title: An Israeli Arab patient with a de novo TNFRSF1A mutation causing tumor necrosis factor receptor-associated periodic syndrome.
abstract: OBJECTIVE
  To investigate genetic susceptibility to recurrent fevers, generalized severe myalgia, and migratory erythema in an Israeli Arab child with no family history of similar disease.
  
  
  METHODS
  DNA sequencing of exons 1-6 of the TNFRSF1A gene (formerly TNFR1) was performed in the patient and his parents to determine the presence of the autosomal-dominant tumor necrosis factor receptor-associated periodic syndrome (TRAPS); informative markers spanning the TNFRSF1A locus were used to genotype all available members of the patient's family. The TNFRSF1A gene was subsequently screened in 69 healthy Arab controls and 96 Caucasian controls. Formal forensic paternity testing was performed on the child.
  
  
  RESULTS
  We found a de novo missense mutation in exon 3 of the TNFRSF1A gene, involving a novel C-->T transition encoding a Cys70Arg (C70R) variant, in the Israeli Arab patient. Eight of the common familial Mediterranean fever (FMF) gene MEFV mutations were excluded. This mutation was not present in the parents or siblings, or among the 69 healthy Arab controls. However, another TNFRSF1A variant, Pro46Lys (P46L), was present in 1 of the Arab controls.
  
  
  CONCLUSIONS
  We have identified a TNFRSF1A mutation associated with periodic fever in an Arab patient, and a TNFRSF1A variant, which is variably pathogenic in Caucasians, in an Arab control. This is the first report of a de novo mutation in periodic fevers in general, and also of TRAPS in the Arab population. These findings demonstrate the need to include TRAPS in the differential diagnosis of recurrent fevers in this population.
authors.affiliation: MRCPI: Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, UK.
authors.forename: Ebun
authors.initials: E
authors.lastname: Aganna
authors.forename: Avraham
authors.initials: A
authors.lastname: Zeharia
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hitman
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Allotey
authors.forename: David R
authors.initials: DR
authors.lastname: Booth
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
authors.forename: Catherine
authors.initials: C
authors.lastname: Thacker
authors.forename: Denise
authors.initials: D
authors.lastname: Syndercombe-Court
authors.forename: Michael F
authors.initials: MF
authors.lastname: McDermott
mesh_terms: D000293:Adolescent; D015703:Antigens, CD / Q000235:genetics*; D018912:Arabs / Q000235:genetics*; D010505:Familial Mediterranean Fever / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007557:Israel; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I
chemical_list: D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I