title: Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study.
abstract: BACKGROUND
  Periodic fever syndromes (PFS) are an emerging group of autoinflammatory disorders. Clinical overlap exists and multiple genetic analyses may be needed to assist diagnosis. We evaluated the diagnostic value of a 5-gene sequencing panel (5GP) in patients with undiagnosed PFS.
  
  
  METHODS
  Simultaneous double strand Sanger sequencing of MEFV, MVK, TNFRSF1A, NLRP3, NLRP12 genes was performed in 42 patients with unexplained PFS. Clinical features were correlated with genetic results.
  
  
  RESULTS
  None of 42 patients analyzed displayed a causative genotype. However, single or multiple genetic variants of uncertain significance were detected in 24 subjects. Only in 5 subjects a definite diagnosis was made by taking into account both genetic and clinical data (2 TRAPS syndrome; 2 FMF; 1 FCAS). Statistical analysis showed that patients carrying genetic variants in one or more of the five selected genes displayed a significantly lower response to glucocorticoids compared with subjects who had completely negative genetic results.
  
  
  CONCLUSIONS
  The sequencing of multiple genes is of little help in the diagnostics of PFS and can often lead to results of uncertain interpretation, thus the clinically driven sequencing of single genes should remain the recommended approach. However, the presence of single or multiple genetic variants of uncertain significance, even if not allowing any specific diagnosis, correlated with a poorer response to glucocorticoids, possibly indicating a multifactorial subgroup of PFS with differential response to pharmacological treatment.
authors: Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy.
authors: Carlo
authors: C
authors: De Pieri
authors: University of Trieste, Trieste, Italy.
authors: Josef
authors: J
authors: Vuch
authors: Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy.
authors: Eleonora
authors: E
authors: De Martino
authors: Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy.
authors: Anna M
authors: AM
authors: Bianco
authors: Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy.
authors: Luca
authors: L
authors: Ronfani
authors: Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy.
authors: Emmanouil
authors: E
authors: Athanasakis
authors: Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy.
authors: Barbara
authors: B
authors: Bortot
authors: Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy ; University of Trieste, Trieste, Italy.
authors: Sergio
authors: S
authors: Crovella
authors: Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy ; University of Trieste, Trieste, Italy.
authors: Andrea
authors: A
authors: Taddio
authors: Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy.
authors: Giovanni M
authors: GM
authors: Severini
authors: Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy.
authors: Alberto
authors: A
authors: Tommasini
mesh_terms: D000293:Adolescent; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D056587:Cryopyrin-Associated Periodic Syndromes / Q000175:diagnosis / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics; D010505:Familial Mediterranean Fever / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005334:Fever; D020869:Gene Expression Profiling; D005838:Genotype; D056660:Hereditary Autoinflammatory Diseases / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D016015:Logistic Models; D008297:Male; D009154:Mutation / Q000235:genetics; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D011446:Prospective Studies; D000071198:Pyrin; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D013577:Syndrome
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000604192:MEFV protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C476731:NLRP12 protein, human; C453881:NLRP3 protein, human; D000071198:Pyrin; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase
keywords: Auto-inflammatory diseases; Genetics; Periodic fever syndromes