title: Evidence of digenic inheritance in autoinflammation-associated genes.
abstract: Familial Mediterranean fever (FMF) has traditionally been considered as a monogenic autosomal recessive disorder caused by mutations in the MEFV gene with highest incidence among Mediterranean populations. In a considerable number of patients with typical FMF, only one MEFV mutation was identified and the possibility that more than one autoinflammatory gene may be responsible for their disease was investigated. In the present study, an extensive search for possible mutations in three hereditary recurrent fever (HRF) genes was performed in 128 MEFV heterozygous Greek-Cypriots clinically diagnosed based on their phenotype with FMF-like disease from a previous study. Sequence analysis was performed for MVK, TNFRSF1A and NLRP3 genes which is also known to cause HRFs. In total, three patients were identified with heterozygous mutations and a second mutation in an autoinflammatory gene. Two patients carried a MEFV mutation and a NLRP3 mutation, and an additional third carried a MEFV mutation and a TNFRSF1A mutation. Patient 1 carried MEFV p.[Val726Ala] (NM_000243.2:c.2177T>C) and NLRP3 p.[Val198Met] (NM_001243133.1:c.592G>A) variants and patient 2 carried MEFV p.[Glu148Gln] (NM_000243.2:c.442G>C) variant which is of uncertain significance and NLRP3 p.[Arg176Trp] (NM_001243133.1:c.526C>T). Lastly, patient 3 was identified to carry MEFV p.[Met694Val] (NM_000243.2:c.2080A>G) and TNFRSF1A p.[Arg121Gln] (NM_001065.3:c.362G>A) variants. The results from this study indicate that screening of genes known to cause HRFs in patients already identified with a single MEFV mutation, can reveal quite rare but potentially causative mutational combinations at different loci. Such interaction provide further evidence for possible locus-locus interactions and phenotypes resulting from digenic inheritance.
authors.affiliation: Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus. laphylac@cing.ac.cy.
authors.forename: Vassos
authors.initials: V
authors.lastname: Neocleous
authors.forename: Stefania
authors.initials: S
authors.lastname: Byrou
authors.forename: Meropi
authors.initials: M
authors.lastname: Toumba
authors.forename: Constantina
authors.initials: C
authors.lastname: Costi
authors.forename: Christos
authors.initials: C
authors.lastname: Shammas
authors.forename: Christina
authors.initials: C
authors.lastname: Kyriakou
authors.forename: Violetta
authors.initials: V
authors.lastname: Christophidou-Anastasiadou
authors.forename: George A
authors.initials: GA
authors.lastname: Tanteles
authors.forename: Adamos
authors.initials: A
authors.lastname: Hadjipanayis
authors.forename: Leonidas A
authors.initials: LA
authors.lastname: Phylactou
mesh_terms: D000293:Adolescent; D000328:Adult; D010505:Familial Mediterranean Fever / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D040582:Inheritance Patterns; D008297:Male; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D000071198:Pyrin / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D055815:Young Adult
chemical_list: D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000071198:Pyrin; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human