Comprehensive analysis of mutations in the MEFV gene reveal that the location and not the substitution type determines symptom severity in FMF

Background Familial Mediterranean Fever (FMF) is an autoinflammatory disorder caused by mutations in the MEFV gene. These mutations appear in different populations with different frequencies and their caused symptom severities vary from mild to moderate to severe depending on the mutation type. Methods In this study, we analyzed the mutations that have been reported in the MEFV gene from symptomatic FMF patients and compared their frequencies in different populations from the 1000 Genome and the Exome databases, using statistical clustering. We also analyzed the nucleotide and amino acid substitution patterns across the MEFV gene. Results We found 16 (8%) nonsynonymous mutations outside exon 10 that did not cluster with known disease‐causing mutations (DCMs), due to their high frequencies in other populations. We also studied the substitution patterns for nucleotides and amino acids to determine the conserved and variable regions in the MEFV gene. In general more nonsynonymous substitutions were reported in exons 2, 3, and 10 from the FMF database (symptomatic FMF patients) compared to the 1000 Genome and the Exome databases. The same was true for amino acid (AA) substitutions where there were 1.5 times more radical (RAD) to conservative (CON) changes. However, when it came to AA substitutions exon 10 was quite conserved with a RAD/CON ratio of 0.9. In fact, we report that the most severe FMF symptoms are caused by conservative mutations in two highly conserved exon 10 regions. Conclusion We found presumptive FMF‐causing mutations that did not cluster with DCMs based on their allele frequencies. We also observed that the type of mutation is less likely to determine the severity of the FMF symptoms; rather it was the location of the mutations that was the determining factor. The mutations in the MEFV gene responsible for FMF symptoms were extensively analyzed through statistical clustering and identification of nucleotide and amino acid substitution patterns. This study showed that about 8% of the reported nonsynonymous substitutions may not be of pathogenic nature due to significance difference in their allele frequencies in different populations compared to known disease‐causing mutations. Also, we found that the mutation location and not the type are responsible for symptom severity in FMF.