title: Brief Report: Association of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome With Gonosomal Mosaicism of a Novel 24-Nucleotide TNFRSF1A Deletion.
abstract: To investigate the molecular cause of persistent fevers in a patient returning from working overseas, in whom investigations for tropical diseases yielded negative results.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: University College London, London, UK.
authors.forename: Dorota M
authors.initials: DM
authors.lastname: Rowczenio
authors.affiliation: University College London, London, UK.
authors.forename: Hadija
authors.initials: H
authors.lastname: Trojer
authors.affiliation: University College London, London, UK.
authors.forename: Ebun
authors.initials: E
authors.lastname: Omoyinmi
authors.affiliation: Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Aróstegui
authors.affiliation: Institute of Molecular Biology NAS RA, Laboratory of Computation Modeling of Biological Processes, and Russian-Armenian Slavonic University, Group for Bioinformation Technologies of Research Center for Critical Technologies, Yerevan, Armenia.
authors.forename: Grigor
authors.initials: G
authors.lastname: Arakelov
authors.affiliation: Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Mensa-Vilaro
authors.affiliation: University College London, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Baginska
authors.affiliation: University College London, London, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Silva Pilorz
authors.affiliation: University College London, London, UK.
authors.forename: Guosu
authors.initials: G
authors.lastname: Wang
authors.affiliation: University College London, London, UK.
authors.forename: Thirusha
authors.initials: T
authors.lastname: Lane
authors.affiliation: University College London, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Brogan
authors.affiliation: University College London, London, UK.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
authors.affiliation: University College London, London, UK.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Lachmann
mesh_terms: D000328:Adult; D005334:Fever / Q000235:genetics*; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics*; D006801:Humans; D008297:Male; D009030:Mosaicism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human