Results of genetic analyses on 225 consecutive FMF patients from the Apulian network on recurrent hereditary fevers

Familial Mediterranean Fever (FMF), is the most common and thoroughly studied among the hereditary recurrent fever syndromes. Although initially recognized as inherited with an autosomal recessive mechanism, several recent reports have suggested that patients carrying single MEFV variants may present clinical symptoms, not different although generally milder compared with patients either homozygotes or compound heterozygotes. Further, the severity of clinical symptoms appear to be partly depending on gene dosage effects, yet to be determined environmental factors, and genetic background including modifier loci. The largest collections of FMF patients so far reported, document genotype-phenotype correlations on rather homogenous populations such as Turks, Israeli, Armenians, Iranians, and Japanese. Italian FMF patients represent a different type of patients’ cohort considering that Italians are a rather admixed population due to the rich history of past dominations and being at the center of commercial relationships since centuries. Here, we present the results of one of the largest collections of Italian FMF patients collected at a single hospital center. 225 different subjects were referred to our unit over a 10 years span. The average age at diagnosis was 23 years. Of the 225 patients, 32 were deemed ineligible for gene testing. The remaining 193 subject were tested with a next generation sequence gene target panel which included the following genes: MEFV, TNFRSFS1A, MVK, NLRP3 (NALP3). In 113/193 tested individuals (58.6%) no variants were identified, while in 80/193 (41.4%) at least one genetic change was detected. The large majority of variants were identified in the MEFV gene (67/80, 83.75%) while 5 variants each were present in both NLRP3 and TNFRSFS1A genes and three in MVK. Among the MEFV variants carriers, 21 were simple heterozygous, 38 had two variants, 6 carried three MEFV variants and finally, there was a single quadruplet. The most significant genotype-phenotype correlations will be discussed.