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1. Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations

Author

Adhya, Zoe, Alachkar, Hana, Anantharachagan, Ariharan, Antrobus, Richard, Arumugakani, Gururaj, Ashford, Sofie, Astle, William J., Attwood, Anthony, Bacchelli, Chiara, Batista, Joana, Baxendale, Helen E., Bethune, Claire, Bibi, Shahnaz, Bleda, Marta, Boardman, Barbara, Booth, Claire, Bradley, John R., Breen, Gerome, Brown, Matthew, Browning, Michael J., Brownlie, Mary, Buckland, Matthew S., Burns, Siobhan O., Burren, Oliver S., Carss, Keren, Chambers, John, Chandra, Anita, Brod, Naomi Clements, Clifford, Hayley, Cooper, Nichola, Daugherty, Louise C., Davies, E.G., Davies, Sophie, Davis, John, Deacock, Sarah, Deevi, Sri V.V., Dempster, John, Devlin, Lisa A., Dewhurst, Eleanor F., Downes, Kate, Drewe, Elizabeth, Duarte, Daniel, Edgar, J. David M., Edwards, Karen, Egner, William, El-Shanawany, Tariq, Erwood, Marie, Fletcher, Debra, Fox, James, Frary, Amy J., Frontini, Mattia, Furnell, Abigail, Gaspar, H. Bobby, Ghurye, Rohit, Gilmour, Kimberly C., Gleadall, Nicholas S., Goddard, Sarah, Gordins, Pavels, Gräf, Stefan, Grassi, Luigi, Greene, Daniel, Grigoriadou, Sofia, Hackett, Scott, Hague, Rosie, Haimel, Matthias, Harper, Lorraine, Hayman, Grant, Herwadkar, Archana, Hu, Fengyuan, Hughes, Stephen, Huissoon, Aarnoud P., James, Roger, Jolles, Stephen, Jolley, Jennifer, Jones, Julie, Karim, Yousuf, Kasanicki, Mary A., Kelleher, Peter, Kempster, Carly, Kiani, Sorena, Kingston, Nathalie, Klein, Nigel, Kostadima, Myrto, Kreuzhuber, Roman, Kuijpers, Taco W., Kumararatne, Dinakantha, Laffan, James, Allen, Hana Lango, Lear, Sara E., Linger, Rachel, Longhurst, Hilary, Lorenzo, Lorena E., Lyons, Paul A., Maimaris, Jesmeen, Manson, Ania, Mapeta, Rutendo, Martin, Jennifer, McCarthy, Mark I., McDermott, Elizabeth M., McKinney, Harriet, Meacham, Stuart, Megy, Karyn, Millar, Hazel, Mistry, Anoop, Morrisson, Valerie, Murng, Sai H.K., Nasir, Iman, Nejentsev, Sergey, Noorani, Sadia, Oksenhendler, Eric, Ouwehand, Willem H., Papadia, Sofia, Penkett, Christopher J., Petersen, Romina, Ponsford, Mark J., Qasim, Waseem, Quinn, Ellen, Quinti, Isabella, Raymond, F. Lucy, Rayner-Matthews, Paula J., Richter, Alex, Samani, Nilesh, Samarghitean, Crina, Sanchis-Juan, Alba, Sargur, Ravishankar B., Savic, Sinisa, Seneviratne, Suranjith L., Sewell, W.A. Carrock, Seyres, Denis, Shackley, Fiona, Shamardina, Olga, Simeoni, Ilenia, Simpson, Michael A., Smith, Kenneth G.C., Staines, Simon, Staples, Emily, Stark, Hannah, Stauss, Hans, Steele, Cathal L., Stephens, Jonathan, Stirrups, Kathleen E., Thaventhiran, James E., Thomas, David, Thomas, Moira J., Thomas, Patrick, Thrasher, Adrian J., Tilly, Tobias, Titterton, Catherine, Treadaway, Paul, Tuna, Salih, Turro, Ernest, Urniaz, Rafal, von Ziegenweidt, Julie, Walker, Neil, Watt, Christopher, Welch, Steven B., Whitehorn, Deborah, Willcocks, Lisa, Wood, Nicholas, Wood, Yvette, Workman, Sarita, Worth, Austen, Yates, Katherine, Yeatman, Nigel, Yong, Patrick F.K., Young, Timothy, Yu, Ping, Zlamalova, Eliska, 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., Schröder, Claudia, Stepensky, Polina, Shadur, Bella, Pedroza, Luis A., van der Flier, Michiel, Martínez-Gallo, Mónica, Gonzalez-Granado, Luis Ignacio, Allende, Luis M., Shcherbina, Anna, Kuzmenko, Natalia, Zakharova, Victoria, Neves, João Farela, Svec, Peter, Fischer, Ute, Ip, Winnie, Bartsch, Oliver, Barış, 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, Deyà-Martínez, Angela, Slade, Charlotte A., Aghamohammadi, Asghar, Abolhassani, Hassan, Hammarström, Lennart, Kuismin, Outi, Helminen, Merja, Freeman, Alexandra F., Cook, Matthew, Bakhtiar, Shahrzad, Christiansen, Mette, Cunningham-Rundles, Charlotte, Patel, Niraj C., Rae, William, Niehues, Tim, Brauer, Nina, Syrjänen, Jaana, Seppänen, Mikko R.J., Tuijnenburg, Paul, Warnatz, Klaus, and Grimbacher, Bodo

Published
2020
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2. Whole-genome sequencing of patients with rare diseases in a national health system

