exome sequencing, Cells, Cultured, Genetics, Cardiovascular Medicine And Haematology, Hematology, Syndrome, Middle Aged, Cell biology, Pedigree, Formins, Sensorineural hearing loss, Female, Adult, Adolescent, Clinical Sciences, Immunology, Biology, Filamentous actin, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, medicine, Humans, Genetic Predisposition to Disease, Hearing Loss, Genetic Association Studies, Adaptor Proteins, Signal Transducing, Aged, BRIDGE-BPD Consortium, Cell Biology, medicine.disease, Thrombocytopenia, 030104 developmental biology, HEK293 Cells, A549 Cells, Case-Control Studies, Mutation, biology.protein, Paediatrics And Reproductive Medicine
Abstract

Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MK). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping and similarity regression. We describe two unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 p.R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was associated with reduced proplatelet formation from cultured MKs, cell clustering and abnormal cortical filamentous actin. Similarly, in platelets there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Over-expression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insights into the autoregulation of DIAPH1 activity.

Published
2015

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