MEFV gene allele frequency and genotype distribution in 3230 patients' analyses by next generation sequencing methods.

Familial Mediterranean Fever (FMF, OMIM ID: 249100) is the most common autoinflammatory, autosomal recessive disease caused by mutations in the MEFV gene. It is widespread in the Mediterranean, primarily among Turkish, Armenian, Arab and Jewish. This study aims to examine genotype distributions of common MEFV variants in the Turkish population using targeted NGS and to evaluate all rare mutations. It included 3230 people applying to Ege University Children's Hospital Molecular Medicine Laboratory with the suspicion of autoinflammatory disease between 2017 and 2021. MEFV missense variant was detected in 1839 (56.9%) individuals. One or more mutations were found in them. 1063 patients were heterozygous (57.8%), 410 were compound heterozygous (22.3%), 238 were complex genotype (12.9%), and 128 were homozygous (7%). 56 different mutations and 141 genotypes were detected, two of which were novel (p.His87Arg, c.260A > G and p.Leu396Phe, c.1186C > T). These were determined as 6benign, 40 uncertain significant, 3 likely pathogenic and 7 pathogenic according to the ACMG classification. The most common ones were R202Q (n = 1097, 37.48%), E148Q (n = 512, 17.49%), M694V (n = 493, 16.84%), V726A (n = 155, 5.30%), M680I (n = 150, 5.12%), P369S (n = 108, 3.69%), R408Q (n = 95, 3.25%) respectively. They constitute 89.17 % of the entire patient population. In conclusion, DNA variants/mutations in the MEFV gene were evaluated in 3230 patients. To date, no mutation screening has been encountered in such a large population using NGS. Genotype distributions of both common and rare mutations were revealed. The obtained data will hopefully contribute to the future genotype-phenotype studies of FMF disease.

Screening of OTULIN gene mutation with targeted next generation sequencing in Turkish populations and in silico analysis of these mutations.

BACKGROUND: OTULIN-related autoinflammatory syndrome (ORAS) is an autosomal recessive disease characterized by systemic inflammation, recurrent fever. Due to limited knowledge about the OTULIN DNA variants that cause ORAS, the diagnosis and treatment of this disease is difficult. In this study, we aim to identify OTULIN DNA variants responsible for the genetic pathology of ORAS and observe the effects of these variants on the OTULIN protein structure and the function with different bioinformatics approaches. METHODS: The present study included 3230 individuals with the suspicion of an autoinflammatory disease who were referred to Ege University Children's Hospital Molecular Medicine Laboratory. OTULIN variants were detected using a panel consisting of 37 different autoinflammatory diseases (AID) genes via targeted Next-Generation Sequencing. RESULTS: As a result of the study, DNA variants associated with various AID were detected in 65% of the individuals to whom the panel was applied. Among these variants, only three different OTULIN variants (p.Val82Ile, p.Gln115His and p.Leu131_Arg132insLeuCysThrGlu) were detected. The pathogenic effects of the variants detected in the OTULIN gene were determined by using Polyphen2 as "Probably Pathogenic" for the p.Val82Ile and "benign" for the p.Gln115His. At the same time, the effects of these variants on the structure and function of the OTULIN protein were investigated by in silico approaches. Both variants reduce protein stability and binding affinity. CONCLUSION: The results of the current study suggest that the evaluation of OTULIN variants with in silico approaches will contribute to the development of personalized treatments by diagnosing the disease specific to the variant.