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Whole-genome sequencing of a sporadic primary immunodeficiency cohort

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  • James E.D. Thaventhiran, Jeffrey Cheah Biomedical Centre, University of Cambridge, University of Cambridge School of Clinical Medicine
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  • Hana Lango Allen, University of Cambridge, NHS Blood and Transplant, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • Oliver S. Burren, Jeffrey Cheah Biomedical Centre, University of Cambridge School of Clinical Medicine
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  • William Rae, Jeffrey Cheah Biomedical Centre, University of Cambridge School of Clinical Medicine
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  • Daniel Greene, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine, Medical Research Council Biostatistics Unit
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  • Emily Staples, University of Cambridge, School of Clinical Medicine.
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  • Zinan Zhang, Jeffrey Cheah Biomedical Centre, National Institutes of Health, University of Cambridge School of Clinical Medicine
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  • James H.R. Farmery, University of Cambridge, Medical Research Council Biostatistics Unit
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  • Ilenia Simeoni, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • Elizabeth Rivers, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust
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  • Jesmeen Maimaris, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust
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  • Christopher J. Penkett, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • Jonathan Stephens, NHS Blood and Transplant, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • Sri V.V. Deevi, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • Alba Sanchis-Juan, NHS Blood and Transplant, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • Nicholas S. Gleadall, NHS Blood and Transplant, University of Cambridge School of Clinical Medicine
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  • Moira J. Thomas, Queen Elizabeth University Hospital, Gartnavel General Hospital
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  • Ravishankar B. Sargur, Sheffield Teaching Hospitals NHS Foundation Trust, University of Sheffield
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  • Pavels Gordins, Hull and East Yorkshire Hospitals NHS Trust
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  • Helen E. Baxendale, Jeffrey Cheah Biomedical Centre, University of Cambridge School of Clinical Medicine, Royal Papworth Hospital NHS Foundation Trust
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  • Matthew Brown, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • Paul Tuijnenburg, University of Amsterdam, Emma Children’s Hospital, Amsterdam
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  • Austen Worth, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust
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  • Steven Hanson, University College London, Royal Free London NHS Foundation Trust
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  • Rachel J. Linger, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge
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  • Matthew S. Buckland, University College London, Royal Free London NHS Foundation Trust
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  • Paula J. Rayner-Matthews, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • Kimberly C. Gilmour, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust
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  • Crina Samarghitean, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • Suranjith L. Seneviratne, University College London, Royal Free London NHS Foundation Trust
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  • David M. Sansom, University College London, Royal Free London NHS Foundation Trust
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  • Andy G. Lynch, University of Cambridge, University of St Andrews
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  • Karyn Megy, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • Eva Ellinghaus, Oslo University Hospital
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  • David Ellinghaus, Christian Albrechts University of Kiel, Oslo University Hospital
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  • Silje F. Jorgensen, Oslo University Hospital
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  • Tom H. Karlsen, Oslo University Hospital
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  • Kathleen E. Stirrups, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • Antony J. Cutler, University of Oxford
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  • Dinakantha S. Kumararatne, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • Anita Chandra, Jeffrey Cheah Biomedical Centre, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge School of Clinical Medicine
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  • J. David M. Edgar, Trinity College Dublin, St James’s Hospital, Dublin
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  • Archana Herwadkar, Salford Royal NHS Foundation Trust
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  • Nichola Cooper, Imperial College London
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  • Sofia Grigoriadou, Barts Health NHS Foundation Trust
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  • Aarnoud P. Huissoon, University Hospitals Birmingham NHS Foundation Trust
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  • Mark Johnson, Chelsea and Westminster Hospital NHS Foundation Trust
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  • David C. Thomas, University of Cambridge
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  • Wei Wei, University of Cambridge, Medical Research Council
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  • Primary Immunodeficiency Consortium for the NIHR Bioresource

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.

Original languageEnglish
JournalNature
Volume583
Issue7814
Pages (from-to)90-95
Number of pages6
ISSN0028-0836
DOIs
Publication statusPublished - Jul 2020

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