Author

Turro, Ernest, Astle, William J., Megy, Karyn, Gräf, Stefan, Greene, Daniel, Shamardina, Olga, Allen, Hana Lango, Sanchis-Juan, Alba, Frontini, Mattia, Thys, Chantal, Stephens, Jonathan, Mapeta, Rutendo, Burren, Oliver S., Downes, Kate, Haimel, Matthias, Tuna, Salih, Deevi, Sri V.V., Aitman, Timothy J., Bennett, David L., Calleja, Paul, Carss, Keren, Caulfield, Mark J., Chinnery, Patrick F., Dixon, Peter H., Gale, Daniel P., James, Roger, Koziell, Ania, Laffan, Michael A., Levine, Adam P., Maher, Eamonn R., Markus, Hugh S., Morales, Joannella, Morrell, Nicholas W., Mumford, Andrew D., Ormondroyd, Elizabeth, Rankin, Stuart, Rendon, Augusto, Richardson, Sylvia, Roberts, Irene, Roy, Noemi B.A., Saleem, Moin A., Smith, Kenneth G.C., Stark, Hannah, Tan, Rhea Y.Y., Themistocleous, Andreas C., Thrasher, Adrian J., Watkins, Hugh, Webster, Andrew R., Wilkins, Martin R., Williamson, Catherine, Whitworth, James, Humphray, Sean, Bentley, David R., Abbs, Stephen, Abulhoul, Lara, Adlard, Julian, Ahmed, Munaza, Alachkar, Hana, Allsup, David J., Almeida-King, Jeff, Ancliff, Philip, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Ashford, Sofie, Attwood, Anthony, Aurora, Paul, Babbs, Christian, Bacchelli, Chiara, Bakchoul, Tamam, Banka, Siddharth, Bariana, Tadbir, Barwell, Julian, Batista, Joana, Baxendale, Helen E., Beales, Phil L., Bierzynska, Agnieszka, Biss, Tina, Bitner-Glindzicz, Maria A.K., Black, Graeme C., Bleda, Marta, Blesneac, Iulia, Bockenhauer, Detlef, Bogaard, Harm, Bourne, Christian J., Boyce, Sara, Bradley, John R., Bragin, Eugene, Breen, Gerome, Brennan, Paul, Brewer, Carole, Brown, Matthew, Browning, Andrew C., Browning, Michael J., Buchan, Rachel J., Buckland, Matthew S., Bueser, Teofila, Diz, Carmen Bugarin, Burn, John, Burns, Siobhan O., Burrows, Nigel, Campbell, Carolyn, Carr-White, Gerald, Casey, Ruth, Chambers, Jenny, Chambers, John, Chan, Melanie M.Y., Cheah, Calvin, Cheng, Floria, Chitre, Manali, Christian, Martin T., Church, Colin, Clayton-Smith, Jill, Cleary, Maureen, Brod, Naomi Clements, Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor R.P., Collins, Janine, Collins, Peter W., Colombo, Camilla, Compton, Cecilia J., Condliffe, Robin, Cook, Stuart, Cook, H. Terence, Cooper, Nichola, Corris, Paul A A., Furnell, Abigail, Cunningham, Fiona, Curry, Nicola S., Cutler, Antony J., Daniels, Matthew J., Dattani, Mehul, Daugherty, Louise C., Davis, John, De Soyza, Anthony, Dent, Timothy, Deshpande, Charu, Dewhurst, Eleanor F., Douzgou, Sofia, Drazyk, Anna M., Drewe, Elizabeth, Duarte, Daniel, Dutt, Tina, Edgar, J. David M., Edwards, Karen, Egner, William, Ekani, Melanie N., Elliott, Perry, Erber, Wendy N., Erwood, Marie, Estiu, Maria C., Evans, Dafydd Gareth, Evans, Gillian, Everington, Tamara, Eyries, Mélanie, Fassihi, Hiva, Favier, Remi, Findhammer, Jack, Fletcher, Debra, Flinter, Frances A., Floto, R. Andres, Fowler, Tom, Fox, James, Frary, Amy J., French, Courtney E., Freson, Kathleen, Gall, Henning, Ganesan, Vijeya, Gattens, Michael, Geoghegan, Claire, Gerighty, Terence S.A., Gharavi, Ali G., Ghio, Stefano, Ghofrani, Hossein Ardeschir, Gibbs, J. Simon R., Gibson, Kate, Gilmour, Kimberly C., Girerd, Barbara, Gleadall, Nicholas S., Goddard, Sarah, Goldstein, David B., Gomez, Keith, Gordins, Pavels, Gosal, David, Graham, Jodie, Grassi, Luigi, Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip, Grigoriadou, Sofia, Grocock, Russell J., Grozeva, Detelina, Gurnell, Mark, Hackett, Scott, Hadinnapola, Charaka, Hague, William M., Hague, Rosie, Hall, Matthew, Hanson, Helen L., Haque, Eshika, Harkness, Kirsty, Harper, Andrew R., Harris, Claire L L., Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Henderson, Alex, Herwadkar, Archana, Hoffman, Jonathan, Holden, Simon, Horvath, Rita, Houlden, Henry, Houweling, Arjan C C., Howard, Luke S., Hu, Fengyuan, Hudson, Gavin, Hughes, Joseph, Huissoon, Aarnoud P., Humbert, Marc, Hunter, Sarah, Hurles, Matthew, Irving, Melita, Izatt, Louise, Johnson, Sally A., Jolles, Stephen, Jolley, Jennifer, Josifova, Dragana, Jurkute, Neringa, Karten, Tim, Karten, Johannes, Kasanicki, Mary A., Kazkaz, Hanadi, Kazmi, Rashid, Kelleher, Peter, Kelly, Anne M., Kelsall, Wilf, Kempster, Carly, Kiely, David G., Kingston, Nathalie, Klima, Robert, Koelling, Nils, Kostadima, Myrto, Kovacs, Gabor, Kreuzhuber, Roman, Kuijpers, Taco W., Kumar, Ajith, Kumararatne, Dinakantha, Kurian, Manju A., Lalloo, Fiona, Lambert, Michele, Lawrie, Allan, Layton, D. Mark, Lench, Nick, Lentaigne, Claire, Lester, Tracy, Linger, Rachel, Longhurst, Hilary, Lorenzo, Lorena E., Louka, Eleni, Lyons, Paul A., Machado, Rajiv D., MacKenzie Ross, Robert V., Madan, Bella, Maimaris, Jesmeen, Malka, Samantha, Mangles, Sarah, Marchbank, Kevin J., Marks, Stephen, Marschall, Hanns Ulrich, Marshall, Andrew, Martin, Jennifer, Mathias, Mary, Matthews, Emma, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark I., McKinney, Harriet, McMahon, Aoife, Meacham, Stuart, Mead, Adam J., Castello, Ignacio Medina, Mehta, Sarju G G., Michaelides, Michel, Millar, Carolyn, Mohammed, Shehla N., Moledina, Shahin, Montani, David, Moore, Anthony T., Mozere, Monika, Muir, Keith W., Nemeth, Andrea H., Newman, William G., Newnham, Michael, Noorani, Sadia, Nurden, Paquita, O’Sullivan, Jennifer, Obaji, Samya, Odhams, Chris, Okoli, Steven, Olschewski, Andrea, Olschewski, Horst, Ong, Kai Ren, Oram, S. Helen, Ouwehand, Willem H., Palles, Claire, Papadia, Sofia, Park, Soo Mi, Parry, David, Patel, Smita, Paterson, Joan, Peacock, Andrew, Pearce, Simon H H., Peden, John, Peerlinck, Kathelijne, Penkett, Christopher J., Pepke-Zaba, Joanna, Petersen, Romina, Pilkington, Clarissa, Poole, Kenneth E.S., Prathalingam, Radhika, Psaila, Bethan, Pyle, Angela, Quinton, Richard, Rahman, Shamima, Rao, Anupama, Raymond, F. Lucy, Rayner-Matthews, Paula J., Rees, Christine, Renton, Tara, Rhodes, Christopher J., Rice, Andrew S.C., Richter, Alex, Robert, Leema, Rogers, Anthony, Rose, Sarah J., Ross-Russell, Robert, Roughley, Catherine, Roy, Noemi B. A, Ruddy, Deborah M., Sadeghi-Alavijeh, Omid, Samani, Nilesh, Samarghitean, Crina, Sargur, Ravishankar B., Sarkany, Robert N., Satchell, Simon, Savic, Sinisa, Sayer, John A., Sayer, Genevieve, Scelsi, Laura, Schaefer, Andrew M., Schulman, Sol, Scott, Richard, Scully, Marie, Searle, Claire, Seeger, Werner, Sen, Arjune, Sewell, W. A.Carrock, Seyres, Denis, Shah, Neil, Shapiro, Susan E., Shaw, Adam C., Short, Patrick J., Sibson, Keith, Side, Lucy, Simeoni, Ilenia, Simpson, Michael A A., Sims, Matthew C., Sivapalaratnam, Suthesh, Smedley, Damian, Smith, Katherine R., Snape, Katie, Soranzo, Nicole, Soubrier, Florent, Southgate, Laura, Spasic-Boskovic, Olivera, Staines, Simon, Staples, Emily, Steward, Charles, Stirrups, Kathleen E., Stuckey, Alex, Suntharalingam, Jay, Swietlik, Emilia M., Syrris, Petros, Tait, R. Campbell, Talks, Kate, Tate, Katie, Taylor, John M., Taylor, Jenny C., Thaventhiran, James E., Thomas, Ellen, Thomas, David, Thomas, Moira J., Thomas, Patrick, Thomson, Kate, Threadgold, Glen, Tilly, Tobias, Tischkowitz, Marc, Titterton, Catherine, Todd, John A., Toh, Cheng Hock, Tolhuis, Bas, Tomlinson, Ian P., Toshner, Mark, Traylor, Matthew, Treacy, Carmen, Treadaway, Paul, Trembath, Richard, Turek, Wojciech, Twiss, Philip, Vale, Tom, Geet, Chris Van, Zuydam, Natalie van, Vandekuilen, Maarten, Vandersteen, Anthony M., Vazquez-Lopez, Marta, von Ziegenweidt, Julie, Vonk Noordegraaf, Anton, Wagner, Annette, Waisfisz, Quinten, Walker, Suellen M., Walker, Neil, Walter, Klaudia, Ware, James S., Watt, Christopher, Wedderburn, Lucy, Wei, Wei, Welch, Steven B., Wessels, Julie, Westbury, Sarah K., Westwood, John Paul, Wharton, John, Whitehorn, Deborah, Wilkie, Andrew O. M, Wilson, Brian T., Wong, Edwin K.S., Wood, Nicholas, Wood, Yvette, Woods, Christopher Geoffrey, Woodward, Emma R R., Wort, Stephen J., Worth, Austen, Wright, Michael, Yates, Katherine, Yong, Patrick F.K., Young, Timothy, Yu, Ping, Yu-Wai-Man, Patrick, Zlamalova, Eliska, University of Cambridge [UK] (CAM), John Wyeth & Brother Limited, Medical Research Council (MRC), Wellcome Trust, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, and Project, NIHR BioResource for the 100,000 Genomes

