Imperial College London
Alternate

Dr Peter Kelleher

Faculty of Medicine, Department of Infectious Disease

Reader in Immunology
 
 
 
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Contact

 

+44 (0)20 3315 8251p.kelleher

 
 
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Location

 

J.2.10Chelsea and Westminster HospitalChelsea and Westminster Campus

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Summary

 

Publications

Citation

BibTex format

@article{Thaventhiran:2020:10.1038/s41586-020-2265-1,
author = {Thaventhiran, JED and Lango, Allen H and Burren, OS and Rae, W and Greene, D and Staples, E and Zhang, Z and Farmery, JHR and Simeoni, I and Rivers, E and Maimaris, J and Penkett, CJ and Stephens, J and Deevi, SVV and Sanchis-Juan, A and Gleadall, NS and Thomas, MJ and Sargur, RB and Gordins, P and Baxendale, HE and Brown, M and Tuijnenburg, P and Worth, A and Hanson, S and Linger, RJ and Buckland, MS and Rayner-Matthews, PJ and Gilmour, KC and Samarghitean, C and Seneviratne, SL and Sansom, DM and Lynch, AG and Megy, K and Ellinghaus, E and Ellinghaus, D and Jorgensen, SF and Karlsen, TH and Stirrups, KE and Cutler, AJ and Kumararatne, DS and Chandra, A and Edgar, JDM and Herwadkar, A and Cooper, N and Grigoriadou, S and Huissoon, AP and Goddard, S and Jolles, S and Schuetz, C and Boschann, F and Primary, Immunodeficiency Consortium for the NIHR Bioresource and Lyons, PA and Hurles, ME and Savic, S and Burns, SO and Kuijpers, TW and Turro, E and Ouwehand, WH and Thrasher, AJ and Smith},
doi = {10.1038/s41586-020-2265-1},
journal = {Nature},
pages = {90--95},
title = {Whole-genome sequencing of a sporadic primary immunodeficiency cohort.},
url = {http://dx.doi.org/10.1038/s41586-020-2265-1},
volume = {583},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
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.
AU  - Thaventhiran,JED
AU  - Lango,Allen H
AU  - Burren,OS
AU  - Rae,W
AU  - Greene,D
AU  - Staples,E
AU  - Zhang,Z
AU  - Farmery,JHR
AU  - Simeoni,I
AU  - Rivers,E
AU  - Maimaris,J
AU  - Penkett,CJ
AU  - Stephens,J
AU  - Deevi,SVV
AU  - Sanchis-Juan,A
AU  - Gleadall,NS
AU  - Thomas,MJ
AU  - Sargur,RB
AU  - Gordins,P
AU  - Baxendale,HE
AU  - Brown,M
AU  - Tuijnenburg,P
AU  - Worth,A
AU  - Hanson,S
AU  - Linger,RJ
AU  - Buckland,MS
AU  - Rayner-Matthews,PJ
AU  - Gilmour,KC
AU  - Samarghitean,C
AU  - Seneviratne,SL
AU  - Sansom,DM
AU  - Lynch,AG
AU  - Megy,K
AU  - Ellinghaus,E
AU  - Ellinghaus,D
AU  - Jorgensen,SF
AU  - Karlsen,TH
AU  - Stirrups,KE
AU  - Cutler,AJ
AU  - Kumararatne,DS
AU  - Chandra,A
AU  - Edgar,JDM
AU  - Herwadkar,A
AU  - Cooper,N
AU  - Grigoriadou,S
AU  - Huissoon,AP
AU  - Goddard,S
AU  - Jolles,S
AU  - Schuetz,C
AU  - Boschann,F
AU  - Primary,Immunodeficiency Consortium for the NIHR Bioresource
AU  - Lyons,PA
AU  - Hurles,ME
AU  - Savic,S
AU  - Burns,SO
AU  - Kuijpers,TW
AU  - Turro,E
AU  - Ouwehand,WH
AU  - Thrasher,AJ
AU  - Smith,KGC
DO  - 10.1038/s41586-020-2265-1
EP  - 95
PY  - 2020///
SP  - 90
TI  - Whole-genome sequencing of a sporadic primary immunodeficiency cohort.
T2  - Nature
UR  - http://dx.doi.org/10.1038/s41586-020-2265-1
UR  - https://www.ncbi.nlm.nih.gov/pubmed/32499645
UR  - http://hdl.handle.net/10044/1/80000
VL  - 583
ER  -
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