• Alper Sarı, Erdal Bodakçi, Berkan Armağan, Hasan Satış, Nuh Ataş, Nazife Şule Yaşar Bilge, Reyhan Bilici Salman, YardımcıGözde KübraGK0000-0001-9543-4685Department of Rheumatology, Faculty of Medicine, Hacettepe University, Ankara, Turkey, Hakan Babaoğlu, Levent Kılıç, Mehmet Akif Öztürk, Şeminur Haznedaroğlu, Berna Göker, Umut Kalyoncu, Timuçin Kaşifoğlu, and Abdurrahman Tufan.
• Department of Rheumatology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
• Turk J Med Sci. 2021 Aug 30; 51 (4): 1695-1701.

Background/AimFamilial Mediterranean Fever (FMF) is the prototype of hereditary autoinflammatory disorders and caused by mutations on the MEFV gene located on the short arm of chromosome 16. 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.Materials And MethodsAll 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 nonresponsiveness, amyloidosis, and 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 autoinflammatory disease damage index (ADDI), respectively.ResultsAmong 971 participants included, MEFV gene analysis results were available for 814 patients. Twenty-six (3.2%) patients had single heterozygous VUS and 54 (6.6%) had pathogenic/VUS complex heterozygous variants. Patients with single heterozygous VUS had similar demographic/clinical features, ISSF and ADDI scores compared to those with single heterozygous pathogenic variant (p > 0.05 for all). No difference was observed in the demographic and clinical features of patients with single 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).ConclusionOur 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.This work is licensed under a Creative Commons Attribution 4.0 International License.

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