Subjects
0301 basic medicine, Erythrocytes, Internationality, Databases, Factual, National Health Programs, [SDV]Life Sciences [q-bio], Disease, VARIANTS, Genome, State Medicine, NIHR BioResource for the 100,000 Genomes Project, 0302 clinical medicine, Medicine, GATA1 Transcription Factor, Genetics, Multidisciplinary, Translational bioinformatics, ASSOCIATION, 3. Good health, Multidisciplinary Sciences, Phenotype, 030220 oncology & carcinogenesis, disease genetics, Medical genetics, Science & Technology - Other Topics, Receptors, Thrombopoietin, medicine.medical_specialty, General Science & Technology, Quantitative Trait Loci, Genomics, Computational biology, Biology, DIAGNOSIS, computational biology and bioinformatics, Actin-Related Protein 2-3 Complex, Article, LRBA, LINKS, 03 medical and health sciences, Rare Diseases, Humans, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, National health, Science & Technology, Whole Genome Sequencing, MUTATIONS, business.industry, THROMBOCYTOPENIA, United Kingdom, MACROTHROMBOCYTOPENIA, genetics research, 030104 developmental biology, business, Rare disease
Abstract

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. 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 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that 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
2021
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3. Publisher Correction:Whole-genome sequencing of a sporadic primary immunodeficiency cohort (Nature, (2020), 583, 7814, (90-95), 10.1038/s41586-020-2265-1)

