The spectrum of Familial Mediterranean Fever gene ( MEFV ) mutations and genotypes in Iran, and report of a novel missense variant (R204H)

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.

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“…To date, nonetheless the abovementioned findings, it is not possible to attribute to R202Q mutation a clear disease‐causing significance.…”

Section: Resultsmentioning

confidence: 89%

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

et al. 2018

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“…Recent reports have described patients who are compound heterozygotes for mutations in other known PFS genes (CIAS1 and TNFRSF1A) [26,27], suggesting that a spectrum of atypical clinical presentations may be possible with various combinations of allelic variants. In fact, a substantial proportion of patients meeting clinical criteriaup to 40% in a recent studyhave none of the 12 most common MEFV mutations [28]. This is a far greater proportion than has been previously reported in some studies [11].…”

Section: Interpreting Allelic Variants Of Uncertain Significancementioning

confidence: 80%

Periodic fever syndromes: beyond the single gene paradigm

et al. 2019

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Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease in Canada and is characterized by a clinical syndrome of episodic inflammatory symptoms. Traditionally, the disease is defined by autosomal recessive inheritance of MEFV gene variants, yet FMF also not uncommonly manifests in individuals with only one identified disease-associated allele. Increasing availability and affordability of gene sequencing has led to the identification of multiple MEFV variants; however, they are often of unknown clinical significance. Variants in other genes affecting overlapping or distinct inflammatory signaling pathwaystogether with gene-environment interactions including epigenetic modulationlikely underlie the significant genetic and phenotypic heterogeneity seen among patients with this disease. We review recent evidence of the expanding spectrum of FMF genotype and phenotype and suggest that current drug funding schemes restricting biologic agents to patients with homozygous mutations have not kept pace with our biological understanding of the disease.

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“…234 patients (60%) had at least one mutation, and 156 patients (40%) were without any common mutations. The most common variants were M694V (13.6%), followed by E148Q (10.4%), M694I (6.5%), V726A (4.1%), and M680I (3.8%), respectively [16].…”

Section: Discussionmentioning

confidence: 99%

MEFV Gene Variant Alleles in Normal Population of Northwest of Iran, Which Is Near to Mediterranean Sea

Salehzadeh

Sharghi

Motayayagheni

et al. 2019

Genetics Research International

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Background and Objective. MEFV gene codes the pyrine protein that has major role in FMF as an autoinflammatory disorder. FMF is more often seen in the people of the Mediterranean area. Considering the significant role of MEFV gene in many rheumatologic diseases and even nonrheumatologic disorders, it is necessary to identify different variations of these mutations in the healthy and normal population of this area. Methods. 224 healthy (unaffected or control) people based on the Cochran formula entered this study. The blood samples were screened for the 12 common MEFV gene variants polymorphisms according to manufacturer’s instructions (FMF Strip Assay, Vienna lab, Vienna, Austria). They filled a questionnaire containing required information. All healthy control cases initially were evaluated for FMF symptoms and signs in themselves and their first-degree relatives based on clinical criteria. All data were analyzed by simple statistical method. Results. Among 224 healthy control cases, 113 (50.4%) were male and 111 (49.6%) female. There were MEFV variants alleles in 57 patients (25%): 28 were male (49.1%) and 29 female (50.9%). The most frequent variants were E148Q (18.3%), followed by P369S (3.1%), V726A (2.2%), A744S (1.3%), and F479L, M694V, and R761H (0.8%), and eventually K695R (0.4%), respectively. Some variants such as M694I, M680I (G/C), M680I (G/A), and I692del were not seen in these samples. There were compound heterozygote variations of E148Q/P369S, E148Q/V726A, E148Q/P369S, and P369S/F479L in normal population without any findings in favor of FMF. Conclusion. Twenty-five percent of the normal populations of the northwest of Iran are carrying MEFV gene variants, and the most common mutation is E148Q (18.3%). The presence of M694I, M680I (G/C), M680I (G/A), I692del mutations in the normal population can be interpreted cautiously, while particular compound heterozygote mutations can be considered as normal variants.

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The spectrum of Familial Mediterranean Fever gene ( MEFV ) mutations and genotypes in Iran, and report of a novel missense variant (R204H)

Cited by 9 publications

References 21 publications

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

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

Periodic fever syndromes: beyond the single gene paradigm

MEFV Gene Variant Alleles in Normal Population of Northwest of Iran, Which Is Near to Mediterranean Sea

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