MEFV variant spectrum and geographic distribution in 2,250 Palestinian familial Mediterranean fever test records over 20 years

Abstract Background. Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease and is highly prevalent among Mediterranean populations, including Palestinians. It is caused by variants in the MEFV gene encoding pyrin. Large, long-term laboratory datasets describing the MEFV mutation landscape in Palestine remain scarce. Methods. We retrospectively reviewed all FMF genetic tests performed at Medicare Diagnostic Laboratories, a Palestinian laboratory network, between February 2006 and May 2026. Reports generated under several testing platforms (PCR–restriction analysis, Sanger sequencing, and mutation-specific real-time PCR / reverse-hybridization assays screening up to 24 MEFV variants) were harmonized into a single dataset. Each record was classified as negative, heterozygous (single variant), homozygous, or compound heterozygous, and allele-level frequencies were computed. Associations with age, sex, and collection center were tested with the chi-square and Mann–Whitney tests. Results. Of 2,252 tests, 2,246 (99.7%) were evaluable. At least one MEFV variant was detected in 1,076 individuals (47.9%): 596 (26.5%) were heterozygous carriers, 322 (14.3%) compound heterozygous, and 158 (7.0%) homozygous; 480 (21.4%) carried a biallelic (homozygous or compound heterozygous) genotype consistent with FMF. Among 1,566 mutant alleles, five variants accounted for 94.6% of the burden: V726A (33.5%), M694V (20.4%), E148Q (16.1%), M680I (14.1%) and M694I (10.5%). V726A was the single most frequent variant, present in 468 individuals. The most common compound genotype was M680I/V726A (n = 83). Mutation positivity rose markedly with age at testing, from 36.0% in children aged 6–10 years to 64.6% in adults aged ≥ 46 years (p < 0.001); no significant sex difference was observed (p = 0.16). Conclusions. This is one of the largest MEFV datasets reported from Palestine. The Palestinian FMF mutation landscape is dominated by five variants, with an unusually high contribution from V726A. These findings support a focused, cost-effective primary screening panel and strengthen the case for genetic counselling and carrier screening in this high-prevalence population.