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Guidelines for the Genetic Diagnosis of Hereditary Recurrent Fevers

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Guidelines for the Genetic Diagnosis of Hereditary Recurrent Fevers Recommendation Ann Rheum Dis: first published as 10.1136/annrheumdis-2011-201271 on 1 June 2012. Downloaded from Guidelines for the genetic diagnosis of hereditary recurrent fevers Y Shinar,1 L Obici,2 I Aksentijevich,3 B Bennetts,4 F Austrup,5 I Ceccherini,6 J M Costa,7 A De Leener,8 M Gattorno,9 U Kania,10 I Kone-Paut,11 S Lezer,12 A Livneh,13 I Moix,14 R Nishikomori,15 S Ozen,16 L Phylactou,17 L Risom,18 D Rowczenio,19 T Sarkisian,20 M E van Gijn,21 M Witsch-Baumgartner,22 M Morris,23 H M Hoffman,24 I Touitou25 ▶ Additional material is ABSTRACT Since the discovery of these four HRF genes, published online only. To view Hereditary recurrent fevers (HRFs) are a group of almost 700 nucleotide variants have been identi- these fi les please visit the journal fi ed and recorded in Infevers, a database dedicated online (http://dx.doi.org/10.1136/ monogenic autoinfl ammatory diseases characterised by annrheumdis-2011-201271). recurrent bouts of fever and serosal infl ammation that to autoinfl ammatory sequence variants (http:// are caused by pathogenic variants in genes important fmf.igh.cnrs.fr/ISSAID/infevers/).4–6 Some of these For numbered affi liations see variants are clearly pathogenic, but most are uncon- end of article for the regulation of innate immunity. Discovery of the molecular defects responsible for these diseases has fi rmed or seemingly non-pathogenic variants. A Correspondence to initiated genetic diagnostics in many countries around signifi cant number of patients clinically diagnosed Isabelle Touitou, Unité the world, including the Middle East, Europe, USA, with recessive HRFs have been found to carry only médicale des maladies Japan and Australia. However, diverse testing methods one disease-associated mutation in the respective autoinfl ammatoires, CHRU and reporting practices are employed and there is a genes7 despite extensive searching for a second Montpellier, INSERM 8 9 U844, Université UM1, clear need for consensus guidelines for HRF genetic pathogenic mutation in the coding region, and Montpellier, France; testing. continuing search for mutations affecting regula- [email protected] Draft guidelines were prepared based on current tory sequences or transcript splicing that would practice deduced from previous HRF external quality affect gene expression.10 11 Accepted 8 April 2012 assurance schemes and data from the literature. Genetic testing for HRF is a logical and feasible way The draft document was disseminated through the to corroborate clinical diagnosis.12 13 Five-year experi- European Molecular Genetics Quality Network for ence of external quality assessment and profi ciency broader consultation and amendment. A workshop testing (PT) (external quality assurance/PT) conducted was held in Bruges (Belgium) on 18 and 19 September between 2006 and 2010 showed that although there 2011 to ratify the draft and obtain a fi nal consensus has been an impressive improvement in the quality document. An agreed set of best practice guidelines of HRF testing and reporting, many issues still remain was proposed for genetic diagnostic testing of HRFs, for to be addressed and standardised.14 Guidelines using reporting the genetic results and for defi ning their clinical the standard defi nition by Field and Lohr15 are now http://ard.bmj.com/ signifi cance. proposed to provide a framework for best labora- tory practice and reporting on the genetic diagnosis of HRFs as agreed by an international consortium of experts in the fi eld. They are intended to be INTRODUCTION used primarily by molecular geneticists and by other Patients with hereditary recurrent fevers (HRFs) health professionals involved in the care of these present with recurrent bouts of fever and infl amma- patients. on September 28, 2021 by guest. Protected copyright. tory symptoms involving, in particular, the abdo- men, joints and skin.1 2 The causative genes for HRFs encode proteins involved in the regulation of METHODOLOGY innate immunity, mainly by affecting proinfl am- A draft report was written by the organisers and matory cytokines and apoptosis pathways. While assessors of the European Molecular Genetics familial Mediterranean fever (FMF) is relatively com- Quality Network for HRFs with reference to mon in several Mediterranean and Middle Eastern relevant literature, reviews of reports issued dur- populations,3 most HRFs are rare diseases. The ing the fi ve previous international HRF meetings, best-characterised HRFs are two recessively inher- web-based resources relating to the subject and ited diseases: (FMF, gene MEFV, MIM 608107) and examples of guidelines for other hereditary dis- mevalonate kinase defi ciency (MKD, gene MVK, eases (eg, haemochromatosis,16 cystic fi brosis17 and MIM 251170) and two dominantly inherited dis- von Willebrand18 diseases). The draft was dissemi- eases: tumour necrosis factor (TNF) receptor-asso- nated to molecular geneticists and clinicians work- ciated periodic syndrome (TRAPS, gene TNFRSF1A, ing in the fi eld of HRFs and discussed with them MIM 191190) and