FMF is caused by mutations in the MEFV gene (MEditerranean FeVer which encodes for the pyrin/marinostrin protein that is expressed exclusively in granulocytes, a type of white blood cell that contains enzyme granules inside and is part of the immune system.

To date, more than 170 pathogenic variants have been identified in FMFV with different diagnostic, prognostic and therapeutic implications. In those populations where FMF is more frequent, 5 predominant variants have been identified, representing 85% of the variants detected: M694V (c.2080A>G), V726A (c.2177T>C), M680I (c.2040G>C), M694I (c.2082G>A) and E148Q (c.442G>C).

M694V (c.2080A>G) is the frequent pathogenic variant and produces an amino acid change that alters protein function. Studies suggest that the M694V variant is highly associated with amyloidosis and the presence of two copies of M694V is considered the major risk factor for renal amyloidosis in non-Ashkenazi Jewish, Turkish, Arab and Armenian patients.

It is important to note that the disease, although autosomal recessive can also develop in compound heterozygosis, i.e. when the person carries two different pathogenic variants in heterozygosis. In addition, some of the variants have incomplete penetrance, which means that in some cases individuals are observed who even presenting two copies of the same mutation in MEFV are asymptomatic, as for example happens with E148Q (c.442G>C). It is estimated that about 55% of E148Q homozygotes are asymptomatic.

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