MEFV gene mutation spectrum in patients with familial mediterranean fever

Familial Mediterranean fever (FMF) is an autosomal recessive, inherited inflammatory disease that is characterized by recurrent episodes of fever with abdominal, chest, or joint pain caused by inflammation of the serosa. FMF mainly affects Mediterranean and Middle Eastern populations, including Sephardic Jews, Turks, Arabs, and Armenians. The first episode of FMF usually begins during childhood. Fever develops before the age of 10 and 20 years in ∼75% and ∼90% patients, respectively. The most severe complication of untreated FMF is amyloidosis. Lifelong treatment is required to prevent febrile episodes and long-term damage to internal organs. Oral colchicine therapy is effective in preventing attacks. Recent studies have reported that drugs that block interleukin-1, a protein involved in the inflammatory process, may be effective for patients who do not respond well or cannot tolerate colchicine. FMF is confirmed in most cases via a genetic mutation. The gene (MEditerranean FeVer, MEFV) responsible for this disease contains 10 exons and 781 codons. The clinical presentations are caused by mutations in the MEFV gene encoding the pyrin protein. Pyrin plays a role in the control of inflammation and is considered a negative regulator of inflammation; >0 MEFV gene mutations cause FMF. The number of cases has increased among different ethnic groups and countries with the discovery of these gene defects, such as Italians, Greeks, Ashkenazi Jews, and Asians. Rare mutations occur preferentially in populations not usually affected by FMF. Genotype–phenotype correlations have been intensively studied in patients with FMF; however, no clear consensus has been reached. M694V, V726A, M694I, M680I (in exon 10), and E148Q (in exon 2) are the most common FMF mutations. M694V is associated with an increased risk of developing amyloidosis. Some evidence suggests that normal variants in the SAA1 gene further modify the risk of amyloidosis in patients with the M694V variant. The clinical manifestations of FMF vary among different ethnic groups. The heterogeneity in the clinical FMF presentation reflects that its genetic variants may vary by ethnicity. Significant associations between amyloidosis and the M694V mutation have been reported in North African Jews, Armenians, and Turks.1Shohat M. Magal N. Shohat T. Chen X. Dagan T. Mimouni A. et al.Phenotype–genotype correlation in familial Mediterranean fever: evidence for an association between Met694Val and amyloidosis.Eur J Hum Genet. 1999; 7: 287-292Crossref PubMed Scopus (184) Google Scholar M694V is also the most common mutation in Syrian FMF patients and is associated with disease severity and the development of amyloidosis.2Mattit H. Joma M. Al-Cheikh S. El-Khateeb M. Medlej-Hashim M. Salem N. et al.Familial Mediterranean fever in the Syrian population: gene mutation frequencies, carrier rates and phenotype–genotype correlation.Eur J Med Genet. 2006; 49: 481-486Crossref PubMed Scopus (68) Google Scholar The M694V/M694V genotype is associated with more severe disease in Israeli FMF patients. Another study showed that missense mutations are not associated with the development of severe disease or amyloidosis in Turkish FMF patients residing in Turkey.3Yalçınkaya F. Çakar N. Mısırlıoğlu M. Tümer N. Akar N. Tekin M. et al.Genotype–phenotype correlation in a large group of Turkish patients with familial Mediterranean fever: evidence for mutation-independent amyloidosis.Rheumatology(Oxford). 2000; 39: 67-72Crossref PubMed Scopus (148) Google Scholar The most common mutation among Japanese patients is E148Q (40.2%), followed by M694I (21.0%), L110P (18.8%), P369S (5.4%), and R408Q (5.4%). In contrast, mutations commonly seen in Mediterranean patients, such as M694V, V726A, and M680I, are not detected in Japanese patients. The clinical features of M694I are associated with an extremely severe clinical course compared with those of E148Q.4Kishida D. Nakamura A. Yazaki M. Tsuchiya-Suzuki A. Matsuda M. Ikeda S. Genotype-phenotype correlation in Japanese patients with familial Mediterranean fever: differences in genotype and clinical features between Japanese and Mediterranean populations.Arthritis Res Ther. 2014; 16: 439Crossref PubMed Scopus (57) Google Scholar Further, MEFV exon 10 mutations have been associated with a more typical FMF phenotype in Japanese patients. A recent study reported that the most frequent mutations in FMF patients in the Inner Black Sea region of Turkey are M694V and R202Q.5Sönmezgöz E. Özer S. Gül A. Yılmaz R. Kasap T. Takcı Ş. et al.Clinical and demographic evaluation according to MEFV genes in patients with familial mediterranean fever.Biochem Genet. 2019; 57: 289-300Crossref PubMed Scopus (11) Google Scholar R202Q occurs at a high rate in the Egyptian FMF population and may be a pathogenic variant. R202Q is associated with the full spectrum of FMF features in a Jordanian FMF population and is the most common mutation.6Eyad A. Dua` N S. Dima Bani I. Saied J. Wail H. Genotype–phenotype correlation in Jordanian children with genetically proven familial Mediterranean fever: the effect of R202Q mutation.Pediatr Neonatol. 2022; https://doi.org/10.1016/j.pedneo.2022.06.014Abstract Full Text Full Text PDF Scopus (0) Google Scholar Frequent involvement of R202Q in the pathogenesis of FMF has also been reported in Greek patients.7Sgouropoulou V. Farmaki E. Papadopoulos T. Tzimouli V. Pratsidou-Gertsi J. Trachana M. Sequence analysis in Familial Mediterranean Fever patients with no confirmatory genotype.Rheumatol Int. 2022; 42: 15-22Crossref PubMed Scopus (5) Google Scholar These findings suggest that rare or unknown variants are detectable using MEFV gene sequencing. Understanding the correlation between FMF phenotypes and genotypes in different ethnic groups will help our understanding of this disease. The combination of clinical presentation and genetic studies will aid in diagnosing FMF. Genetic testing increases the understanding of complex alleles, genetic heterogeneity, and possible epigenetic factors. Genetic testing can also be used to identify genetically affected individuals before symptoms appear, detect carriers, and assess the risk of developing amyloidosis later in life. MEFV gene sequencing will be useful to detect more FMF-related gene variants, establish more clinical phenotypic correlations, and help clarify the prognosis of patients. The author has no conflicts of interest relevant to this article.