Frequency and Potential Disease-Modifying Role of MEFV Variants in Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Retrospective Case–Control Study

Background and Objectives: Familial Mediterranean Fever (MEFV) gene variants exhibit a high carrier frequency in the Turkish population and modulate clinical phenotypes through persistent low-grade innate immune activation. However, their role in myeloid malignancies—where aberrant inflammasome signaling contributes to immunopathogenesis—remains poorly defined. We aimed to investigate the carrier frequency and potential disease-modifying role of common MEFV variants in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Materials and Methods: In this retrospective case–control study, 80 clinical evaluations from 75 unique patients with myeloid malignancies (53 AML and 27 MDS, including 5 patients evaluated in both cohorts before and after leukemic transformation) and 186 healthy controls from the Turkish population were analyzed. Four established pathogenic exon 10 variants (M694V, V726A, M680I, and M694I) and two variants of uncertain significance (VUS; K695R and E148Q) were genotyped using rhAmp™ SNP Genotyping and polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assays. Clinical characteristics, blastic progression, and survival outcomes were evaluated. Results: Overall MEFV variant carriage did not differ significantly between the unique patient cohort and healthy controls (24.0% [18/75] vs. 19.9% [37/186], p = 0.462; or 23.8% [19/80] across all disease evaluations, p = 0.479). In the MDS cohort (n = 27), 10 mutant alleles were detected in 9 unique patients (variant frequency: 37.0% vs. 19.9% in controls, p = 0.045; unique carrier frequency: 33.3% vs. 19.9%, p = 0.113), as one female MDS patient was a compound heterozygote (M694V/V726A). Stratified analysis revealed that this enrichment in MDS was driven by established pathogenic exon 10 variants (22.2% [6/27] vs. 9.1% [17/186], p = 0.041; allele frequency: 11.1% [6/54] vs. 4.6% [17/372], p = 0.047), whereas VUS frequencies were comparable (14.8% vs. 10.8%, p = 0.533). Within the MDS group, male patients showed an exploratory trend toward a higher carrier rate than females (60.0% [6/10] vs. 17.6% [3/17], Fisher’s exact p = 0.039). Conversely, MEFV variant frequency in AML mirrored that of controls (20.8% [11/53] vs. 19.9%, p = 0.890). Baseline clinical parameters and overall survival did not differ significantly by genotype, although MEFV-positive MDS patients exhibited a non-significant numerical trend toward a shorter interval to blast progression (12.7 vs. 36.2 months). Conclusions: Our findings provide exploratory, hypothesis-generating evidence suggesting a potential enrichment of pathogenic exon 10 MEFV variants in MDS—particularly among male patients—but not in AML. Given the small sample size and retrospective design, these observations require validation in larger multi-center cohorts, and future studies may explore whether MEFV genotyping offers clinical or prognostic utility in high-prevalence populations.