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Brief Report: Association of Tumor Necrosis Factor Receptor–Associated Periodic Syndrome With Gonosomal Mosaicism of a Novel 24-Nucleotide TNFRSF1A Deletion

Rowczenio, DM; Trojer, H; Omoyinmi, E; Arostegui, JI; Arakelov, G; Mensa-Vilaro, A; Baginska, A; ... Lachmann, HJ; + view all (2016) Brief Report: Association of Tumor Necrosis Factor Receptor–Associated Periodic Syndrome With Gonosomal Mosaicism of a Novel 24-Nucleotide TNFRSF1A Deletion. Arthritis & Rheumatology , 68 (8) pp. 2044-2049. 10.1002/art.39683. Green open access

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Abstract

Objective: To investigate the molecular cause of persistent fevers in a patient returning from working overseas, in whom investigations for tropical diseases yielded negative results. / Methods: DNA was extracted from the patient's whole blood, leukocyte subpopulations, saliva, hair root, and sperm. The TNFRSF1A gene was analyzed by polymerase chain reaction (PCR), allele-specific PCR, Sanger sequencing, and next-generation sequencing. In silico molecular modeling was performed to predict the structural and functional consequences of the tumor necrosis factor receptor (TNFR) type I protein mutation in the extracellular domain. / Results: Sanger sequencing corroborated by allele-specific PCR detected a novel in-frame deletion of 24 nucleotides (c.255_278del) in the TNFRSF1A gene, and this was subsequently confirmed using next-generation sequencing methods (targeted sequencing and amplicon-based deep sequencing). Results of amplicon-based deep sequencing revealed variable frequency of the mutant allele among different cell lines, including sperm, thus supporting the presence of gonosomal TNFRSF1A mosaicism. The patient had a complete response to treatment with interleukin-1 (IL-1) blockade, with resolution of symptoms and normalization of acute-phase protein levels. / Conclusion: We describe the first case of gonosomal TNFRSF1A mosaicism in a patient with TNFR-associated periodic syndrome (TRAPS), which was attributable to a novel, somatic 24-nucleotide in-frame deletion. The clinical picture in this patient, including the complete response to IL-1 blockade, was typical of that found in TRAPS. This case adds TRAPS to the list of dominantly inherited autoinflammatory diseases reported to be caused by somatic (or postzygotic) mutation.

Type: Article
Title: Brief Report: Association of Tumor Necrosis Factor Receptor–Associated Periodic Syndrome With Gonosomal Mosaicism of a Novel 24-Nucleotide TNFRSF1A Deletion
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/art.39683
Publisher version: http://dx.doi.org/10.1002/art.39683
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1572255
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