R202Q homozygosity of Mediterranean fever gene is associated with atypical clinical phenotype of familial Mediterranean fever.

Abstract

Apart from the classical phenotypes, familial Mediterranean fever (FMF) has several atypical manifestations making its diagnosis quite challenging. Our aim was to address the characteristics of FMF patients and the clinical importance of R202Q variant in a large cohort of patients from Greece. Prospectively collected data from 321 FMF patients were retrospectively reviewed and analyzed. All patients were tested for Mediterranean fever gene/MEFV alterations in exon-2 and exon-10, by non-isotopic RNase-cleavage assay, and subsequent sequencing analysis. Hardy-Weinberg equilibrium (HWE) was used to assess R202Q allelic and genotypic frequencies in relation to FMF HWE. Among 223 FMF patients with available follow-up data, 54.3 % were females and mean age at diagnosis was 35.4 ± 16.7 years. Regarding genetic analysis, 38.2 % had pathogenic/likely pathogenic variants, 12.1 % had variants of unknown significance, 16.1 % were R202Q homozygotes, while 33.6 % had negative genetic test. As explained by the strong deviation from HWE observed among FMF patients (p < 0.0001), R202Q homozygosity is considered disease-related. R202Q homozygosity was identified mainly among native Greeks (77.8 %) and was associated with a higher age of disease onset (p < 0.001) and a lower occurrence of abdominal pain (p < 0.001) compared to pathogenic/likely pathogenic variants. R202Q homozygosity (10/30, 33.3 %) was associated with atypical disease phenotype (OR: 1.95, 95 %CI: 1.24-3.08, p = 0.004) after adjustment for age, origin and sex. Excess R202Q homozygosity was observed among Greek FMF patients presenting atypical/non-criteria manifestations. In patients with periodic fevers and atypical clinical phenotype, the identification of R202Q homozygosity is linked with the diagnosis of FMF.