An interferonopathy associated with a monoallelic variant in TRIM28.
7 affiliations
- 1UCL GOS Institute of Child Health, London, UK. [email protected].
- 2UCL GOS Institute of Child Health, London, UK.
- 3Division of Evolution, Infection and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
- 4Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163, Paris, France.
- 5Great Ormond Street NHS Foundation Trust, London, UK.
- 6University of Bath, Bath, UK.
- 7Instituto Portugues de Reumatologia, Lisbon, Portugal.
Abstract
Background
In this work, we describe the clinical and functional changes in a family with a novel type I interferonopathy phenotype which we suggest could be associated with a TRIM28 variant, presenting with chilblains, skin ulceration, lipodystrophy and calcinosis. TRIM28 has multiple roles in regulating human health and disease, which include DNA repair and anti-viral response. The latter includes negative regulation of IRF7, one of the master regulators of the interferon response.Methods
Whole exome sequencing and targeted panel sequencing was performed on DNA extracted from peripheral blood. Functional work included gene (qPCR), protein (WB) and cytokine (MSD and SIMOA) expression studies. Transfection studies of siRNA in control Human Dermal Fibroblast Cells (HDFCs) using RNAiMAX and of wild-type protein in patient HDFCs using FuGENE HD were also performed.Results
Analysis of WES data according to a dominant model with incomplete penetrance revealed TRIM28 c.A623G; p.Y208C in the proband of Family A and his mildly affected mother. Gene expression studies revealed persistent elevation of interferon inducible proteins including increased gene as well as protein expression of IRF7. Cytokine measurements revealed a marked elevation of pro-inflammatory cytokines particularly IFNβ in affected individuals. A good clinical and functional response to treatment with baricitinib was documented, however the proband subsequently died of septic complications. TRIM28-siRNA transfection into control HDFCs resulted in changes in gene, protein and cytokine expression similar to those seen in the proband. Transfection of a wild-type pEGFP-TRIM28 plasmid into the proband's HDFCs achieved partial rescue of the cellular phenotype.Discussion
We describe a novel and severe interferonopathy potentially associated with an autosomal dominant TRIM28 variant with an incomplete penetrance disease model, presenting with skin ulceration, calcinosis, high interferon scores, and upregulation of IRF7. Pathogenicity was supported by TRIM28 gene silencing in healthy HDFCs. Polymorphisms in other genes such as ITGAM could modulate penetrance and expressivity.
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BibTeX
@article{gomes2026interferonopathy,
title = {{An interferonopathy associated with a monoallelic variant in TRIM28.}},
author = {Sonia Melo Gomes and Ebun Omoyinmi and Ying Hong and Gillian Rice and Luis Seabra and Vincent Bondet and Darragh Duffy and Glenn Anderson and Florence Adams and Fionnuala McMorrow and Charalampia Papadopoulou and J A Melo Gomes and Paul Brogan},
journal = {Pediatric rheumatology online journal},
year = {2026},
month = jul,
doi = {10.1186/s12969-026-01248-x},
url = {https://europepmc.org/article/MED/42908010},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - An interferonopathy associated with a monoallelic variant in TRIM28.
AU - Sonia Melo Gomes
AU - Ebun Omoyinmi
AU - Ying Hong
AU - Gillian Rice
AU - Luis Seabra
AU - Vincent Bondet
AU - Darragh Duffy
AU - Glenn Anderson
AU - Florence Adams
AU - Fionnuala McMorrow
AU - Charalampia Papadopoulou
AU - J A Melo Gomes
AU - Paul Brogan
PY - 2026
DA - 2026/07/01
JO - Pediatric rheumatology online journal
DO - 10.1186/s12969-026-01248-x
UR - https://europepmc.org/article/MED/42908010
AB - Background In this work, we describe the clinical and functional changes in a family with a novel type I interferonopathy phenotype which we suggest could be associated with a TRIM28 variant, presenting with chilblains, skin ulceration, lipodystrophy and calcinosis. TRIM28 has multiple roles in regulating human health and disease, which include DNA repair and anti-viral response. The latter includes negative regulation of IRF7, one of the master regulators of the interferon response.Methods Whole exome sequencing and targeted panel sequencing was performed on DNA extracted from peripheral blood. Functional work included gene (qPCR), protein (WB) and cytokine (MSD and SIMOA) expression studies. Transfection studies of siRNA in control Human Dermal Fibroblast Cells (HDFCs) using RNAiMAX and of wild-type protein in patient HDFCs using FuGENE HD were also performed.Results Analysis of WES data according to a dominant model with incomplete penetrance revealed TRIM28 c.A623G; p.Y208C in the proband of Family A and his mildly affected mother. Gene expression studies revealed persistent elevation of interferon inducible proteins including increased gene as well as protein expression of IRF7. Cytokine measurements revealed a marked elevation of pro-inflammatory cytokines particularly IFNβ in affected individuals. A good clinical and functional response to treatment with baricitinib was documented, however the proband subsequently died of septic complications. TRIM28-siRNA transfection into control HDFCs resulted in changes in gene, protein and cytokine expression similar to those seen in the proband. Transfection of a wild-type pEGFP-TRIM28 plasmid into the proband's HDFCs achieved partial rescue of the cellular phenotype.Discussion We describe a novel and severe interferonopathy potentially associated with an autosomal dominant TRIM28 variant with an incomplete penetrance disease model, presenting with skin ulceration, calcinosis, high interferon scores, and upregulation of IRF7. Pathogenicity was supported by TRIM28 gene silencing in healthy HDFCs. Polymorphisms in other genes such as ITGAM could modulate penetrance and expressivity.
SN - 1546-0096
ER -