TY - JOUR
T1 - Whole-genome sequencing of a sporadic primary immunodeficiency cohort
AU - Primary Immunodeficiency Consortium for the NIHR Bioresource
AU - Thaventhiran, James E.D.
AU - Lango Allen, Hana
AU - Burren, Oliver S.
AU - Rae, William
AU - Greene, Daniel
AU - Staples, Emily
AU - Zhang, Zinan
AU - Farmery, James H.R.
AU - Simeoni, Ilenia
AU - Rivers, Elizabeth
AU - Maimaris, Jesmeen
AU - Penkett, Christopher J.
AU - Stephens, Jonathan
AU - Deevi, Sri V.V.
AU - Sanchis-Juan, Alba
AU - Gleadall, Nicholas S.
AU - Thomas, Moira J.
AU - Sargur, Ravishankar B.
AU - Gordins, Pavels
AU - Baxendale, Helen E.
AU - Brown, Matthew
AU - Tuijnenburg, Paul
AU - Worth, Austen
AU - Hanson, Steven
AU - Linger, Rachel J.
AU - Buckland, Matthew S.
AU - Rayner-Matthews, Paula J.
AU - Gilmour, Kimberly C.
AU - Samarghitean, Crina
AU - Seneviratne, Suranjith L.
AU - Sansom, David M.
AU - Lynch, Andy G.
AU - Megy, Karyn
AU - Ellinghaus, Eva
AU - Ellinghaus, David
AU - Jorgensen, Silje F.
AU - Karlsen, Tom H.
AU - Stirrups, Kathleen E.
AU - Cutler, Antony J.
AU - Kumararatne, Dinakantha S.
AU - Chandra, Anita
AU - Edgar, J. David M.
AU - Herwadkar, Archana
AU - Cooper, Nichola
AU - Grigoriadou, Sofia
AU - Huissoon, Aarnoud P.
AU - Goddard, Sarah
AU - Jolles, Stephen
AU - Schuetz, Catharina
AU - Boschann, Felix
AU - Abbs, Stephen
AU - Adhya, Zoe
AU - Adlard, Julian
AU - Afzal, Maryam
AU - Ahmed, Irshad
AU - Ahmed, Munaza
AU - Ahmed, Saeed
AU - Aitman, Timothy J.
AU - Alachkar, Hana
AU - Alamelu, Jayanthi
AU - Alikhan, Raza
AU - Allen, Carl E.
AU - Allen, Louise
AU - Allsup, David J.
AU - Alvi, Arif
AU - Ambegaonkar, Gautam
AU - Anantharachagan, Ariharan
AU - Ancliff, Philip
AU - Anderson, Julie
AU - Antrobus, Richard
AU - Armstrong, Ruth
AU - Arno, Gavin
AU - Arumugakani, Gururaj
AU - Arya, Rita
AU - Ashford, Sofie
AU - Astle, William J.
AU - Attwood, Anthony
AU - Austin, Steve
AU - Aydinok, Yesim
AU - Ayub, Waqar
AU - Babbs, Christian
AU - Bacchelli, Chiara
AU - Baglin, Trevor
AU - Bakchoul, Tamam
AU - Bariana, Tadbir K.
AU - Barratt, Jonathan
AU - Barwell, Julian
AU - Baski, John
AU - Bates, Rachel W.
AU - Batista, Joana
AU - Baxendale, Helen E.
AU - Baynam, Gareth
AU - Bennett, David L.
AU - Bethune, Claire
AU - Bhatnagar, Neha
AU - Bibi, Shahnaz
AU - Bierzynska, Agnieszka
AU - Biss, Tina
AU - Bitner-Glindzicz, Maria A.K.
AU - Bleda, Marta
AU - Blesneac, Iulia
AU - Boardman, Barbara
AU - Boddana, Preetham
AU - Bogaard, Harm J.
AU - Booth, Claire
AU - Boyce, Sara
AU - Bradley, John R.
AU - Brady, Angela
AU - Breen, Gerome
AU - Brennan, Paul
AU - Brewer, Carole
AU - Briley, Annette
AU - Brown, Matthew
AU - Brown, Richard
AU - Browning, Michael J.
AU - Brownlie, Mary
AU - Bryson, Christine J.
AU - Buchan, Rachel J.
AU - Buck, Jackie
AU - Buckland, Matthew S.
AU - Bueser, Teofila
AU - Diz, Carmen Bugarin
AU - Burns, Siobhan O.
AU - Burren, Oliver S.
AU - Calleja, Paul
AU - Carmichael, Jenny
AU - Carr-White, Gerald
AU - Carss, Keren J.