Author

Thaventhiran, James E.D., Lango Allen, Hana, Burren, Oliver S., Rae, William, Greene, Daniel, Staples, Emily, Zhang, Zinan, Farmery, James H.R., Simeoni, Ilenia, Rivers, Elizabeth, Maimaris, Jesmeen, Penkett, Christopher J., Stephens, Jonathan, Deevi, Sri V.V., Sanchis-Juan, Alba, Gleadall, Nicholas S., Thomas, Moira J., Sargur, Ravishankar B., Gordins, Pavels, Baxendale, Helen E., Brown, Matthew, Tuijnenburg, Paul, Worth, Austen, Hanson, Steven, Linger, Rachel J., Buckland, Matthew S., Rayner-Matthews, Paula J., Gilmour, Kimberly C., Samarghitean, Crina, Seneviratne, Suranjith L., Sansom, David M., Lynch, Andy G., Megy, Karyn, Ellinghaus, Eva, Ellinghaus, David, Jorgensen, Silje F., Karlsen, Tom H., Stirrups, Kathleen E., Cutler, Antony J., Kumararatne, Dinakantha S., Chandra, Anita, Edgar, J. David M., Herwadkar, Archana, Cooper, Nichola, Grigoriadou, Sofia, Huissoon, Aarnoud P., Goddard, Sarah, Jolles, Stephen, Schuetz, Catharina, Boschann, Felix, Abbs, Stephen, Adhya, Zoe, Adlard, Julian, Afzal, Maryam, Ahmed, Irshad, Ahmed, Munaza, Ahmed, Saeed, Aitman, Timothy J., Alachkar, Hana, Alamelu, Jayanthi, Alikhan, Raza, Allen, Carl E., Allen, Louise, Allsup, David J., Alvi, Arif, Ambegaonkar, Gautam, Anantharachagan, Ariharan, Ancliff, Philip, Anderson, Julie, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Arumugakani, Gururaj, Arya, Rita, Ashford, Sofie, Astle, William J., Attwood, Anthony, Austin, Steve, Aydinok, Yesim, Ayub, Waqar, Babbs, Christian, Bacchelli, Chiara, Baglin, Trevor, Bakchoul, Tamam, Bariana, Tadbir K., Barratt, Jonathan, Barwell, Julian, Baski, John, Bates, Rachel W., Batista, Joana, Baynam, Gareth, Bennett, David L., Bethune, Claire, Bhatnagar, Neha, Bibi, Shahnaz, Bierzynska, Agnieszka, Biss, Tina, Bitner-Glindzicz, Maria A.K., Bleda, Marta, Blesneac, Iulia, Boardman, Barbara, Boddana, Preetham, Bogaard, Harm J., Booth, Claire, Boyce, Sara, Bradley, John R., Brady, Angela, Breen, Gerome, Brennan, Paul, Brewer, Carole, Briley, Annette, Brown, Richard, Browning, Michael J., Brownlie, Mary, Bryson, Christine J., Buchan, Rachel J., Buck, Jackie, Bueser, Teofila, Diz, Carmen Bugarin, Burns, Siobhan O., Calleja, Paul, Carmichael, Jenny, Carr-White, Gerald, Carss, Keren J., Casey, Ruth, Chalmers, Elizabeth, Chambers, Jenny, Chambers, John, Chan, Melanie M.Y., Chan, Melissa V., Cheng, Floria, Chinn, Ivan K., Chinnery, Patrick F., Chitre, Manali, Chong, Sam, Christian, Martin T., Church, Colin, Clement, Emma M., Brod, Naomi Clements, Clifford, Hayley, Clowes, Virginia E., Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor R.P., Collins, Janine H., Collins, Peter W., Condliffe, Robin, Cook, H. Terence, Cook, Stuart, Cookson, Victoria, Corris, Paul A., Creaser-Myers, Amanda, Crisp-Hihn, Abigail, Curry, Nicola S., Da Costa, Rosa, Danesino, Cesare, Daniels, Matthew J., Darby, Damaris, Daugherty, Louise C., Davies, E. G., Davies, Sophie, Davis, John, de Bree, Godelieve J., Deacock, Sarah, Deegan, Patrick B., Dempster, John, Dent, Timothy, Deshpande, Charu, Devlin, Lisa A., Dewhurst, Eleanor F., Dixit, Anand K., Dixon, Peter H., Doffinger, Rainer, Dolling, Helen, Dormand, Natalie, Downes, Kate, Drazyk, Anna M., Drewe, Elizabeth, Duarte, Daniel, Dutt, Tina, Edwards, Karen E., Egner, William, Ekani, Melanie N., El-Shanawany, Tariq, Elkhalifa, Shuayb, Elston, Tony, Emmerson, Ingrid, Erber, Wendy N., Erwood, Marie, Estiu, Maria C., Evans, Dafydd Gareth, Evans, Gillian, Everington, Tamara, Eyries, Mélanie, Favier, Remi, Firth, Helen V., Fitzpatrick, Maggie M., Fletcher, Debra, Flinter, Frances A., Fox, James C., Frary, Amy J., French, Courtney E., Freson, Kathleen, Frontini, Mattia, Furie, Bruce, Gale, Daniel P., Gall, Henning J., Gardham, Alice, Gaspar, H. Bobby, Gattens, Michael, Ghali, Neeti, Ghataorhe, Pavandeep K., Ghio, Stefano, Ghofrani, Hossein Ardeschir, Ghurye, Rohit, Gibbs, J. Simon R., Gilbert, Rodney D., Girerd, Barbara, Girling, Joanna C., Gissen, Paul, Gorman, Kathleen M., Gosal, David, Graf, Stefan, Grassi, Luigi, Greenhalgh, Alan J., Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip G., Griffiths, Sian, Grozeva, Detelina, Hackett, Scott J., Hadden, Robert D.M., Hadinnapola, Charaka, Hague, Rosie, Hague, William M., Haimel, Matthias, Hall, Matthew, Halmagyi, Csaba, Hammerton, Tracey, Hanson, Helen L., Harkness, Kirsty, Harper, Andrew R., Harper, Lorraine, Harris, Claire, Harrison, Claire, Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Heemskerk, Johan W.M., Hegde, Shivaram, Henderson, Alex, Henderson, Robert H., Hensiek, Anke, Henskens, Yvonne M.C., Hodgson, Joshua, Hoffman, Jonathan, Holden, Simon, Holder, Muriel, Horvath, Rita, Houlden, Henry, Houweling, Arjan C., Howard, Luke S., Hu, Fengyuan, Hudson, Gavin, Hughes, Sean, Hughes, Stephen, Huis in ‘t Veld, Anna E., Humbert, Marc, Hurles, Matthew E., Hurst, Jane A., Irvine, Val, Izatt, Louise, James, Roger, Jeevaratnam, Praveen, Johnson, Mark, Johnson, Sally A., Jolley, Jennifer D., Jones, Bryony, Jones, Julie, Josifova, Dragana, Jurkute, Neringa, Karim, Yousuf M., Karoshi, Mahantesh A., Kasanicki, Mary A., Kazkaz, Hanadi, Kazmi, Rashid, Keeling, David, Kelleher, Peter, Kelly, Anne M., Kempster, Carly, Kennedy, Fiona, Kiani, Sorena, Kiely, David G., Kingston, Nathalie, Kinsey, Sally, Klein, Nigel, Klima, Robert, Knox, Ellen, Kostadima, Myrto A., Kovacs, Gabor, Koziell, Ania B., Kreuzhuber, Roman, Krishnakumar, Deepa, Kuijpers, Taco W., Kumar, Ajith, Kurian, Manju A., Laffan, James, Laffan, Michael A., Lalloo, Fiona, Lambert, Michele P., Lawman, Sarah H.A., Lawrie, Allan, Layton, D. Mark, Lear, Sara E., Lees, Melissa M., Lentaigne, Claire, Levine, Adam P., Lewington, Andrew J.P., Li, Wei, Liesner, Ri, Liu, Bin, Longhurst, Hilary, Lorenzo, Lorena E., Louka, Eleni, Hadeler, Silvia Lucato, Lyons, Paul A., Macdougall, Malcolm, Machado, Rajiv D., MacKenzie Ross, Robert V., Mackillop, Lucy H., MacLaren, Robert, Madan, Bella, Magee, Laura, Mahdi-Rogers, Mohamed, Maher, Eamonn R., Makris, Mike, Mangles, Sarah, Manson, Ania, Manzur, Adnan, Mapeta, Rutendo, Marchbank, Kevin J., Mark, Patrick B., Marks, Stephen, Markus, Hugh S., Marschall, Hanns Ulrich, Marshall, Andrew, Martin, Jennifer M., Masati, Larahmie, Mathias, Mary, Matser, Vera, Matthews, Emma L., Maw, Anna, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark I., McDermott, Elizabeth M., McGowan, Simon J., McJannet, Coleen, McKinney, Harriet, Meacham, Stuart, Mead, Adam J., Castello, Ignacio Medina, Meehan, Sharon, Mehta, Sarju, Mercer, Catherine L., Michaelides, Michel, Michell, Anna C., Milford, David, Millar, Carolyn M., Millar, Hazel, Mistry, Anoop, Moenen, Floor, Moledina, Shahin, Montani, David, Moore, Anthony T., Moore, Jason, Morrell, Nicholas W., Morrisson, Valerie, Mozere, Monika, Muir, Keith W., Mumford, Andrew D., Murng, Sai H.K., Nasir, Iman, Nejentsev, Sergey, Newnham, Michael, Ng, Joanne, Ngoh, Adeline, Noorani, Sadia, Noori, Muna, Nurden, Paquita, O’Sullivan, Jennifer M., Obaji, Samya, Okoli, Steven, Oksenhendler, Eric, Olschewski, Andrea, Olschewski, Horst, Ong, Albert C.M., Ong, Kai Ren, Oram, Helen, Ormondroyd, Elizabeth, Othman, Shokri, Ouwehand, Willem H., Pantazis, Antonis, Papadia, Sofia, Papandreou, Apostolos, Park, Soo Mi, Parker, Alasdair P.J., Parry, David, Parsons, Georgina, Pasi, K. John, Paterson, Joan, Payne, Jeanette H., Peacock, Andrew J., Peerlinck, Kathelijne, Pepke-Zaba, Joanna, Perry, David, Petersen, Romina, Piechowski-Jozwiak, Bartlomiej, Pinto, Fernando, Polwarth, Gary J., Ponsford, Mark J., Prasad, Sanjay, Prokopenko, Inga, Psaila, Beth, Pyle, Angela, Qasim, Waseem, Quinn, Ellen, Quinti, Isabella, Raina, Sanjay, Ranganathan, Lavanya, Rankin, Julia, Rankin, Stuart, Rao, Anupama, Raymond, F. Lucy, Rehnstrom, Karola, Reid, Evan, Reilly, Mary M., Renton, Tara, Revel-Vilk, Shoshana, Rhodes, Christopher J., Rice, Andrew S.C., Richards, Emma E., Richards, Mike, Richardson, Sylvia, Richter, Alex, Robert, Leema, Roberts, Irene, Rondina, Matthew T., Rosser, Elisabeth, Rothwell, Peter, Roughley, Catherine, Roy, Noemi B., Rue-Albrecht, Kevin, Sadeghi-Alavijeh, Omid, Saleem, Moin A., Salmon, Richard M., Samani, Nilesh J., Sambrook, Jennifer G., Sandford, Richard, Santra, Saikat, Satchell, Simon C., Savic, Sinisa, Scelsi, Laura, Schotte, Gwen, Schulman, Sol, Schulze, Harald, Scott, Richard, Scully, Marie, Searle, Claire, Seeger, Werner, Sewell, W. A.Carrock, Seyres, Denis, Shackley, Fiona, Shamardina, Olga, Shapiro, Susan E., Sharma, Pankaj, Shehata, Hassan A., Shipley, Deborah, Shtoyerman, Rakefet, Sibson, Keith, Side, Lucy, Simpson, Michael, Sims, Matthew C., Sinha, Manish D., Sivapalaratnam, Suthesh, Skytte, Anne Bine, Smith, Kenneth G.C., Snape, Katie, Sneddon, Linda, Sohal, Aman, Soubrier, Florent, Southgate, Laura, Southwood, Mark, Splitt, Miranda, Staines, Simon, Stark, Hannah, Stauss, Hans, Steele, Cathal L., Stein, Daniel, Stein, Penelope E., Stock, Sophie, Stubbs, Matthew J., Suntharalingam, Jay, Swietlik, Emilia M., Symington, Emily, Tait, R. Campbell, Talks, Kate, Tan, Rhea Y.Y., Taylor, Gordon B., Thachil, Jecko, Themistocleous, Andreas C., Thomas, David C., Thomas, Ellen, Thomas, Patrick, Thompson, Dorothy A., Thomson, Kate, Thrasher, Adrian J., Thys, Chantal, Tilly, Tobias, Tischkowitz, Marc, Titterton, Catherine, Todd, John A., Toh, Cheng Hock, Tool, Anton T.J., Toshner, Mark R., Traylor, Matthew, Treacy, Carmen M., Treadaway, Paul, Trembath, Richard C., Trippier, Sarah, Tuna, Salih, Turek, Wojciech, Turro, Ernest, Upton, Paul D., Urniaz, Rafal, Vale, Tom, Van Geet, Chris, van Zuydam, Natalie, Vandersteen, Anthony M., Vazquez-Lopez, Marta, Veltman, Marijcke W.M., Vogt, Julie, von Ziegenweidt, Julie, Noordegraaf, Anton Vonk, Vora, Ajay, Vries, Minka J.A., Wakeling, Emma L., Walker, Neil, Walker, Suellen M., Walsh, Roddy, Wanjiku, Ivy, Ware, James S., Warner, Timothy Q., Wassmer, Evangeline, Watkins, Hugh, Watson, Henry G., Watt, Christopher, Waugh, Dean, Webb, Nick, Webster, Andrew R., Wei, Wei, Welch, Angela, Welch, Steven B., Werring, David, Wessels, Julie, Westbury, Sarah K., Westwood, John Paul W., Wharton, John, Whitehorn, Deborah, Whitworth, James, Wilkins, Martin R., Willcocks, Lisa, Williams, David J., Williamson, Catherine, Wong, Edwin K.S., Wood, Nicholas, Wood, Yvette, Woods, Christopher Geoffrey, Woodward, Emma R., Workman, Sarita, Wort, Stephen J., Yates, Katherine, Yeatman, Nigel, Yong, Patrick F.K., Young, Timothy, Yu, Ping, Yu-Wai-Man, Patrick, Zlamalova, Eliska, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
Full Text
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4. Whole-genome sequencing of a sporadic primary immunodeficiency cohort

