title: Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome.
abstract: PFAPA syndrome is the most common autoinflammatory syndrome in children from Western countries. In spite of its strong familial clustering, its genetic basis and inheritance pattern are still unknown. We performed a comprehensive genetic study on 68 individuals from 14 families. Linkage analysis suggested a susceptibility locus on chromosome 8, but direct molecular sequencing did not support this initial statistical finding. Exome sequencing revealed the absence of any gene that was mutated in all patients. Exhaustive screening of genes involved in other autoinflammatory syndromes or encoding components of the human inflammasome showed no DNA variants that could be linked to PFAPA molecular pathology. Among these, the previously-reported missense mutation V198M in the NLRP3 gene was clearly shown not to co-segregate with PFAPA. Our results on this relatively large cohort indicate that PFAPA syndrome is unlikely to be a monogenic condition. Moreover, none of the several genes known to be involved in inflammation or in autoinflammatory disorders seem to be relevant, alone, to its etiology, suggesting that PFAPA results from oligogenic or complex inheritance of variants in multiple disease genes and/or non-genetic factors.
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Silvio Alessandro
authors.initials: SA
authors.lastname: Di Gioia
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Bedoni
authors.affiliation: Pediatric Rheumatology Unit of Western Switzerland, Department of Pediatrics, CHUV, University Hospital of Lausanne, Lausanne, Switzerland.
authors.forename: Annette
authors.initials: A
authors.lastname: von Scheven-Gête
authors.affiliation: Pediatric Rheumatology Unit of Western Switzerland, Department of Pediatrics, CHUV, University Hospital of Lausanne, Lausanne, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Vanoni
authors.affiliation: Department of Pediatrics, CHUV, University Hospital of Lausanne, Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.affiliation: 1] Pediatric Rheumatology Unit of Western Switzerland, Department of Pediatrics, CHUV, University Hospital of Lausanne, Lausanne, Switzerland [2] Department of Pediatrics, HUG, Geneva, Switzerland.
authors.forename: Michaël
authors.initials: M
authors.lastname: Hofer
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D005260:Female; D005334:Fever / Q000235:genetics*; D055106:Genome-Wide Association Study; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics*; D006801:Humans; D008199:Lymphadenitis / Q000235:genetics*; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; D010612:Pharyngitis / Q000235:genetics*; D012008:Recurrence; D017422:Sequence Analysis, DNA; D013281:Stomatitis, Aphthous / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; C427903:NLRP1 protein, human; C453881:NLRP3 protein, human