@article { , title = {Whole-genome sequencing of a sporadic primary immunodeficiency cohort}, 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.}, doi = {10.1038/s41586-020-2265-1}, eissn = {1476-4687}, issn = {0028-0836}, issue = {7814}, journal = {Nature}, pages = {90-95}, publicationstatus = {Published}, publisher = {Nature Publishing Group}, url = {https://hull-repository.worktribe.com/output/3504021}, volume = {583}, keyword = {Health and Health Inequalities, Genomics, Immunology}, year = {2020}, author = {Thaventhiran, James E.D. and Farmery, James H.R. and Deevi, Sri V.V. and Cooper, Nichola and Abbs, Stephen and Adhya, Zoe and Adlard, Julian and Afzal, Maryam and Ahmed, Irshad and Ahmed, Munaza and Ahmed, Saeed and Aitman, Timothy J. and Alachkar, Hana and Alamelu, Jayanthi and Alikhan, Raza and Allen, Carl E. and Allen, Louise and Alvi, Arif and Ambegaonkar, Gautam and Anantharachagan, Ariharan and Ancliff, Philip and Anderson, Julie and Antrobus, Richard and Armstrong, Ruth and Arno, Gavin and Arumugakani, Gururaj and Arya, Rita and Ashford, Sofie and Astle, William J. and Attwood, Anthony and Austin, Steve and Aydinok, Yesim and Ayub, Waqar and Babbs, Christian and Bacchelli, Chiara and Baglin, Trevor and Bakchoul, Tamam and Bariana, Tadbir K. and Barratt, Jonathan and Barwell, Julian and Baski, John and Bates, Rachel W. and Batista, Joana and Baynam, Gareth and Bennett, David L. and Bethune, Claire and Bhatnagar, Neha and Bibi, Shahnaz and Bierzynska, Agnieszka and Biss, Tina and Bitner-Glindzicz, Maria A.K. and Bleda, Marta and Schuetz, Catharina and Boschann, Felix and Goddard, Sarah and Jolles, Stephen and Grigoriadou, Sofia and Huissoon, Aarnoud P. and Edgar, J. David M. and Chandra, Anita and Kumararatne, Dinakantha S. and Cutler, Antony J. and Herwadkar, Archana and Stirrups, Kathleen E. and Karlsen, Tom H. and Jorgensen, Silje F. and Ellinghaus, David and Ellinghaus, Eva and Lynch, Andy G. and Sansom, David M. and Megy, Karyn and Seneviratne, Suranjith L. and Samarghitean, Crina and Gilmour, Kimberly C. and Rayner-Matthews, Paula J. and Buckland, Matthew S. and Hanson, Steven and Linger, Rachel J. and Tuijnenburg, Paul and Worth, Austen and Thaventhiran, James E. D. and Allsup, David J. and Lango Allen, Hana and Burren, Oliver S. and Rae, William and Greene, Daniel and Staples, Emily and Zhang, Zinan and Farmery, James H. R. and Simeoni, Ilenia and Rivers, Elizabeth and Maimaris, Jesmeen and Penkett, Christopher J. and Stephens, Jonathan and Deevi, Sri V. V. and Sanchis-Juan, Alba and Gleadall, Nicholas S. and Thomas, Moira J. and Sargur, Ravishankar B. and Gordins, Pavels and Baxendale, Helen E. and Brown, Matthew and Tuijnenburg, Paul and Worth, Austen and Hanson, Steven and Linger, Rachel J. and Buckland, Matthew S. and Rayner-Matthews, Paula J. and Gilmour, Kimberly C. and Samarghitean, Crina and Seneviratne, Suranjith L. and Sansom, David M. and Lynch, Andy G. and Megy, Karyn and Ellinghaus, Eva and Ellinghaus, David and Jorgensen, Silje F. and Karlsen, Tom H. and Stirrups, Kathleen E. and Cutler, Antony J. and Kumararatne, Dinakantha S. and Chandra, Anita and Edgar, J. David M. and Herwadkar, Archana and Grigoriadou, Sofia and Huissoon, Aarnoud P. and Goddard, Sarah and Jolles, Stephen and Schuetz, Catharina and Boschann, Felix and Lyons, Paul A. and Hurles, Matthew E. and Savic, Sinisa and Burns, Siobhan O. and Kuijpers, Taco W. and Turro, Ernest and Ouwehand, Willem H. and Thrasher, Adrian J. and Smith, Kenneth G. C.} }