Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity: a retrospective cohort study
- Radboud University Nijmegen Medical Centre, Netherlands
- University Medical Center Groningen, Netherlands
- Maastricht University Medical Centre, Netherlands
- Leiden University Medical Center, Netherlands
Abstract
Background: De novo variants (DNVs) are currently not routinely evaluated as part of diagnostic whole exome sequencing (WES) analysis in patients with suspected inborn errors of immunity (IEI).
Methods: This study explored the potential added value of systematic assessment of DNVs in a retrospective cohort of 123 patients with a suspected sporadic IEI that underwent patient-parent trio-based WES.
Results: A (likely) molecular diagnosis for (part) of the immunological phenotype was achieved in 12 patients with the diagnostic in silico IEI WES gene panel. Systematic evaluation of rare, non-synonymous DNVs in coding or splice site regions led to the identification of 14 candidate DNVs in genes with an annotated immune function. DNVs were found in IEI genes (NLRP3 and RELA) and in potentially novel candidate genes, including PSMB10, DDX1, KMT2C and FBXW11. The FBXW11 canonical splice site DNV was shown to lead to defective RNA splicing, increased NF-κB p65 signalling, and elevated IL-1β production in primary immune cells extracted from the patient with autoinflammatory disease.<
Conclusions: Our findings in this retrospective cohort study advocate the implementation of trio-based sequencing in routine diagnostics of patients with sporadic IEI. Furthermore, we provide functional evidence supporting a causal role for FBXW11 loss-of-function mutations in autoinflammatory disease.
Funding: This research was supported by grants from the European Union, ZonMW and the Radboud Institute for Molecular Life Sciences.
Data availability
The code used to filter DNA sequencing data for candidate de novo mutations (DNMs) and to generate output files is provided in Figure 1 - source code 1. Source data linked to Figure 1 - figure supplement 1 is provided as an additional, numerical data file. Source data for candidate DNM evaluation is provided in Figure 1 - source data 2. Source data linked to Figure 2 - figure supplement 1A is an uncropped, raw gel image used to create this figure. Source data linked to Figure 2B-D is provided as an additional, numerical data file. Raw DNA sequencing data of patients are not publicly available as it is confidential human subject data that would compromise anonymity. Researchers that are interested to access the sequencing data of our cohort are advised to contact the corresponding author, A. Hoischen (alexander.hoischen@radboudumc.nl). Anonymized subject data will be shared on request from qualified investigators for the purposes of replicating procedures and results, and for other non-commercial research purposes within the limits of participants' consent. Any data sharing will also require evaluation of the request by the regional Arnhem and Nijmegen Ethics Committee and the signature of a data transfer agreement (DTA).
Article and author information
Author details
Frank L van de Veerdonk
Alexander Hoischen
Caspar I van der Made
Funding
European Research Council (No. 833247)
- Mihai G Netea
ZonMw (Spinoza Grant)
- Mihai G Netea
Radboud Institute for Molecular Life Sciences (Internal grant)
- Mihai G Netea
ZonMw (Vidi)
- Frank L van de Veerdonk
H2020 European Research Council (HDM-FUN)
- Frank L van de Veerdonk
H2020 European Research Council (Solve-RD (No. 779257))
- Alexander Hoischen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Tony Yuen, Icahn School of Medicine at Mount Sinai, United States
Ethics
Human subjects: Patients and their parents provided written informed consent for in silico inborn errors of immunity whole exome sequencing gene panel analysis with or without exome-wide variant analysis in line with the diagnostic procedure and clinical question, as approved by the Medical Ethics Review Committee Arnhem-Nijmegen (2011/188 and 2020-7142). This research is in compliance with the principles of the Declaration of Helsinki.
Version history
- Received: March 8, 2022
- Preprint posted: April 18, 2022 (view preprint)
- Accepted: October 5, 2022
- Accepted Manuscript published: October 17, 2022 (version 1)
- Version of Record published: November 4, 2022 (version 2)
Copyright
© 2022, Hebert et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity: a retrospective cohort study
eLife 11:e78469.
https://doi.org/10.7554/eLife.78469
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