MEFV variant spectrum and exploratory in silico stratification of uncommon variants in 611 individuals tested for suspected familial Mediterranean fever in the Eastern Black Sea region of Türkiye.

Abstract

Background: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, caused by variants in the MEFV gene. Regional MEFV variant spectra differ across Türkiye. We characterised the MEFV variant spectrum in a single-centre series of individuals tested for suspected FMF in the Eastern Black Sea region and explored in silico stratification of uncommon variants. No standardised clinical diagnostic criteria were applied; the study is therefore framed as a molecular variant-spectrum study.

Methods: We retrospectively analysed MEFV next-generation sequencing (NGS) reports from 611 consecutive individuals referred with a clinical suspicion of FMF (January 2022-October 2025). Standardised FMF classification criteria (Tel-Hashomer; Eurofever/PRINTO) were not applied; the cohort was defined by referral indication. For each variant, two metrics were reported: the proportion within the detected mutant-allele pool (n/591) and the allele frequency across all tested chromosomes (n/1222; 2 × 611). Uncommon variants were defined as all detected missense variants other than the recognised common FMF alleles (R202Q, M694V, M680I, M694I, V726A, E148Q, P369S, R408Q). Uncommon variants were submitted to the seven-tier framework of Alay (2025) as an exploratory layer supplementary to - not a replacement for - ACMG/AMP classification.

Results: At least one variant was detected in 379/611 individuals (62.0%); 591 alleles across 22 distinct missense variants were tabulated. R202Q was the most frequently detected allele in the spectrum (44.0% of detected mutant alleles; 21.3% of all tested chromosomes), exceeding M694V (22.3%; 10.8%). When restricted to high-penetrance exon 10 founder variants (M694V, M680I, M694I, V726A), the pathogenic-allele burden was substantially lower (202 alleles; 16.5% of tested chromosomes). Compound/complex genotypes were present in 25.7% of the cohort (cis/trans phase not determined). Exploratory in silico stratification flagged 7 of 10 evaluable uncommon variants toward likely-pathogenic and 3 toward likely-benign; four variants could not be mapped. A previously unreported substitution, p.Ser179Gly, was detected in one individual and is reported only as a candidate variant of uncertain significance, without pathogenicity inference.

Conclusions: In this region, R202Q predominates in the detected MEFV variant spectrum; however, its contested pathogenicity means that spectrum dominance should not be equated with regional clinical or pathogenic-allele burden. The findings describe a molecular variant spectrum, and clinical interpretation is constrained by the absence of phenotype, segregation and standardised diagnostic data. In silico stratification is exploratory and does not replace ACMG/AMP classification.