AU - Casey, Ruth
AU - Chalmers, Elizabeth
AU - Chambers, Jenny
AU - Chambers, John
AU - Chan, Melanie M.Y.
AU - Chan, Melissa V.
AU - Chandra, Anita
AU - Cheng, Floria
AU - Chinn, Ivan K.
AU - Chinnery, Patrick F.
AU - Chitre, Manali
AU - Chong, Sam
AU - Christian, Martin T.
AU - Church, Colin
AU - Clement, Emma M.
AU - Brod, Naomi Clements
AU - Clifford, Hayley
AU - Clowes, Virginia E.
AU - Coghlan, Gerry
AU - Colby, Elizabeth
AU - Cole, Trevor R.P.
AU - Collins, Janine H.
AU - Collins, Peter W.
AU - Condliffe, Robin
AU - Cook, H. Terence
AU - Cook, Stuart
AU - Cookson, Victoria
AU - Cooper, Nichola
AU - Corris, Paul A.
AU - Creaser-Myers, Amanda
AU - Crisp-Hihn, Abigail
AU - Curry, Nicola S.
AU - Cutler, Antony J.
AU - Da Costa, Rosa
AU - Danesino, Cesare
AU - Daniels, Matthew J.
AU - Darby, Damaris
AU - Daugherty, Louise C.
AU - Davies, E. G.
AU - Davies, Sophie
AU - Davis, John
AU - de Bree, Godelieve J.
AU - Deacock, Sarah
AU - Deegan, Patrick B.
AU - Deevi, Sri V.V.
AU - Dempster, John
AU - Dent, Timothy
AU - Deshpande, Charu
AU - Devlin, Lisa A.
AU - Dewhurst, Eleanor F.
AU - Dixit, Anand K.
AU - Dixon, Peter H.
AU - Doffinger, Rainer
AU - Dolling, Helen
AU - Dormand, Natalie
AU - Downes, Kate
AU - Drazyk, Anna M.
AU - Drewe, Elizabeth
AU - Duarte, Daniel
AU - Dutt, Tina
AU - Edgar, J. David M.
AU - Edwards, Karen E.
AU - Egner, William
AU - Ekani, Melanie N.
AU - El-Shanawany, Tariq
AU - Elkhalifa, Shuayb
AU - Elston, Tony
AU - Emmerson, Ingrid
AU - Erber, Wendy N.
AU - Erwood, Marie
AU - Estiu, Maria C.
AU - Evans, Dafydd Gareth
AU - Evans, Gillian
AU - Everington, Tamara
AU - Eyries, Mélanie
AU - Farmery, James H.R.
AU - Favier, Remi
AU - Firth, Helen V.
AU - Fitzpatrick, Maggie M.
AU - Fletcher, Debra
AU - Flinter, Frances A.
AU - Fox, James C.
AU - Frary, Amy J.
AU - French, Courtney E.
AU - Freson, Kathleen
AU - Frontini, Mattia
AU - Furie, Bruce
AU - Gale, Daniel P.
AU - Gall, Henning J.
AU - Gardham, Alice
AU - Gaspar, H. Bobby
AU - Gattens, Michael
AU - Ghali, Neeti
AU - Ghataorhe, Pavandeep K.
AU - Ghio, Stefano
AU - Ghofrani, Hossein Ardeschir
AU - Ghurye, Rohit
AU - Gibbs, J. Simon R.
AU - Gilbert, Rodney D.
AU - Gilmour, Kimberly C.
AU - Girerd, Barbara
AU - Girling, Joanna C.
AU - Gissen, Paul
AU - Gleadall, Nicholas S.
AU - Goddard, Sarah
AU - Gordins, Pavels
AU - Gorman, Kathleen M.
AU - Gosal, David
AU - Graf, Stefan
AU - Grassi, Luigi
AU - Greene, Daniel
AU - Greenhalgh, Alan J.
AU - Greenhalgh, Lynn
AU - Greinacher, Andreas
AU - Gresele, Paolo
AU - Griffiths, Philip G.
AU - Griffiths, Sian
AU - Grigoriadou, Sofia
AU - Smith, Kenneth G.C.
AU - Wei, Wei
AU - Williams, David J.
PY - 2020/7/2
Y1 - 2020/7/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085120745&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-2265-1
DO - 10.1038/s41586-020-2265-1
M3 - Article
C2 - 32499645
AN - SCOPUS:85085120745
SN - 0028-0836
VL - 583
SP - 90
EP - 95
JO - Nature
JF - Nature
IS - 7814
ER -