Acknowledgements
We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health and Care Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
Funding:
This work was supported by the National Institute for Health Research UCLH Biomedical Research Centre (ASA, ECM) and the National Institute for Health Research Integrated Academic Training scheme (JM).
Conflict of Interest Statement:
SOB has received grant support from CSL Behring and personal fees or travel expenses from Immunodeficiency Canada/IAACI, CSL Behring, Baxalta US Inc and Biotest. ECM has received honoraria from GlaxoSmithKline, AstraZeneca and Orchard Therapeutics. BG was an advisor to the following companies: UCB Pharma S.A., Epimune GmbH, Octapharma, Atheneum Partners GmbH, and GigaGen Inc. and a speaker for Janssen-Cilag GmbH. The rest of the authors declare that they have no conflicts of interest.
Availability of data and other material
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
JM, ECM and SOB contributed to the study conception and design. Experimental work, material preparation, data collection and analysis were performed by EK, JM, PJ and AA. Consortium facilitated sequencing of patients. JM, RG, BG and SOB contributed to the clinical care of the family. JM, FM and BG facilitated patient recruitment and collected samples for the study. ECM and SOB supervised the study. The first draft of the manuscript was written by JM and all authors read, and approved the final manuscript.
Ethics approval
The NIHR BioResource Rare Diseases project was approved by the national institutional review board (13/EE/0325). Informed consent for obtaining blood and skin biopsy samples for functional assays were taken in accordance with the Declaration of Helsinki and with approvals from local ethics committees with ethical approval (reference numbers 04/Q0501/119 and 06/Q0508/16).
Consent to participate
All participants provided written informed consent prior to participation.
Consent for publication
Not applicable
Consortia
NIHR BioResource – Rare Diseases Consortium:
The members of the NIHR BioResource – Rare Diseases PID Consortium are Zoe Adhya, Hana Alachkar, Ariharan Anantharachagan, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Barbara Boardman, Claire Booth, Michael Browning, Mary Brownlie, Siobhan Burns, Anita Chandra, Hayley Clifford, Nichola Cooper, Sophie Davies, John Dempster, Lisa Devlin, Rainer Doffinger, Elizabeth Drewe, David Edgar, William Egner, Tariq El-Shanawany, Bobby Gaspar, Rohit Ghurye, Kimberley Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Stephen Hughes, Aarnoud Huissoon, Stephen Jolles, Julie Jones, Peter Kelleher, Nigel Klein, Taco Kuijpers (principal investigator), Dinakantha Kumararatne, James Laffan, Hana Lango Allen, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Hazel Millar, Anoop Mistry, Valerie Morrisson, Sai Murng, Iman Nasir, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Ellen Quinn, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith Seneviratne, Carrock Sewall, Fiona Shackley, Ilenia Simeoni, Kenneth G. C. Smith (principal investigator), Emily Staples, Hans Stauss, Cathal Steele, James Thaventhiran, Moira Thomas, Adrian Thrasher (principal investigator), Steve Welch, Lisa Willcocks, Sarita Workman, Austen Worth, Nigel Yeatman, and Patrick Yong.
The members of the NIHRBR-RD Management Team are Sofie Ashford, John Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Willem Ouwehand, Christopher Penkett, F Lucy Raymond, Kathleen Stirrups, Marijke Veltman, and Tim Young.
The members of the NIHRBR-RD Enrolment and Ethics Team are Sofie Ashford, Matthew Brown, Naomi Clements-Brod, John Davis, Eleanor Dewhurst, Marie Erwood, Amy Frary, Rachel Linger, Jennifer Martin, Sofia Papadia, and Karola Rehnstrom.
The members of the NIHRBR-RD Bioinformatics Team are William Astle, Antony Attwood, Marta Bleda, Keren Carss, Louise Daugherty, Sri Deevi, Stefan Graf, Daniel Greene, Csaba Halmagyi, Matthias Haimel, Fengyuan Hu, Roger James, Hana Lango Allen, Vera Matser, Stuart Meacham, Karyn Megy, Christopher Penkett, Olga Shamardina, Kathleen Stirrups, Catherine Titterton, Salih Tuna, Ernest Turro, Ping Yu, and Julie von Ziegenweldt.
The members of the Cambridge Translational Genomics Laboratory are Abigail Furnell, Rutendo Mapeta, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Kathleen Stirrups, Deborah Whitehorn, Paula Rayner-Matthews, and Christopher Watt.