The enigma of familial Mediterranean fever: phenotypic characterization of patients harboring variants of uncertain significance

To assess the phenotypic characteristics of the patients carrying variants of uncertain significance (VUS) in the Mediterranean fever (MEFV) gene. The study included patients carrying only VUS in the MEFV gene. Patients were excluded if they did not meet the pediatric criteria for familial Mediterranean fever (FMF). Patients were assigned to homozygous, compound heterozygous, or heterozygous groups according to their genotype. Additionally, analyses were conducted based on specific genotypes. A total of 2,326 MEFV gene records were reviewed. Of these, 310 (F : 152/M : 158) met the inclusion criteria for analysis. The mean age at diagnosis and symptom onset was 7.51 ± 3.9 and 6.03 ± 3.86 years, respectively. Among the patients, 75.5% had a single variant, 17.1% were compound heterozygous, and 7.4% were homozygous. The common VUS alleles accounted for 93% of the cohort: E148Q (65.7%), P369S (15.6%), R408Q (7.6%), and A744S (4.1%). Most cases exhibited mild disease severity, while those with multiple variants were more likely to experience moderate disease severity. Patients with a homozygous allele had a higher mean number of annual attacks (11.2/year), a higher Pras severity score (5.86), and a greater proportion of moderate disease severity (56.5%). The most common clinical manifestations were abdominal pain (90.6%), fever (84.2%), and arthralgia (58.7%). Individuals with VUS variants in the MEFV gene may present with a classic FMF phenotype characterized by mild to moderate disease activity. Patients carrying various VUS genotypes in the MEFV gene exhibit comparable clinical features with some degree of variation.