MEFV-gene analysis in Armenian patients with familial Mediterranean fever:Diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype - Genetic and therapeutic implications

Familial Mediterranean fever (FMF) is a recessively inherited disorder that is common in patients of Armenian ancestry. To date, its diagnosis, which can be made only retrospectively, is one of exclusion, based entirely on no nspecific clinical signs that result from serosal inflammation and that may lead to unnecessary surgery. Renal amyloidosis, prevented by colchicine, i s the most severe complication of FMF, a disorder associated with mutations in the MEFV gene. To evaluate the diagnostic and prognostic value of MEFV- gene analysis, we investigated 90 Armenian FMF patients from 77 unrelated f amilies that were not selected through genetic-linkage analysis. Eight muta tions, one of which (R408Q) is new were found to account for 93% of the 163 independent FMF alleles, with both FMF alleles identified in 89% of the pa tients. In several instances, family studies provided molecular evidence fo r pseudodominant transmission and incomplete penetrance of the disease phen otype. The M694V homozygous genotype was found to be associated with a high er prevalence of renal amyloidosis and arthritis, compared with other genot ypes (P = .0002 and P = .006, respectively). The demonstration of both the diagnostic and prognostic value of MEFV analysis and particular modes of in heritance should lead to new ways for management of FMF-including genetic c ounseling and therapeutic decisions in affected families.