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Clin Genet. 2018 Jul;94(1):81-94. doi: 10.1111/cge.13223. Epub 2018 Mar 9.

Lack of clear and univocal genotype-phenotype correlation in familial Mediterranean fever patients: A systematic review.

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Department of Clinical and Experimental Medicine, School and Division of Allergy and Clinical Immunology, University of Messina, Messina, Italy.
Department of Pediatric, University of Messina, Messina, Italy.
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy.
Department of Pediatrics, Nephrology Unit, University School of Medicine, Messina, Italy.


Familial Mediterranean fever (FMF) is the most common autosomal recessive autoinflammatory disease. To date, following the isolation of more than 280 MEFV sequence variants, the genotype-phenotype correlation in FMF patients has been intensively investigated; however, an univocal and clear consensus has not been yet reached. Thus, the aim of this systematic review was to analyze the available literature findings in order to provide to scientific community an indirect estimation of the impact of genetic factors on the phenotypic variability of FMF. This systematic review has been conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. The p.M694V mutation was reported to have a relatively severe clinical course, similarly, patients homozygous for M694I and M680I, or carrying a combination of both at codons 694 and 680, have a severe disease. Also, patients homozygous for M694V and V726A variants experienced more severe clinical picture. Conversely, heterozygous p.V726A and p.E148Q genotypes have been correlated with a milder disease course. At present, doubts remain on the potential pathogenic role of E148Q variant. The heterogenity in clinical FMF manifestations reflects the changes occuring in repertoire of mutations. We believe that clinical criteria and gene tests, enhancing each other, could better support the diagnosis of FMF.


familial Mediterranean fever; genotype; model of inheritance; phenotype


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