FMF (Familial Mediterranean Fever), MEFV Gene
Definition
An inherited disease characterized by recurrent attacks of inflammation, caused by a defect in the pyrin protein encoded by the MEFV gene (16p13.3). Pyrin acts as an intracellular sensor in neutrophils and monocytes.
Inheritance
Autosomal recessive; the disease requires a pathogenic variant in both copies of the MEFV gene. The parents are typically heterozygous carriers.
Critical information for Turkish and Mediterranean populations, carrier frequency:
| Population | Carrier frequency |
|---|---|
| Turkish | 1:8 to 1:10 |
| Armenian | up to 1:9 |
| Arab | up to 1:9 |
| Non-Ashkenazi Jewish | up to 1:9 |
In other words, one in every 8 to 10 Turkish people is an MEFV carrier. This explains why FMF testing is requested so often in Turkey and Cyprus, and it markedly increases the risk in the case of consanguineous marriage.
Clinical features:
- Recurrent, self-limiting attacks of serositis lasting one to three days
- Fever, peritonitis (abdominal pain), arthritis/arthralgia
- Less common: rash on the legs, pleuritis, pericarditis, acute scrotal swelling
- Symptoms typically begin in early childhood; between attacks the person is symptom-free
- Risk of AA amyloidosis in untreated severe cases
Diagnosis: Requires the detection of biallelic pathogenic variants in MEFV by molecular genetic testing. Sequence analysis detects ~100% of pathogenic variants; the variants typically cluster in exon 10 (B30.2 domain).
Note: The Genetiks test covers the entire gene (Exons 1 to 10), which is more comprehensive than restricted panels that look only at the common variants.
Risks and Limitations
Detection of a single variant (heterozygous) means carrier status, not disease. However, if the clinical picture is consistent, it is known that some patients can have symptoms with a single variant as well, so the result should be interpreted together with the clinical findings.