Author

Thaventhiran, James E. D., Lango Allen, Hana, Burren, Oliver S., Rae, William, Greene, Daniel, Staples, Emily, Zhang, Zinan, Farmery, James H. R., Simeoni, Ilenia, Rivers, Elizabeth, Maimaris, Jesmeen, Penkett, Christopher J., Stephens, Jonathan, Deevi, Sri V. V., Sanchis-Juan, Alba, Gleadall, Nicholas S., Thomas, Moira J., Sargur, Ravishankar B., Gordins, Pavels, Baxendale, Helen E., Brown, Matthew, Tuijnenburg, Paul, Worth, Austen, Hanson, Steven, Linger, Rachel J., Buckland, Matthew S., Rayner-Matthews, Paula J., Gilmour, Kimberly C., Samarghitean, Crina, Seneviratne, Suranjith L., Sansom, David M., Lynch, Andy G., Megy, Karyn, Ellinghaus, Eva, Ellinghaus, David, Jorgensen, Silje F., Karlsen, Tom H., Stirrups, Kathleen E., Cutler, Antony J., Kumararatne, Dinakantha S., Chandra, Anita, Edgar, J. David M., Herwadkar, Archana, Cooper, Nichola, Grigoriadou, Sofia, Huissoon, Aarnoud P., Goddard, Sarah, Jolles, Stephen, Schuetz, Catharina, Boschann, Felix, Lyons, Paul A., Hurles, Matthew E., Savic, Sinisa, Burns, Siobhan O., Kuijpers, Taco W., Turro, Ernest, Ouwehand, Willem H., Thrasher, Adrian J., Smith, Kenneth G. C., Tait, R. Campbell, Chalmers, Elizabeth, Hague, Rosie, Maxwell, Heather, Peacock, Andrew J., Mark, Patrick B., and Muir, Keith W.

Abstract

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most 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 malignancies1,2,3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization 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 the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.

Published
2020

5. Whole-genome sequencing of patients with rare diseases in a national health system

Author

Turro, Ernest, Astle, William J., Megy, Karyn, Gräf, Stefan, Greene, Daniel, Shamardina, Olga, Allen, Hana Lango, Sanchis-Juan, Alba, Frontini, Mattia, Thys, Chantal, Stephens, Jonathan, Mapeta, Rutendo, Burren, Oliver S., Downes, Kate, Haimel, Matthias, Tuna, Salih, Deevi, Sri V. V., Aitman, Timothy J., Bennett, David L., Calleja, Paul, Carss, Keren, Caulfield, Mark J., Chinnery, Patrick F., Dixon, Peter H., Gale, Daniel P., James, Roger, Koziell, Ania, Laffan, Michael A., Levine, Adam P., Maher, Eamonn R., Markus, Hugh S., Morales, Joannella, Morrell, Nicholas W., Mumford, Andrew D., Ormondroyd, Elizabeth, Rankin, Stuart, Rendon, Augusto, Richardson, Sylvia, Roberts, Irene, Roy, Noemi B. A., Saleem, Moin A., Smith, Kenneth G. C., Stark, Hannah, Tan, Rhea Y. Y., Themistocleous, Andreas C., Thrasher, Adrian J., Watkins, Hugh, Webster, Andrew R., Wilkins, Martin R., Williamson, Catherine, Whitworth, James, Humphray, Sean, Bentley, David R., Kingston, Nathalie, Walker, Neil, Bradley, John R., Ashford, Sofie, Penkett, Christopher J., Freson, Kathleen, Stirrups, Kathleen E., Raymond, F. Lucy, Ouwehand, Willem H., Peacock, Andrew, Hague, Rosie, Maxwell, Heather, Muir, Keith W., Tait, R. Campbell, and Thomas, Moira J.

Abstract

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. 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 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that 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
2020

