Genotype–phenotype studies in a large cohort of Armenian patients with familial Mediterranean fever suggest clinical disease with heterozygous MEFV mutations

Familial Mediterranean fever (FMF) is an autoinflammatory disorder generally caused by recessively inherited mutations in the MEFV gene. FMF is quite prevalent in Armenian population in which majority of patients have two mutated alleles, yet in 18% of symptomatic patients just one mutation has been detected. To explain this finding, we analyzed the symptoms and genotypes of 1299 patients, including 236 affected heterozygous patients with definite diagnosis of FMF. We selected a subset of 63 heterozygous, homozygous and asymptomatic normal individuals and completely sequenced their MEFV genes (exons) to discover any other mutations potentially missed by currently used screening method. Besides four synonymous polymorphisms in exon two and five, we found a T267I mutation in one heterozygous patient with a severe case of FMF who should have been designated as compound heterozygous, yet the other genotypes were all accurate. We used binomial probability distribution of symptoms in homozygous FMF patients to estimate the likelihood of their occurrences in heterozygous patients and demonstrated the assemblage of patients into groups with similar clinical criteria using statistical clustering. We found extremely high probabilities for the presence of FMF symptoms in heterozygous individuals and determined that symptoms were equally likely to occur in both analyzed genotypes. Therefore, our study supports the rising evidence that a single MEFV mutation could be associated with mild FMF symptoms. However, heterozygous patients presenting with severe phenotype should be further analyzed for less common second MEFV mutation using gene sequencing.