Whole-genome sequencing of a sporadic primary immunodeficiency cohort

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

Research output: Contribution to journalArticleAcademicpeer-review

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 malignancies1–3. 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.

Original languageEnglish
Number of pages6
JournalNature
Volume583
Issue number7814
DOIs
Publication statusAccepted/In press - 1 Jan 2020

Cite this

Thaventhiran, J. E. D., Lango Allen, H., Burren, O. S., Rae, W., Greene, D., Staples, E., ... Primary Immunodeficiency Consortium for the NIHR Bioresource (Accepted/In press). Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature, 583(7814). https://doi.org/10.1038/s41586-020-2265-1