Phenotypic characterisation of Familial Mediterranean Fever patients harboring variants of uncertain significance.

BACKGROUND Familial Mediterranean Fever (FMF) is the prototype of hereditary autoinflammatory disorders and caused by mutations in the MEFV gene region. Although some MEFV variants are clearly associated with disease phenotype, there are numerous variants with unknown clinical association which are termed as variants of uncertain significance (VUS). Here, we present clinical correlations of VUS in a large cohort of adult FMF patients from three tertiary centers located in Central Anatolia. METHODS All patients were recruited from FMF in Central Anatolia (FiCA) cohort. Demographic (sex, age at disease onset) and clinical features (disease characteristics, attack frequency, mean colchicine dose, colchicine non-responsiveness, amyloidosis, persistent inflammation) of patients with VUS were compared with those harboring pathogenic variants. Disease severity and damage were also evaluated using International Severity Score for FMF (ISSF) and Auto-inflammatory Disease Damage Index (ADDI), respectively. Results Among 971 participants included, MEFV gene analysis results were available for 814 patients. 26 (3.2%) patients had heterozygous VUS and 54 (6.6%) had pathogenic/VUS complex heterozygous variant. Patients with single heterozygous VUS had similar demographic/clinical features, ISSF and ADDI scores compared to those with heterozygous pathogenic variant (p>0.05 for all). No difference was observed in the demographic and clinical features of patients with heterozygous pathogenic mutation and pathogenic/VUS complex heterozygous variant (p>0.05 for all). ISSF and ADDI scores were lower in pathogenic/VUS complex heterozygous patients than those harboring single pathogenic mutation (p=0.006 and 0.004, respectively). Conclusion Our findings suggest that patients with single heterozygous VUS has mild FMF phenotype similar to those with single pathogenic mutation. Pathogenic/VUS complex heterozygosity does not lead to a more severe clinical phenotype than having a single pathogenic variant.