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Guidelines for the genetic diagnosis of hereditary recurrent fevers
  1. Y Shinar1,
  2. L Obici2,
  3. I Aksentijevich3,
  4. B Bennetts4,
  5. F Austrup5,
  6. I Ceccherini6,
  7. J M Costa7,
  8. A De Leener8,
  9. M Gattorno9,
  10. U Kania10,
  11. I Kone-Paut11,
  12. S Lezer12,
  13. A Livneh13,
  14. I Moix14,
  15. R Nishikomori15,
  16. S Ozen16,
  17. L Phylactou17,
  18. L Risom18,
  19. D Rowczenio19,
  20. T Sarkisian20,
  21. M E van Gijn21,
  22. M Witsch-Baumgartner22,
  23. M Morris23,
  24. H M Hoffman24,
  25. I Touitou25
  1. 1Heller Institute of Medical Research, Sheba Medical Center, Tel Hashomer, Israel
  2. 2Amyloid Center, Biotechnology Research Laboratories, Fondazione IRCCS, Policlinico San Matteo, Pavia, Italy
  3. 3National Human Genome Research Institute, Bethesda, Maryland, USA
  4. 4Department of Molecular Genetics, The Children's Hospital at Westmead, Sydney, Australia
  5. 5Department of Human Genetics, LADR-MVZ Recklinghausen, Germany
  6. 6Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova, Italy
  7. 7Department of Molecular Genetics, Laboratoire Cerba, Cergy-Pontoise, France
  8. 8Department of Human Genetics ULB, Hopital Erasme, Brussels, Belgium
  9. 9UO Pediatria II – Reumatologia, Istituto G Gaslini, Genova, Italy
  10. 10Department of Pediatrics, Polish-American Children's Hospital Jagiellonian University Medical College, Poland
  11. 11Department of Paediatric and Paediatric Rheumatology, Reference center for autoinflammatory diseases CEREMAI, Kremlin-Bicêtre Hospital, APHP, University of Paris SUD, Paris, France
  12. 12Pronto diagnostics, Tel Aviv, Israel
  13. 13Heller Institute of Medical Research, Sheba Medical Center, Tel-Hashomer, Tel-Aviv University, Tel-Aviv, Israel
  14. 14Molecular Diagnostic Laboratory, Service of Medical Genetics, Geneva University Hospitals
  15. 15Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
  16. 16Department of Pediatric Rheumatology and Nephrology at Hacettepe University, Ankara, Turkey
  17. 17Department of Molecular Genetics, Function and Therapy, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
  18. 18Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark
  19. 19National Amyloidosis Centre, UCL Medical School, London, UK
  20. 20Center of Medical Genetics and Primary Health Care, Yerevan, Armenia
  21. 21Genome Diagnostics, Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  22. 22Medical University Innsbruck, Sektion Humangenetik, Innsbruck, Austria
  23. 23Molecular Diagnostic Laboratory, Service of Medical Genetics, Geneva University Hospitals, Genève, Switzerland
  24. 24Department of Pediatrics, University of California at San Diego, La Jolla, California, USA
  25. 25CHRU Montpellier, INSERM U844, Université UM1, Montpellier, France
  1. Correspondence to Isabelle Touitou, Unité médicale des maladies autoinflammatoires, CHRU Montpellier, INSERM U844, Université UM1, Montpellier, France; isabelle.touitou{at}


Hereditary recurrent fevers (HRFs) are a group of monogenic autoinflammatory diseases characterised by recurrent bouts of fever and serosal inflammation that are caused by pathogenic variants in genes important for the regulation of innate immunity. Discovery of the molecular defects responsible for these diseases has initiated genetic diagnostics in many countries around the world, including the Middle East, Europe, USA, Japan and Australia. However, diverse testing methods and reporting practices are employed and there is a clear need for consensus guidelines for HRF genetic testing.

Draft guidelines were prepared based on current practice deduced from previous HRF external quality assurance schemes and data from the literature. The draft document was disseminated through the European Molecular Genetics Quality Network for broader consultation and amendment. A workshop was held in Bruges (Belgium) on 18 and 19 September 2011 to ratify the draft and obtain a final consensus document. An agreed set of best practice guidelines was proposed for genetic diagnostic testing of HRFs, for reporting the genetic results and for defining their clinical significance.

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  • Collaborators Hatem El Shanti, Marianne Jakobsen, Kostas Kostantopoulos, Davide Martorana, Maria Grazia Pomponi, Alison Bybee, Catherine Rydlewski

  • Funding EU.

  • Note added in proof While this manuscript was in press, a new article by Verma et al demonstrated a possible functional role of pQ703K (Q705K) in the regulation of inflammation.This variant should therefore be considered a VUS (should be in normal letters in table 1). The Q705K Polymorphism in NLRP3 Is a Gain-of-Function Alteration Leading to Excessive Interleukin-1β and IL-18 Production. Verma D, Särndahl E, Andersson H, et al.PLoS One. 2012;7:e34977. Epub 2012 Apr 17.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it was published Online First.

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