6. Bayesian Inference Associates Rare KDR Variants With Specific Phenotypes in Pulmonary Arterial Hypertension

Author

Swietlik, Emilia M., primary, Greene, Daniel, additional, Zhu, Na, additional, Megy, Karyn, additional, Cogliano, Marcella, additional, Rajaram, Smitha, additional, Pandya, Divya, additional, Tilly, Tobias, additional, Lutz, Katie A., additional, Welch, Carrie C.L., additional, Pauciulo, Michael W., additional, Southgate, Laura, additional, Martin, Jennifer M., additional, Treacy, Carmen M., additional, Penkett, Christopher J., additional, Stephens, Jonathan C., additional, Bogaard, Harm J., additional, Church, Colin, additional, Coghlan, Gerry, additional, Coleman, Anna W., additional, Condliffe, Robin, additional, Eichstaedt, Christina A., additional, Eyries, Mélanie, additional, Gall, Henning, additional, Ghio, Stefano, additional, Girerd, Barbara, additional, Grünig, Ekkehard, additional, Holden, Simon, additional, Howard, Luke, additional, Humbert, Marc, additional, Kiely, David G., additional, Kovacs, Gabor, additional, Lordan, Jim, additional, Machado, Rajiv D., additional, MacKenzie Ross, Robert V., additional, McCabe, Colm, additional, Moledina, Shahin, additional, Montani, David, additional, Olschewski, Horst, additional, Pepke-Zaba, Joanna, additional, Price, Laura, additional, Rhodes, Christopher J., additional, Seeger, Werner, additional, Soubrier, Florent, additional, Suntharalingam, Jay, additional, Toshner, Mark R., additional, Vonk Noordegraaf, Anton, additional, Wharton, John, additional, Wild, James M., additional, Wort, Stephen John, additional, Lawrie, Allan, additional, Wilkins, Martin R., additional, Trembath, Richard C., additional, Shen, Yufeng, additional, Chung, Wendy K., additional, Swift, Andrew J., additional, Nichols, William C., additional, Morrell, Nicholas W., additional, Gräf, Stefan, additional, Abbs, Stephen, additional, Abulhoul, Lara, additional, Adlard, Julian, additional, Ahmed, Munaza, additional, Aitman, Timothy J., additional, Alachkar, Hana, additional, Allsup, David J., additional, Ancliff, Philip, additional, Antrobus, Richard, additional, Armstrong, Ruth, additional, Arno, Gavin, additional, Ashford, Sofie, additional, Astle, William J., additional, Attwood, Anthony, additional, Aurora, Paul, additional, Babbs, Christian, additional, Bacchelli, Chiara, additional, Bakchoul, Tamam, additional, Banka, Siddharth, additional, Bariana, Tadbir, additional, Barwell, Julian, additional, Batista, Joana, additional, Baxendale, Helen E., additional, Beales, Phil L., additional, Bennett, David L., additional, Bierzynska, Agnieszka, additional, Biss, Tina, additional, Bitner-Glindzicz, Maria A.K., additional, Black, Graeme C., additional, Bleda, Marta, additional, Blesneac, Iulia, additional, Bockenhauer, Detlef, additional, Boyce, Sara, additional, Bradley, John R., additional, Breen, Gerome, additional, Brennan, Paul, additional, Brewer, Carole, additional, Brown, Matthew, additional, Browning, Andrew C., additional, Browning, Michael J., additional, Buchan, Rachel J., additional, Buckland, Matthew S., additional, Bueser, Teofila, additional, Diz, Carmen Bugarin, additional, Burn, John, additional, Burns, Siobhan O., additional, Burren, Oliver S., additional, Burrows, Nigel, additional, Campbell, Carolyn, additional, Carr-White, Gerald, additional, Carss, Keren, additional, Casey, Ruth, additional, Caulfield, Mark J., additional, Chambers, Jenny, additional, Chambers, John, additional, Chan, Melanie M.Y., additional, Cheng, Floria, additional, Chinnery, Patrick F., additional, Chitre, Manali, additional, Christian, Martin T., additional, Clayton-Smith, Jill, additional, Cleary, Maureen, additional, Brod, Naomi Clements, additional, Colby, Elizabeth, additional, Cole, Trevor R.P., additional, Collins, Janine, additional, Collins, Peter W., additional, Compton, Cecilia J., additional, Cook, H. Terence, additional, Cook, Stuart, additional, Cooper, Nichola, additional, Corris, Paul A., additional, Curry, Nicola S., additional, Daniels, Matthew J., additional, Dattani, Mehul, additional, Daugherty, Louise C., additional, Davis, John, additional, De Soyza, Anthony, additional, Deevi, Sri V.V., additional, Dent, Timothy, additional, Deshpande, Charu, additional, Dewhurst, Eleanor F., additional, Dixon, Peter H., additional, Douzgou, Sofia, additional, Downes, Kate, additional, Drazyk, Anna M., additional, Drewe, Elizabeth, additional, Duarte, Daniel, additional, Dutt, Tina, additional, Edgar, J. David M., additional, Edwards, Karen, additional, Egner, William, additional, Ekani, Melanie N., additional, Elliott, Perry, additional, Erber, Wendy N., additional, Erwood, Marie, additional, Estiu, Maria C., additional, Evans, Dafydd Gareth, additional, Evans, Gillian, additional, Everington, Tamara, additional, Fassihi, Hiva, additional, Favier, Remi, additional, Fletcher, Debra, additional, Flinter, Frances A., additional, Floto, R. Andres, additional, Fowler, Tom, additional, Fox, James, additional, Frary, Amy J., additional, French, Courtney E., additional, Freson, Kathleen, additional, Frontini, Mattia, additional, Furnell, Abigail, additional, Gale, Daniel P., additional, Ganesan, Vijeya, additional, Gattens, Michael, additional, Ghofrani, Hossein-Ardeschir, additional, Gibbs, J. Simon R., additional, Gibson, Kate, additional, Gilmour, Kimberly C., additional, Gleadall, Nicholas S., additional, Goddard, Sarah, additional, Gomez, Keith, additional, Gordins, Pavels, additional, Gosal, David, additional, Graham, Jodie, additional, Grassi, Luigi, additional, Greenhalgh, Lynn, additional, Greinacher, Andreas, additional, Gresele, Paolo, additional, Griffiths, Philip, additional, Grigoriadou, Sofia, additional, Grozeva, Detelina, additional, Gurnell, Mark, additional, Hackett, Scott, additional, Hadinnapola, Charaka, additional, Hague, Rosie, additional, Hague, William M., additional, Haimel, Matthias, additional, Hall, Matthew, additional, Hanson, Helen L., additional, Haque, Eshika, additional, Harkness, Kirsty, additional, Harper, Andrew R., additional, Harris, Claire L., additional, Hart, Daniel, additional, Hassan, Ahamad, additional, Hayman, Grant, additional, Henderson, Alex, additional, Herwadkar, Archana, additional, Hoffman, Jonathan, additional, Horvath, Rita, additional, Houlden, Henry, additional, Houweling, Arjan C., additional, Hu, Fengyuan, additional, Hudson, Gavin, additional, Huissoon, Aarnoud P., additional, Hurles, Matthew, additional, Irving, Melita, additional, Izatt, Louise, additional, James, Roger, additional, Johnson, Sally A., additional, Jolles, Stephen, additional, Jolley, Jennifer, additional, Josifova, Dragana, additional, Jurkute, Neringa, additional, Kasanicki, Mary A., additional, Kazkaz, Hanadi, additional, Kazmi, Rashid, additional, Kelleher, Peter, additional, Kelly, Anne