FOXP3 TSDR Measurement Could Assist Variant Classification and Diagnosis of IPEX Syndrome
dc.contributor.author | Wyatt, RC | |
dc.contributor.author | Olek, S | |
dc.contributor.author | De Franco, E | |
dc.contributor.author | Samans, B | |
dc.contributor.author | Patel, K | |
dc.contributor.author | Houghton, J | |
dc.contributor.author | Walter, S | |
dc.contributor.author | Schulze, J | |
dc.contributor.author | Bacchetta, R | |
dc.contributor.author | Hattersley, AT | |
dc.contributor.author | Flanagan, SE | |
dc.contributor.author | Johnson, MB | |
dc.date.accessioned | 2023-08-07T14:02:49Z | |
dc.date.issued | 2023-01-05 | |
dc.date.updated | 2023-08-07T13:00:35Z | |
dc.description.abstract | Pathogenic FOXP3 variants cause immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, a progressive autoimmune disease resulting from disruption of the regulatory T cell (Treg) compartment. Assigning pathogenicity to novel variants in FOXP3 is challenging due to the heterogeneous phenotype and variable immunological abnormalities. The number of cells with demethylation at the Treg cell-specific demethylated region (TSDR) is an independent biomarker of IPEX. We aimed to investigate if diagnosing IPEX at presentation with isolated diabetes could allow for effective monitoring of disease progression and assess whether TSDR analysis can aid FOXP3 variant classification and predict disease course. We describe a large genetically diagnosed IPEX cohort (n = 65) and 13 individuals with other monogenic autoimmunity subtypes in whom we quantified the proportion of cells with FOXP3 TSDR demethylation, normalized to the number with CD4 demethylation (%TSDR/CD4) and compare them to 29 unaffected controls. IPEX patients presenting with isolated diabetes (50/65, 77%) often later developed enteropathy (20/50, 40%) with a median interval of 23.5 weeks. %TSDR/CD4 was a good discriminator of IPEX vs. unaffected controls (ROC-AUC 0.81, median 13.6% vs. 8.5%, p < 0.0001) with higher levels of demethylation associated with more severe disease. Patients with other monogenic autoimmunity had a similar %TSDR/CD4 to controls (median 8.7%, p = 1.0). Identifying increased %TSDR/CD4 in patients with novel FOXP3 mutations presenting with isolated diabetes facilitates diagnosis and could offer an opportunity to monitor patients and begin immune modulatory treatment before onset of severe enteropathy. | en_GB |
dc.description.sponsorship | Wellcome Trust | en_GB |
dc.description.sponsorship | Diabetes UK | en_GB |
dc.description.sponsorship | Research England | en_GB |
dc.description.sponsorship | National Institute for Health and Care Research (NIHR) | en_GB |
dc.format.extent | 662-669 | |
dc.format.medium | Print-Electronic | |
dc.identifier.citation | Vol. 43(3), pp. 662-669 | en_GB |
dc.identifier.doi | https://doi.org/10.1007/s10875-022-01428-w | |
dc.identifier.grantnumber | 219606/Z/19/Z | en_GB |
dc.identifier.grantnumber | 19/005971 | en_GB |
dc.identifier.grantnumber | 105636/Z/14/Z | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/133726 | |
dc.identifier | ORCID: 0000-0002-1437-7891 (De Franco, Elisa) | |
dc.identifier | ORCID: 0000-0002-9240-8104 (Patel, Kashyap) | |
dc.identifier | ScopusID: 57188657944 (Patel, Kashyap) | |
dc.identifier | ORCID: 0000-0001-5620-473X (Hattersley, Andrew T) | |
dc.identifier | ORCID: 0000-0002-6519-6687 (Johnson, Matthew B) | |
dc.identifier | ScopusID: 57191429364 (Johnson, Matthew B) | |
dc.language.iso | en | en_GB |
dc.publisher | Springer | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/36600150 | en_GB |
dc.relation.url | https://www.diabetesgenes.org/current-research/genetic-beta-cell-research-bank/ | en_GB |
dc.rights | © The Author(s) 2023. Open access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ | en_GB |
dc.subject | Epigenetics | en_GB |
dc.subject | FOXP3 | en_GB |
dc.subject | IPEX syndrome | en_GB |
dc.subject | Regulatory T cells | en_GB |
dc.title | FOXP3 TSDR Measurement Could Assist Variant Classification and Diagnosis of IPEX Syndrome | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2023-08-07T14:02:49Z | |
dc.identifier.issn | 0271-9142 | |
exeter.place-of-publication | Netherlands | |
dc.description | This is the final version. Available on open access from Springer via the DOI in this record | en_GB |
dc.description | Data Availability: The genotype and clinical data in this study could be used to identify individuals and so cannot be made openly available. Access to data is open to any scientist or institution that complies with the required data protection regulation to protect the identity of the donors, within the framework of the existing consent. Requests for collaboration can be made by application to the Genetic Beta Cell Research Bank (https://www.diabetesgenes.org/current-research/genetic-beta-cell-research-bank/). | en_GB |
dc.identifier.eissn | 1573-2592 | |
dc.identifier.journal | Journal of Clinical Immunology | en_GB |
dc.relation.ispartof | J Clin Immunol, 43(3) | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2022-12-21 | |
dc.rights.license | CC BY | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2023-01-05 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2023-08-07T13:58:54Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2023-08-07T14:02:56Z | |
refterms.panel | A | en_GB |
refterms.dateFirstOnline | 2023-01-05 |
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Except where otherwise noted, this item's licence is described as © The Author(s) 2023. Open access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/