Global epidemiology of Familial Mediterranean fever mutations using population exome sequences

Abstract

Familial Mediterranean fever (FMF) is an inherited disorder characterized by recurrent episodes of fever accompanied by sterile peritonitis, arthritis, and pleuritis. Many mutations in the MEFV gene have been identified as causing FMF. However, accompanying epidemiological information remains quite scarce except in some Mediterranean countries, and the degree of penetrance has been a subject of controversy. Here, I established a genetic epidemiology of full FMF mutations using two population exome studies. Of 57 mutations associated with FMF, 22 were detected in a total of 9007 individuals from two exome sequences. Exome-based epidemiology revealed the carrier rates of FMF in 28 populations in 19 countries by individual mutation and showed strong population specificity for the MEFV mutations. Unexpectedly high carrier rates suggested that some mutations are benign variants with no pathological significance and highlighted the need for caution in analyzing MEFV mutations. Similar approach could be used to uncover the incomplete or no penetrance of mutations in most inherited disorders.

Keywords: Allele frequency; Familial Mediterranean fever; epidemiology; exome; genetic diagnosis.

Figure 1

Strategy of epidemiological research on FMF using population exome sequences. A flowchart used to study epidemiology shows the process of mutation detection using the 1000G and NHLBI datasets. A total of 18,014 alleles were screened for 57 MEFV mutations linked to FMF. A schematic representation of FMF-associated mutations in the MEFV gene is shown below. MEFV mutations most frequently found in FMF patients reside in exon 10 (depicted in green), which encodes the C-terminal PRYSPRY domain. Exons 2, 3, and 5 contain a substantial number of rare mutations (depicted in green). The five founder mutations are indicated in red. # R408Q and P369S mutations had been reported in cis as a single allele resulting in a variable clinical symptoms and R408Q is not likely to be a disease-causing variant (Bell et al. 2011).

Figure 2

Geographical distribution of derived allele frequencies for MEFV mutations of FMF. The pie areas are proportional to derived allele frequency (DAF) of the 21 (except E148Q) MEFV mutations of FMF. The 1000G and NHLBI (26 + 2) populations are displayed separately. The bar chart of DAF distribution is described in the lower right panel.