M, additional, Kelsall, Wilf, additional, Kempster, Carly, additional, Kingston, Nathalie, additional, Koelling, Nils, additional, Kostadima, Myrto, additional, Koziell, Ania, additional, Kreuzhuber, Roman, additional, Kuijpers, Taco W., additional, Kumar, Ajith, additional, Kumararatne, Dinakantha, additional, Kurian, Manju A., additional, Laffan, Michael A., additional, Lalloo, Fiona, additional, Lambert, Michele, additional, Allen, Hana Lango, additional, Layton, D. Mark, additional, Lentaigne, Claire, additional, Lester, Tracy, additional, Levine, Adam P., additional, Linger, Rachel, additional, Longhurst, Hilary, additional, Lorenzo, Lorena E., additional, Louka, Eleni, additional, Lyons, Paul A., additional, Madan, Bella, additional, Maher, Eamonn R., additional, Maimaris, Jesmeen, additional, Malka, Samantha, additional, Mangles, Sarah, additional, Mapeta, Rutendo, additional, Marchbank, Kevin J., additional, Marks, Stephen, additional, Markus, Hugh S., additional, Marschall, Hanns-Ulrich, additional, Marshall, Andrew, additional, Mathias, Mary, additional, Matthews, Emma, additional, Maxwell, Heather, additional, McAlinden, Paul, additional, McCarthy, Mark I., additional, McKinney, Harriet, additional, Meacham, Stuart, additional, Mead, Adam J., additional, Mehta, Sarju G., additional, Michaelides, Michel, additional, Millar, Carolyn, additional, Mohammed, Shehla N., additional, Moore, Anthony T., additional, Mozere, Monika, additional, Muir, Keith W., additional, Mumford, Andrew D., additional, Nemeth, Andrea H., additional, Newman, William G., additional, Newnham, Michael, additional, Noorani, Sadia, additional, Nurden, Paquita, additional, O’Sullivan, Jennifer, additional, Obaji, Samya, additional, Odhams, Chris, additional, Okoli, Steven, additional, Olschewski, Andrea, additional, Ong, Kai Ren, additional, Oram, S. Helen, additional, Ormondroyd, Elizabeth, additional, Ouwehand, Willem H., additional, Palles, Claire, additional, Papadia, Sofia, additional, Park, Soo-Mi, additional, Parry, David, additional, Patel, Smita, additional, Paterson, Joan, additional, Peacock, Andrew, additional, Pearce, Simon H., additional, Peerlinck, Kathelijne, additional, Petersen, Romina, additional, Pilkington, Clarissa, additional, Poole, Kenneth E.S., additional, Psaila, Bethan, additional, Pyle, Angela, additional, Quinton, Richard, additional, Rahman, Shamima, additional, Rao, Anupama, additional, Raymond, F. Lucy, additional, Rayner-Matthews, Paula J., additional, Rendon, Augusto, additional, Renton, Tara, additional, Rice, Andrew S.C., additional, Richter, Alex, additional, Robert, Leema, additional, Roberts, Irene, additional, Rose, Sarah J., additional, Ross-Russell, Robert, additional, Roughley, Catherine, additional, Roy, Noemi B.A., additional, Ruddy, Deborah M., additional, Sadeghi-Alavijeh, Omid, additional, Saleem, Moin A., additional, Samani, Nilesh, additional, Samarghitean, Crina, additional, Sanchis-Juan, Alba, additional, Sargur, Ravishankar B., additional, Sarkany, Robert N., additional, Satchell, Simon, additional, Savic, Sinisa, additional, Sayer, Genevieve, additional, Sayer, John A., additional, Scelsi, Laura, additional, Schaefer, Andrew M., additional, Schulman, Sol, additional, Scott, Richard, additional, Scully, Marie, additional, Searle, Claire, additional, Sen, Arjune, additional, Sewell, W.A. Carrock, additional, Seyres, Denis, additional, Shah, Neil, additional, Shamardina, Olga, additional, Shapiro, Susan E., additional, Shaw, Adam C., additional, Sibson, Keith, additional, Side, Lucy, additional, Simeoni, Ilenia, additional, Simpson, Michael A., additional, Sims, Matthew C., additional, Sivapalaratnam, Suthesh, additional, Smedley, Damian, additional, Smith, Katherine R., additional, Smith, Kenneth G.C., additional, Snape, Katie, additional, Soranzo, Nicole, additional, Spasic-Boskovic, Olivera, additional, Staines, Simon, additional, Staples, Emily, additional, Stark, Hannah, additional, Stirrups, Kathleen E., additional, Stuckey, Alex, additional, Syrris, Petros, additional, Tait, R. Campbell, additional, Talks, Kate, additional, Tan, Rhea Y.Y., additional, Taylor, Jenny C., additional, Taylor, John M., additional, Thaventhiran, James E., additional, Themistocleous, Andreas C., additional, Thomas, David, additional, Thomas, Ellen, additional, Thomas, Moira J., additional, Thomas, Patrick, additional, Thomson, Kate, additional, Thrasher, Adrian J., additional, Thys, Chantal, additional, Tischkowitz, Marc, additional, Titterton, Catherine, additional, Toh, Cheng-Hock, additional, Tomlinson, Ian P., additional, Traylor, Matthew, additional, Treadaway, Paul, additional, Tuna, Salih, additional, Turro, Ernest, additional, Twiss, Philip, additional, Vale, Tom, additional, Van Geet, Chris, additional, van Zuydam, Natalie, additional, Vandersteen, Anthony M, additional, Vazquez-Lopez, Marta, additional, von Ziegenweidt, Julie, additional, Wagner, Annette, additional, Waisfisz, Quinten, additional, Walker, Neil, additional, Walker, Suellen M., additional, Ware, James S., additional, Watkins, Hugh, additional, Watt, Christopher, additional, Webster, Andrew R., additional, Wedderburn, Lucy, additional, Wei, Wei, additional, Welch, Steven B., additional, Wessels, Julie, additional, Westbury, Sarah K., additional, Westwood, John-Paul, additional, Whitehorn, Deborah, additional, Whitworth, James, additional, Wilkie, Andrew O.M., additional, Williamson, Catherine, additional, Wilson, Brian T., additional, Wong, Edwin K.S., additional, Wood, Nicholas, additional, Wood, Yvette, additional, Woods, Christopher Geoffrey, additional, Woodward, Emma R., additional, Worth, Austen, additional, Wright, Michael, additional, Yates, Katherine, additional, Yong, Patrick F.K., additional, Young, Timothy, additional, Yu, Ping, additional, Yu-Wai-Man, Patrick, additional, Zlamalova, Eliska, additional, Hirsch, Russel, additional, White, R. James, additional, Simon, Marc, additional, Badesch, David, additional, Rosenzweig, Erika, additional, Burger, Charles, additional, Chakinala, Murali, additional, Thenappan, Thenappan, additional, Elliott, Greg, additional, Simms, Robert, additional, Farber, Harrison, additional, Frantz, Robert, additional, Elwing, Jean, additional, Hill, Nicholas, additional, Ivy, Dunbar, additional, Klinger, James, additional, Nathan, Steven, additional, Oudiz, Ronald, additional, Robbins, Ivan, additional, Schilz, Robert, additional, Fortin, Terry, additional, Wilt, Jeffrey, additional, Yung, Delphine, additional, Austin, Eric, additional, Ahmad, Ferhaan, additional, Bhatt, Nitin, additional, Lahm, Tim, additional, Frost, Adaani, additional, Safdar, Zeenat, additional, Rehman, Zia, additional, Walter, Robert, additional, Torres, Fernando, additional, Bakshi, Sahil, additional, Archer, Stephen, additional, Argula, Rahul, additional, Barnett, Christopher, additional, Benza, Raymond, additional, Desai, Ankit, additional, and Maddipati, Veeranna, additional

