Genotype–phenotype studies in a large cohort of Armenian patients with familial Mediterranean fever suggest clinical disease with heterozygous MEFV mutations

Abstract

Familial Mediterranean fever (FMF) is an autoinflammatory disorder generally caused by recessively inherited mutations in the MEFV gene. FMF is quite prevalent in Armenian population in which majority of patients have two mutated alleles, yet in 18% of symptomatic patients just one mutation has been detected. To explain this finding, we analyzed the symptoms and genotypes of 1299 patients, including 236 affected heterozygous patients with definite diagnosis of FMF. We selected a subset of 63 heterozygous, homozygous and asymptomatic normal individuals and completely sequenced their MEFV genes (exons) to discover any other mutations potentially missed by currently used screening method. Besides four synonymous polymorphisms in exon two and five, we found a T267I mutation in one heterozygous patient with a severe case of FMF who should have been designated as compound heterozygous, yet the other genotypes were all accurate. We used binomial probability distribution of symptoms in homozygous FMF patients to estimate the likelihood of their occurrences in heterozygous patients and demonstrated the assemblage of patients into groups with similar clinical criteria using statistical clustering. We found extremely high probabilities for the presence of FMF symptoms in heterozygous individuals and determined that symptoms were equally likely to occur in both analyzed genotypes. Therefore, our study supports the rising evidence that a single MEFV mutation could be associated with mild FMF symptoms. However, heterozygous patients presenting with severe phenotype should be further analyzed for less common second MEFV mutation using gene sequencing.

Patient management and the association of less common familial Mediterranean fever symptoms with other disorders

“…The frequency of the E148Q mutation was similar in both healthy and affected individuals, suggesting that these two mutations have lower penetrance as compared with the others but could still contribute to the overall FMF symptoms in compound-heterozygous patients. 13 Phenotype-genotype correlation using data from 3,286 homozygous, 9,254 compound heterozygous, and 2,884 heterozygous patients with symptoms ranging from mild to severe FMF indicated that amyloidosis was associated with M694V, M680I, and V726A homozygous patients. Yet the dominant mutation associated with amyloidosis was M694V, with 256 cases as compared with 108 and 99 cases for V726A and M680I homozygotes, respectively (P = 0.059).…”

“…These 12 mutations cover more than 98.7% of clinically confirmed FMF cases, even in heterozygous patients with mild clinical FMF, which currently represent ~7.6% of the total population. 13 A total of 100 samples, 30 homozygous or compound heterozygous, 45 heterozygous, and 25 asymptomatic wild-type controls, were selected, and their MEFV gene exons and intron junctions were completely sequenced independently in the United States using dideoxy termination methodology on an ABI 3730 capillary electrophoresis instrument (Applied Biosystems, Carlsbad, CA). The sequencing facility and the designed primers for all exons were provided by Morava (Glendale, CA).…”

“…Prophylactic treatment for asymptomatic or mild patients heterozygous for M694V still remains an open question. 13 By contrast, FMF patients with other genotypes still had a good chance to ameliorate the nephrotic syndrome and to maintain renal function. Misdiagnosis of FMF usually occurred in the absence of common symptoms and presence of rare/ uncommon severe symptoms or presence of only one symptom.…”

Alta frecuencia de variación de la secuencia de la mutación E148Q en niños con fiebre mediterránea familiar en el sureste de Turquía

“…2,7 Las características fenotípicas y la secuencia del gen de pacientes con FMF cambian según las regiones geográficas, que incluyen personas de determinados orígenes étnicos tanto en Turquía como en el resto del mundo. 1,2,[7][8][9][10][11][12][13][14][15][16][17] Desafortunadamente, son pocos los estudios en los que se han investigado las variaciones genotípicas y fenotípicas de pacientes con FMF en el sureste de Turquía. 3 Por lo tanto, nuestro objetivo fue investigar las características genotípicas y fenotípicas de niños con FMF en el sureste de Turquía.…”

High frequency of E148Q sequence variation in children with familial Mediterranean fever in southeast Turkey

“…2,7 Gene sequence and phenotypic characteristics of FMF patients change according to geographic regions, which include people from certain ethnic origins both in Turkey and in the World. 1,2,[7][8][9][10][11][12][13][14][15][16][17] Unfortunately, there is a paucity of studies that have investigated the genotypic and phenotypic variations of FMF patients in southeast Turkey. 3 Therefore, we aimed to investigate the genotypic and phenotypic characteristics of children with FMF in southeastern Turkey.…”