cryopyrin-associated periodic during a best practice workshop held in Bruges syndrome (CAPS, gene NLRP3, MIM 606416). (Belgium) on 18 and 19 September 2011. In the Patients with HRF often display similar infl amma- light of feedback of the participants, amendments tory symptoms with variable intensity and localisa- were made and a second draft was disseminated tion of symptoms, making their clinical diagnosis by email, after which, the fi nal document was diffi cult. ratifi ed. Ann Rheum Dis 2012;71:1599–1605. doi:10.1136/annrheumdis-2011-201271 1599 Recommendation Ann Rheum Dis: first published as 10.1136/annrheumdis-2011-201271 on 1 June 2012. Downloaded from INDICATIONS FOR HRF TESTING molecular geneticist. It provides a comprehensive and updated Minimal requirements for the genetic test list of gene variants and a reference database for the mutation We suggest that the following minimum set of requirements nomenclature, but an accurate phenotype–genotype correlation should be obtained: patient name, date of birth, gender, ethnic- is not available. In addition, clinical reference centres were for- ity/origin, written informed consent (depending on country- mally nominated or are recognised in several countries (France, specifi c law), referring doctor’s name and contact details of the Italy, Spain, UK, Germany, Turkey, Israel, USA…). As HRFs are person who will receive the results. rare diseases mostly caused by single-nucleotide substitutions, genetic testing should be referred to specialised laboratories to Symptomatic patients ensure that pertinent tests are performed and proper information The main indication for genetic testing of HRFs is in the case of is reported to clinicians, particularly those inexperienced with a patient with a clinical symptom pattern consistent with one HRFs. These laboratories should work within a comprehensive or more of the syndromes. Thus, clinical data that justify the quality management system (accreditation), use validated meth- choice of one or more HRFs genetic tests are required. It is not ods, participate annually in interlaboratory comparisons such as unusual that when overlapping, partial or atypical clinical symp- external quality assessment and profi ciency testing for HRF and/ toms impede an accurate clinical diagnosis, screening of several or the relevant techniques (eg, DNA sequencing) and defi ne a HRF-responsible genes gives the correct diagnosis. typical turn-around time. The clinical HRF referral usually includes the frequency of attacks, duration, sites affected, acute phase reactants levels, Testing strategy biomarkers for mevalonic aciduria or amyloidosis and a letter by Most laboratories focus the molecular analysis on mutational an expert clinician. An example of a clinical chart is provided in hot-spot regions in various genes. Recommendations on the ref- online supplementary fi gure S1. It has been established in France erence sequence to be used for analysis and for the extent of the by GenMAI, the national network for genetic diagnosis of auto- initial mutation screening are provided in table 1. The minimum infl ammatory diseases, in conjunction with the clinical reference diagnostic screen should include variants that are clearly shown centres. Decision trees for genetic diagnosis in atypical patients to be pathogenic and that are frequently identifi ed in patients. and patients with sporadic disease have been proposed.13 19 In Although this screening recommendation is valid worldwide, addition, a diagnostic score for children with periodic fever has the ethnic background of the patient needs to be considered. For been elaborated in Italy.20 instance, the four clearly pathogenic MEFV variants are almost exclusively found in Mediterranean populations, while the fre- Presymptomatic diagnosis and carrier status quency of the debated p.Glu148Gln (NM_000243.2:c.442G→C) In general, presymptomatic diagnosis is not advisable, as its variant is as high as 20% in Asiatic countries.22 The p.Phe479Leu interpretation is inconclusive, may be complicated for muta- (NM_000243.2:c. 1437C→G) is especially relevant in Greek and tions with incomplete penetrance and it usually does not call Iranian patients.22 The p.Pro75Leu (NM_001065.3:c.224C→T) for medical intervention. Presymptomatic testing may be rec- (usual name P46L) of TNFRSF1A is commonly found in Arabic ommended after genetic counselling for asymptomatic family and African populations.23 Accordingly, many laboratories have members when a severe genotype has been found in relatives adopted a two-step strategy—that is, an initial search for the with an overt disease, or if there is a family history of amy- most common pathogenic variants followed, if necessary, by loidosis. Follow-up of people at risk may avoid occurrence of an extended search spanning the complete coding sequence of http://ard.bmj.com/ this life-threatening complication. However, whether such cases the various genes. For the MEFV gene, there is limited utility in should be given prophylactic treatment remains controversial. searching for rare variants for patients with clinically established Evaluation of carrier status could be recommended in healthy FMF and no mutations in exons 2, 3, 5 and 10.
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