title: Clinical dose effect and functional consequences of R92Q in two families presenting with a TRAPS/PFAPA-like phenotype.
abstract: BACKGROUND
  TNF receptor-associated syndrome (TRAPS) is a dominantly inherited autoinflammatory condition caused by mutations in theTNFRSF1Agene. The mechanism underlying the variable expressivity of the common variant R92Q (rs4149584; c.362G>A; p.Arg121Gln) is unclear and is of critical importance for patient care and genetic counseling. This study evaluated the impact of the number of R92Q mutations in two unique unrelated families.
  
  
  METHODS
  Two patients with undefined but clear autoinflammatory symptoms were referred for genetic diagnosis. Blood samples were collected from the available family members to screen autoinflammatory genes and assess key steps of the TNFR1-mediated signaling pathway using flow cytometry and ex vivo culture.
  
  
  RESULTS
  R92Q homozygosity was demonstrated for the two probands. In family 1, the segregation analysis revealed TRAPS-like symptoms in all carriers, with a more severe presentation in the proband, whereas in family 2, the heterozygous parents were totally asymptomatic, suggesting recessive transmission. Functional studies revealed a nonclassical pathogenesis of TRAPS in the two probands and suggested a compensatory mechanism without clear dose effect.
  
  
  CONCLUSIONS
  We observed for the first time a possible clinical dose effect of R92Q. This work highlights the importance of familial studies to reconcile the contradictory reports published on the pathogenicity of this variant.
authors.affiliation: Département de génétique médicale, maladies rares et médecine personnaliséeCHRU de MontpellierMontpellierFrance; INSERM UMR1183IRMBMontpellierFrance.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Grandemange
authors.affiliation: Service de pédiatrie CHU de Pau Pau France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Cabasson
authors.affiliation: Département de génétique médicale, maladies rares et médecine personnaliséeCHRU de MontpellierMontpellierFrance; INSERM UMR1183IRMBMontpellierFrance; Centre de référence des maladies autoinflammatoiresCeRéMAICHRU de MontpellierMontpellierFrance; Université de MontpellierMontpellierFrance.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sarrabay
authors.affiliation: INSERM UMR1183 IRMB Montpellier France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Pène
authors.affiliation: Département de génétique médicale, maladies rares et médecine personnaliséeCHRU de MontpellierMontpellierFrance; INSERM UMR1183IRMBMontpellierFrance.
authors.forename: Cécile
authors.initials: C
authors.lastname: Rittore
authors.affiliation: Département de génétique médicale, maladies rares et médecine personnaliséeCHRU de MontpellierMontpellierFrance; INSERM UMR1183IRMBMontpellierFrance.
authors.forename: Elodie
authors.initials: E
authors.lastname: Sanchez
authors.affiliation: Service de pédiatrie médicale CHRU de Bordeaux Bordeaux France.
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Chastang
authors.affiliation: Service de pédiatrie générale CHRU de Montpellier Montpellier France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Guyon
authors.affiliation: Service de pédiatrie médicale CHRU de Bordeaux Bordeaux France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Pillet
authors.affiliation: Département de génétique médicale, maladies rares et médecine personnaliséeCHRU de MontpellierMontpellierFrance; INSERM UMR1183IRMBMontpellierFrance; Centre de référence des maladies autoinflammatoiresCeRéMAICHRU de MontpellierMontpellierFrance; Université de MontpellierMontpellierFrance.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Touitou
keywords: Clinical dose effect; R92Q; TNFRSF1A; TRAPS recessive