Clinical and Genetic Spectrum of MEFV Variants in Moroccan Patients with Familial Mediterranean Fever

Background Familial Mediterranean fever (FMF) shows substantial geographic variation in MEFV variant distribution and clinical presentation. Despite the disease's high prevalence among Mediterranean populations, genotype-phenotype data from North Africa remain scarce. This study investigated the distribution of MEFV variants and their clinical correlations in Moroccan patients with FMF. Methods We conducted a retrospective single-center study of 32 clinically diagnosed FMF patients carrying at least one MEFV variant, identified among 51 screened individuals. Genetic testing combined targeted PCR with Sanger sequencing as needed, and variants were classified per ACMG/AMP guidelines. For genotype-phenotype analysis, patients were divided into two predefined groups based on exon 10 involvement: Exon10-biallelic, comprising patients with two exon 10 variants in homozygous or compound heterozygous state (n = 10), and Other-MEFV, encompassing all remaining genotypes (n = 22). Inflammatory markers, attack characteristics, diagnostic delay, and treatment response were compared between groups using non-parametric tests with Benjamini-Hochberg FDR correction. Results M694V was the most frequent variant (37.5%), followed by R202Q (31.2%). Notably, 59.4% of patients carried only low-penetrance or VUS variants. Relative to the Other-MEFV group, Exon10-biallelic patients exhibited higher peak temperatures (median 41.0°C vs 39.0°C; q = 0.003), higher peak CRP levels (121.5 vs 57.5 mg/L; q = 0.084), and greater attack frequency (2.0 vs 1.0 episodes/month; q = 0.084). Individual symptom prevalence was comparable across groups, indicating that increased severity in the biallelic group may manifest as inflammatory intensity rather than symptom diversity. Diagnostic delay was longer among Exon10-biallelic patients (11.5 vs 5.0 years; p = 0.019). AA amyloidosis occurred more frequently in this group (33.3% vs 4.5%; p = 0.079), though the small event count precluded statistical significance. Most patients (93.8%) responded favorably to colchicine. Conclusion Biallelic exon 10 involvement was associated with more pronounced inflammatory activity and longer diagnostic delays compared with other MEFV genotypes. The substantial proportion of VUS and low-penetrance variants in this cohort highlights important limitations of targeted genetic testing strategies. These findings support adopting broader sequencing approaches and strengthening genetic characterization of FMF across Morocco and other North African populations, with the aim of enabling earlier diagnosis and better identification of patients at risk for severe complications such as AA amyloidosis.