Published
2021
Full Text
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7. Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations

Author

Lorenzini, Tiziana, primary, Fliegauf, Manfred, additional, Klammer, Nils, additional, Frede, Natalie, additional, Proietti, Michele, additional, Bulashevska, Alla, additional, Camacho-Ordonez, Nadezhda, additional, Varjosalo, Markku, additional, Kinnunen, Matias, additional, de Vries, Esther, additional, van der Meer, Jos W.M., additional, Ameratunga, Rohan, additional, Roifman, Chaim M., additional, Schejter, Yael D., additional, Kobbe, Robin, additional, Hautala, Timo, additional, Atschekzei, Faranaz, additional, Schmidt, Reinhold E., additional, Schröder, Claudia, additional, Stepensky, Polina, additional, Shadur, Bella, additional, Pedroza, Luis A., additional, van der Flier, Michiel, additional, Martínez-Gallo, Mónica, additional, Gonzalez-Granado, Luis Ignacio, additional, Allende, Luis M., additional, Shcherbina, Anna, additional, Kuzmenko, Natalia, additional, Zakharova, Victoria, additional, Neves, João Farela, additional, Svec, Peter, additional, Fischer, Ute, additional, Ip, Winnie, additional, Bartsch, Oliver, additional, Barış, Safa, additional, Klein, Christoph, additional, Geha, Raif, additional, Chou, Janet, additional, Alosaimi, Mohammed, additional, Weintraub, Lauren, additional, Boztug, Kaan, additional, Hirschmugl, Tatjana, additional, Dos Santos Vilela, Maria Marluce, additional, Holzinger, Dirk, additional, Seidl, Maximilian, additional, Lougaris, Vassilios, additional, Plebani, Alessandro, additional, Alsina, Laia, additional, Piquer-Gibert, Monica, additional, Deyà-Martínez, Angela, additional, Slade, Charlotte A., additional, Aghamohammadi, Asghar, additional, Abolhassani, Hassan, additional, Hammarström, Lennart, additional, Kuismin, Outi, additional, Helminen, Merja, additional, Allen, Hana Lango, additional, Thaventhiran, James E., additional, Freeman, Alexandra F., additional, Cook, Matthew, additional, Bakhtiar, Shahrzad, additional, Christiansen, Mette, additional, Cunningham-Rundles, Charlotte, additional, Patel, Niraj C., additional, Rae, William, additional, Niehues, Tim, additional, Brauer, Nina, additional, Syrjänen, Jaana, additional, Seppänen, Mikko R.J., additional, Burns, Siobhan O., additional, Tuijnenburg, Paul, additional, Kuijpers, Taco W., additional, Warnatz, Klaus, additional, Grimbacher, Bodo, additional, Adhya, Zoe, additional, Alachkar, Hana, additional, Anantharachagan, Ariharan, additional, Antrobus, Richard, additional, Arumugakani, Gururaj, additional, Ashford, Sofie, additional, Astle, William J., additional, Attwood, Anthony, additional, Bacchelli, Chiara, additional, Batista, Joana, additional, Baxendale, Helen E., additional, Bethune, Claire, additional, Bibi, Shahnaz, additional, Bleda, Marta, additional, Boardman, Barbara, additional, Booth, Claire, additional, Bradley, John R., additional, Breen, Gerome, additional, Brown, Matthew, additional, Browning, Michael J., additional, Brownlie, Mary, additional, Buckland, Matthew S., additional, Burren, Oliver S., additional, Carss, Keren, additional, Chambers, John, additional, Chandra, Anita, additional, Brod, Naomi Clements, additional, Clifford, Hayley, additional, Cooper, Nichola, additional, Daugherty, Louise C., additional, Davies, E.G., additional, Davies, Sophie, additional, Davis, John, additional, Deacock, Sarah, additional, Deevi, Sri V.V., additional, Dempster, John, additional, Devlin, Lisa A., additional, Dewhurst, Eleanor F., additional, Downes, Kate, additional, Drewe, Elizabeth, additional, Duarte, Daniel, additional, Edgar, J. David M., additional, Edwards, Karen, additional, Egner, William, additional, El-Shanawany, Tariq, additional, Erwood, Marie, additional, Fletcher, Debra, additional, Fox, James, additional, Frary, Amy J., additional, Frontini, Mattia, additional, Furnell, Abigail, additional, Gaspar, H. 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Published
2020
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8. Whole Genome Sequencing of Primary Immunodeficiency reveals a role for common and rare variants in coding and non-coding sequences

Author

Thaventhiran, James E. D., Allen, Hana Lango, Burren, Oliver S., Farmery, James H. R., Staples, Emily, Zhang, Zinan, Rae, William, Greene, Daniel, Simeoni, Ilenia, Maimaris, Jesmeen, Penkett, Chris, Stephens, Jonathan, Deevi, Sri V.V., Sanchis-Juan, Alba, Gleadall, Nicholas S, Thomas, Moira J., Sargur, Ravishankar B., Gordins, Pavels, Baxendale, Helen E., Brown, Matthew, Tuijnenburg, Paul, Worth, Austen, Hanson, Steven, Linger, Rachel, Buckland, Matthew S., Rayner-Matthews, Paula J., Gilmour, Kimberly C., Samarghitean, Crina, Seneviratne, Suranjith L., Lyons, Paul A., Sansom, David M., Lynch, Andy G., Megy, Karyn, Ellinghaus, Eva, Ellinghaus, David, Jorgensen, Silje F., Karlsen, Tom H, Stirrups, Kathleen E., Cutler, Antony J., Kumararatne, Dinakantha S., Savic, Sinisa, Burns, Siobhan O., Kuijpers, Taco W., Turro, Ernest, Ouwehand, Willem H., Thrasher, Adrian J., and Smith, Kenneth G. C.

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 malignancies. 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 subjects. Analysis of coding regions of 886 index cases found disease-causing mutations in known monogenic PID genes in 8.2%, while a Bayesian approach (BeviMed 1 ) identified multiple potential new disease-associated genes. Exploration of the non-coding space revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified novel 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 determining variation in human immune responsiveness.

Published
2018
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9. Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

Author

Thaventhiran, James E. D., Lango Allen, Hana, Burren, Oliver S., Rae, William, Greene, Daniel, Staples, Emily, Zhang, Zinan, Farmery, James H. R., Simeoni, Ilenia, Rivers, Elizabeth, Maimaris, Jesmeen, Penkett, Christopher J., Stephens, Jonathan, Deevi, Sri V. V., Sanchis-Juan, Alba, Gleadall, Nicholas S., Thomas, Moira J., Sargur, Ravishankar B., Gordins, Pavels, and Baxendale, Helen E.

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Published
2020
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10. Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

Author

Thaventhiran JED, Lango Allen H, Burren OS, Rae W, Greene D, Staples E, Zhang Z, Farmery JHR, Simeoni I, Rivers E, Maimaris J, Penkett CJ, Stephens J, Deevi SVV, Sanchis-Juan A, Gleadall NS, Thomas MJ, Sargur RB, Gordins P, Baxendale HE, Brown M, Tuijnenburg P, Worth A, Hanson S, Linger RJ, Buckland MS, Rayner-Matthews PJ, Gilmour KC, Samarghitean C, Seneviratne SL, Sansom DM, Lynch AG, Megy K, Ellinghaus E, Ellinghaus D, Jorgensen SF, Karlsen TH, Stirrups KE, Cutler AJ, Kumararatne DS, Chandra A, Edgar JDM, Herwadkar A, Cooper N, Grigoriadou S, Huissoon AP, Goddard S, Jolles S, Schuetz C, Boschann F, Lyons PA, Hurles ME, Savic S, Burns SO, Kuijpers TW, Turro E, Ouwehand WH, Thrasher AJ, and Smith KGC

Subjects
Actin-Related Protein 2-3 Complex genetics, Bayes Theorem, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Primary Immunodeficiency Diseases diagnosis, Primary Immunodeficiency Diseases immunology, Protein Tyrosine Phosphatase, Non-Receptor Type 2 genetics, RNA-Binding Proteins genetics, Regulatory Sequences, Nucleic Acid genetics, Suppressor of Cytokine Signaling 1 Protein genetics, Transcription Factors genetics, Primary Immunodeficiency Diseases genetics, Whole Genome Sequencing
Abstract

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most 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 malignancies 1-3 . Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed 4 ) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization 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 the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.

Published
2020
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