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Whole-genome sequencing of a sporadic primary immunodeficiency cohort

Thaventhiran, James E. D.; Primary Immunodeficiency Consortium for the NIHR Bioresource; 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.


James E. D. Thaventhiran

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Dr David Allsup
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


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.

Journal Article Type Article
Journal Nature
Print ISSN 0028-0836
Electronic ISSN 1476-4687
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
APA6 Citation Thaventhiran, J. E. D., Primary Immunodeficiency Consortium for the NIHR Bioresource, , Lango Allen, H., Burren, O. S., Rae, W., Greene, D., …Smith, K. G. C. (in press). Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature,
Keywords Genomics; Immunology
Publisher URL
Additional Information Received: 1 December 2018; Accepted: 26 February 2020; First Online: 6 May 2020; : The authors declare no competing interests.