Whole-genome sequencing of a sporadic primary immunodeficiency cohort

Thaventhiran, James E. D.; Allen, Hana Lango; 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; Cooper, Nichola; 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.

Whole-genome sequencing of a sporadic primary immunodeficiency cohort

James E. D. Thaventhiran (), 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, Nichola Cooper, 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 and Kenneth G. C. Smith ()
Additional contact information
James E. D. Thaventhiran: Cambridge Biomedical Campus
Hana Lango Allen: Cambridge Biomedical Campus
Oliver S. Burren: Cambridge Biomedical Campus
William Rae: Cambridge Biomedical Campus
Daniel Greene: Cambridge Biomedical Campus
Emily Staples: Cambridge Biomedical Campus
Zinan Zhang: Cambridge Biomedical Campus
James H. R. Farmery: Cambridge Biomedical Campus
Ilenia Simeoni: Cambridge Biomedical Campus
Elizabeth Rivers: UCL Great Ormond Street Institute of Child Health
Jesmeen Maimaris: UCL Great Ormond Street Institute of Child Health
Christopher J. Penkett: Cambridge Biomedical Campus
Jonathan Stephens: Cambridge Biomedical Campus
Sri V. V. Deevi: Cambridge Biomedical Campus
Alba Sanchis-Juan: Cambridge Biomedical Campus
Nicholas S. Gleadall: Cambridge Biomedical Campus
Moira J. Thomas: Queen Elizabeth University Hospital
Ravishankar B. Sargur: Sheffield Teaching Hospitals NHS Foundation Trust
Pavels Gordins: Hull and East Yorkshire Hospitals NHS Trust
Helen E. Baxendale: Cambridge Biomedical Campus
Matthew Brown: Cambridge Biomedical Campus
Paul Tuijnenburg: Emma Children’s Hospital
Austen Worth: UCL Great Ormond Street Institute of Child Health
Steven Hanson: University College London
Rachel J. Linger: Cambridge University Hospitals, Cambridge Biomedical Campus
Matthew S. Buckland: University College London
Paula J. Rayner-Matthews: Cambridge Biomedical Campus
Kimberly C. Gilmour: UCL Great Ormond Street Institute of Child Health
Crina Samarghitean: Cambridge Biomedical Campus
Suranjith L. Seneviratne: University College London
David M. Sansom: University College London
Andy G. Lynch: University of Cambridge, Li Ka Shing Centre
Karyn Megy: Cambridge Biomedical Campus
Eva Ellinghaus: University of Oslo, Oslo University Hospital
David Ellinghaus: University of Oslo, Oslo University Hospital
Silje F. Jorgensen: Oslo University Hospital
Tom H. Karlsen: University of Oslo, Oslo University Hospital
Kathleen E. Stirrups: Cambridge Biomedical Campus
Antony J. Cutler: University of Oxford
Dinakantha S. Kumararatne: Cambridge Biomedical Campus
Anita Chandra: Cambridge Biomedical Campus
J. David M. Edgar: St James’s Hospital
Archana Herwadkar: Salford Royal NHS Foundation Trust
Nichola Cooper: Imperial College London
Sofia Grigoriadou: Barts Health NHS Foundation Trust
Aarnoud P. Huissoon: University Hospitals Birmingham
Sarah Goddard: University Hospitals of North Midlands NHS Trust
Stephen Jolles: University Hospital of Wales
Catharina Schuetz: University Hospital Carl Gustav Carus
Felix Boschann: Charité–Universitätsmedizin Berlin
Paul A. Lyons: Cambridge Biomedical Campus
Matthew E. Hurles: Wellcome Genome Campus
Sinisa Savic: St James’s University Hospital
Siobhan O. Burns: University College London
Taco W. Kuijpers: Emma Children’s Hospital
Ernest Turro: Cambridge Biomedical Campus
Willem H. Ouwehand: Cambridge Biomedical Campus
Adrian J. Thrasher: UCL Great Ormond Street Institute of Child Health
Kenneth G. C. Smith: Cambridge Biomedical Campus

Nature, 2020, vol. 583, issue 7814, 90-95

Abstract: 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 malignancies1–3. 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.

Date: 2020
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DOI: 10.1038/s41586-020-2265-1

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