Molecular diagnosis of FMF: lessons from a study of 446 unrelated individuals

Traditionally, the diagnosis of familial Mediterranean fever (FMF) has been based on clinical manifestations and the physician's experience. Following the cloning of the gene associated with this disease (MEFV), genetic analysis of its mutations has become available, providing a new tool for the establishment or confirmation of the diagnosis of FMF.

We analyzed the results of molecular testing for MEFV mutations in 600 individuals. We wished to determine how many of them bore mutations and what percentage had clinically active FMF. We also compared the rate of genetic confirmation of the FMF diagnosis in referrals with suspected FMF seen by general practitioners with that of persons sent for genetic analysis by FMF experts.

Of 600 individuals tested for FMF mutations, we analyzed separately 446 unrelated persons for the combination of their mutations, epidemiological data, and clinical manifestations. The five most common mutations in the present cohort were analyzed using the amplification refractory mutation system (ARMS).

Of the 446 subjects analyzed, 249 (55%) bore mutations: 147 of these were homozygotes or compound heterozygotes, all of whom had FMF according to clinical criteria. Of the remaining 102 heterozygotes, 72 had FMF according to clinical criteria. Two patients with none of the five mutations also had FMF: North African Jews bore mainly mutations M694V and E148Q. The M6941 mutation was found exclusively in Palestinian Arabs. The rate of confirmation of FMF diagnosis by mutation analysis in subjects sent by FMF experts was significantly higher than that of persons referred by general practitioners. Analysis of the molecular testing of the multicase families (154 individuals) revealed that 141 of them bore MEFV mutations and that 4 persons homozygous for E148Q were asymptomatic.

Molecular analysis of FMF mutations confirmed the diagnosis in about 60% of the referrals with suspected FMF. Some (33%) of the patients were heterozygotes, and there were also FMF patients with none of the 5 mutations analyzed. A second opinion by an FMF expert may decrease the need for mutation analysis in subjects suspected of having FMF.