title: Familial Mediterranean fever: the segregation of four different mutations in 13 individuals from one inbred family: genotype-phenotype correlation and intrafamilial variability.
abstract: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurring attacks of fever and serositis. Six sequence alterations (M694V, V726A, K695R, M680I, M694I, and E148Q), in the MEFV gene, account for the majority of FMF chromosomes. Differences in the clinical expression have been mainly attributed to MEFV allelic heterogeneity. Homozygotes for the M694V mutation have a more severe form of the disease and more frequently demonstrate articular and renal complications. The clinical manifestations associated with mutation M680I are considered less severe. Mutations E148Q, K695R and V726A have reduced penetrance, and many individual homozygotes or compound heterozygotes for these mutations remain asymptomatic. Here we report on one inbred family with 13 individuals (one grandparent, three parents, and nine grandchildren), either homozygotes or compound heterozygotes, for one or two of four mutations (V726A, M694V, M680I, and K695R). Three parents and one grandparent who each carried two mutated alleles remained asymptomatic. Of nine grandchildren who were compound heterozygotes for two mutations in the MEFV gene, only those with either the M694V/V726A or the M694V/M680I genotypes manifested the disease, bearing further evidence to the severity of mutation M694V in individuals sharing a similar genetic and environmental background. Nevertheless, one father and one grandmother who carried the M694V/V726A compound heterozygous genotype were symptom-free, while the four grandchildren with the same genotype manifested the disease from early age, providing further evidence for the role of additional environmental and genetic modifiers. The occurrence of four different mutations in two sets of consanguineous parents merits consideration per se.
authors.affiliation: Institute of Human Genetics, Rambam Medical Center, Haifa, Israel. rgershoni@ramba.health.gov.il
authors.forename: Ruth
authors.initials: R
authors.lastname: Gershoni-Baruch
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
authors.forename: Hussein
authors.initials: H
authors.lastname: Shamaly
authors.forename: Leah
authors.initials: L
authors.lastname: Katsinetz
authors.forename: Riva
authors.initials: R
authors.lastname: Brik
mesh_terms: D003241:Consanguinity; D010505:Familial Mediterranean Fever / Q000235:genetics*; D005192:Family Health; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype