incrementalGenetic finding
MEFV variant reclassification efforts underway
Familial Mediterranean Fever →Summary
Systematic review by Shinar et al. highlighted the lack of univocal genotype-phenotype correlation in FMF. Ongoing international efforts aim to reclassify MEFV variants using updated ACMG criteria, particularly for E148Q (debated as pathogenic vs. benign polymorphism) and heterozygous states that may cause mild disease.
Related genes
MEFVM694V (c.2080A>G, p.Met694Val)
The most common and most severe FMF mutation. Located in exon 10 (B30.2/SPRY domain). Homozygosity associated with earliest onset, highest attack frequency, most arthritis, and greatest risk of AA amyloidosis.MEFVM680I (c.2040G>A/C, p.Met680Ile)
Third most common FMF mutation. Located in exon 10. Homozygosity or compound heterozygosity with M694V associated with severe disease. M680I/M694V combination produces severe phenotype.MEFVV726A (c.2177T>C, p.Val726Ala)
Second most common FMF mutation. Located in exon 10. Heterozygosity generally associated with milder phenotype. However, V726A-E148Q complex allele can be severe.MEFVE148Q (c.442G>C, p.Glu148Gln)
Located in exon 2. Highly controversial — debated whether pathogenic variant or benign polymorphism. Extremely high frequency in general population. When part of a complex allele with V726A, significantly increases disease severity.MEFVM694I (c.2082G>A/C, p.Met694Ile)
Located in exon 10. Fifth founder mutation. Homozygosity associated with severe disease. M694I/M694I genotype identified as a specific risk factor for AA amyloidosis in Algerian patients.More from Familial Mediterranean Fever
significantTreatment update
JAK inhibitors (tofacitinib) emerging as potential third-line therapy
significantTreatment update
IL-1 blockade established as standard second-line therapy for colchicine-resistant FMF
significantTreatment update
EULAR/PReS 2024 updated management recommendations published
significantNew research
Colchicine resistance mechanisms linked to pyrin inflammasome microtubule independence
ID: familial-mediterranean-fever-update-4Type: genetic_findingImpact: incremental