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Whole-genome sequencing of a sporadic primary immunodeficiency cohort

Worth, Austen; Attwood, Anthony; Baynam, Gareth; Batista, Joana; Bates, Rachel W.; Baski, John; Barwell, Julian; Barratt, Jonathan; Bariana, Tadbir K.; Bakchoul, Tamam; Baglin, Trevor; Bacchelli, Chiara; Babbs, Christian; Ayub, Waqar; Aydinok, Yesim; Austin, Steve; Astle, William J.; Bethune, Claire; Anantharachagan, Ariharan; Alamelu, Jayanthi; Alikhan, Raza; Allen, Carl E.; Allen, Louise; Alvi, Arif; Ambegaonkar, Gautam; Ancliff, Philip; Ashford, Sofie; Anderson, Julie; Antrobus, Richard; Armstrong, Ruth; Arno, Gavin; Arumugakani, Gururaj; Arya, Rita; Bennett, David L.; Bhatnagar, Neha; Aitman, Timothy J.; Karlsen, Tom H.; Tuijnenburg, Paul; Linger, Rachel J.; Hanson, Steven; Buckland, Matthew S.; Rayner-Matthews, Paula J.; Gilmour, Kimberly C.; Samarghitean, Crina; Seneviratne, Suranjith L.; Megy, Karyn; Sansom, David M.; Lynch, Andy G.; Ellinghaus, Eva; Ellinghaus, David; Jorgensen, Silje F.; Stirrups, Kathleen E.; Bibi, Shahnaz; Goddard, Sarah; Bierzynska, Agnieszka; Biss, Tina; Bitner-Glindzicz, Maria A.K.; Bleda, Marta; Schuetz, Catharina; Boschann, Felix; Jolles, Stephen; Herwadkar, Archana; Grigoriadou, Sofia; Huissoon, Aarnoud P.; Edgar, J. David M.; Chandra, Anita; Kumararatne, Dinakantha S.; Cutler, Antony J.; Alachkar, Hana; Ahmed, Saeed; Ahmed, Munaza; Ahmed, Irshad; Afzal, Maryam; Adlard, Julian; Adhya, Zoe; Abbs, Stephen; Cooper, Nichola; Deevi, Sri V.V.; Farmery, James H.R.; Thaventhiran, James E.D.; Thaventhiran, James E. D.; Allsup, David J.; 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; 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.

Authors

Austen Worth

Anthony Attwood

Gareth Baynam

Joana Batista

Rachel W. Bates

John Baski

Julian Barwell

Jonathan Barratt

Tadbir K. Bariana

Tamam Bakchoul

Trevor Baglin

Chiara Bacchelli

Christian Babbs

Waqar Ayub

Yesim Aydinok

Steve Austin

William J. Astle

Claire Bethune

Ariharan Anantharachagan

Jayanthi Alamelu

Raza Alikhan

Carl E. Allen

Louise Allen

Arif Alvi

Gautam Ambegaonkar

Philip Ancliff

Sofie Ashford

Julie Anderson

Richard Antrobus

Ruth Armstrong

Gavin Arno

Gururaj Arumugakani

Rita Arya

David L. Bennett

Neha Bhatnagar

Timothy J. Aitman

Tom H. Karlsen

Paul Tuijnenburg

Rachel J. Linger

Steven Hanson

Matthew S. Buckland

Paula J. Rayner-Matthews

Kimberly C. Gilmour

Crina Samarghitean

Suranjith L. Seneviratne

Karyn Megy

David M. Sansom

Andy G. Lynch

Eva Ellinghaus

David Ellinghaus

Silje F. Jorgensen

Kathleen E. Stirrups

Shahnaz Bibi

Sarah Goddard

Agnieszka Bierzynska

Tina Biss

Maria A.K. Bitner-Glindzicz

Marta Bleda

Catharina Schuetz

Felix Boschann

Stephen Jolles

Archana Herwadkar

Sofia Grigoriadou

Aarnoud P. Huissoon

J. David M. Edgar

Anita Chandra

Dinakantha S. Kumararatne

Antony J. Cutler

Hana Alachkar

Saeed Ahmed

Munaza Ahmed

Irshad Ahmed

Maryam Afzal

Julian Adlard

Zoe Adhya

Stephen Abbs

Nichola Cooper

Sri V.V. Deevi

James H.R. Farmery

James E.D. Thaventhiran

James E. D. Thaventhiran

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Dr David Allsup hycda1@hyms.ac.uk
Senior Lecturer in Haematology and Honorary Consultant

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. Baxendale

Matthew 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

Sofia Grigoriadou

Aarnoud P. Huissoon

Sarah Goddard

Stephen Jolles

Catharina Schuetz

Felix Boschann

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



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.

Citation

Cooper, N., Abbs, S., Farmery, J. H., Deevi, S. V., Thaventhiran, J. E., Adhya, Z., …Smith, K. G. C. (2020). Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature, 583(7814), 90-95. https://doi.org/10.1038/s41586-020-2265-1

Journal Article Type Article
Acceptance Date Feb 26, 2020
Online Publication Date May 6, 2020
Publication Date Jul 2, 2020
Deposit Date May 7, 2020
Publicly Available Date Nov 7, 2020
Journal Nature
Print ISSN 0028-0836
Electronic ISSN 1476-4687
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 583
Issue 7814
Pages 90-95
DOI https://doi.org/10.1038/s41586-020-2265-1
Keywords Genomics; Immunology
Public URL https://hull-repository.worktribe.com/output/3504021
Publisher URL https://www.nature.com/articles/s41586-020-2265-1
Additional Information Received: 1 December 2018; Accepted: 26 February 2020; First Online: 6 May 2020; : The authors declare no competing interests.

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©2020 The authors. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder






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