Investigation of familial mediterranean fever cases without MEFV mutation or with single MEFV mutation for different gene variants

Familial Mediterranean Fever (FMF); is an autoinflammatory disease characterized by periodic fever and concurrent episodes of serous membrane inflammation. FMF is one of the most common genetic diseases in Turkey and is considered to be inherited in an autosomal recessive manner. Although biallelic mutations in MEFV gene is associated with disease, in approximately 25-30% of cases only a single mutation is detected. In this study, we performed whole exome sequencing (WES) in 17 individuals, including 5 index cases and their first-degree relatives, who were diagnosed in accordance with the Tel-Hashomer criteria in 2019, responded positively to colchicine treatment, but had no biallelic MEFV mutation in genetic evaluation. We aimed to find novel gene variants that can contribute to FMF. An average of 33.474 variants per person were revealed as a result of WES. We filtered rare non-synonymous exonic variants and analyzed clinically according to current guidelines. No shared gene or variant was detected in index cases. The cellular pathways which filtered variants are associated with were identified and compared, but no common affected pathway was identified. When the cases were examined individually, de novo variants were found in one case in the BIRC2 gene and in another case in the BCL10 gene. Additional studies are needed to confirm the physiopathological relationship of these genes with FMF. This study is the most extensive etiological research in FMF cases with monoallelic MEFV mutation performed in the literature. We have shown that genotype-phenotype correlation in these cases may not be established by a single rare genetic variant. The necessity of additional investigations in larger series for polygenic/multifactorial factors has been revealed. By increasing knowledge about FMF genetics, accurate diagnosis, treatment and follow-up algorithms can be developed in the future.