oa MEFV gene mutation detection in Arab patients

MEFV Gene Mutation Detection In Arabic Patients With Familial Mediterranean Fever Rowaida Taha1, Suheil Ayesh2, Abdulghani Kohilan1, Vasiliki Chini1, Marios Kambouris 1,3, Hatem El-Shanti 1,4 1Shafallah Medical Genetics Center, Doha, Qatar, 2Gene Medical Labs, Gaza, Palestinian Territory, 3Yale University School of Medicine, Genetics, New Haven CT, USA, 4University of Iowa, Pediatrics, Iowa City, IA, USA Auto-inflammatory diseases are characterized by inflammation in the absence of high-titer autoantibodies or antigen-specific T cells. Familial Mediterranean fever (FMF) is the archetypal hereditary autosomal recessive periodic fever syndrome and auto-inflammatory disease characterized by recurrent self-limiting episodes of fever and painful polyserositis. It is most often found in families of Mediterranean ancestry, especially non-Ashkenazi Jews, Armenians, Turks, and Arabs. The offending MEFV gene localizes at Hsa 16p, encodes the pyrin or marenostrin protein, it is highly polymorphic with multiple disease causing mutations and normal polymorphisms. In Arabic FMF patients the spectrum and distribution of MEFV mutations are distinctive and the portion of unidentified mutations [50%] is the highest amongst the groups commonly affected by FMF. The MEFV genomic region in 100 hundred Palestinian patients with clear FMF symptomatology consistent with the clinical diagnostic criteria and with only one identified pathogenic mutation was screened to identify the second pathogenic mutation as well as coding and non-coding variations, large duplications or deletions and intronic variations. Mutation analyses involved sequencing of exons and splice sites, sequencing putative regulatory regions by using Long range PCR, Multiplex Ligation-dependent Probe Amplification (MLPA) to detect large deletions or duplications, and sequencing of the entire genomic region of MEFV. No second pathogenic mutation was identified in any of the samples by sequencing MEFV exons and splice sites, as well as putative regulatory regions. MLPA did not detect any large MEFV genomic deletions or duplications. Twenty different rare intronic variants (each identified in 1-3 patients) and were not present in about 700 ethnically matched control chromosomes. The biological significance of these variations could not be determined. There is strong evidence of preferential amplification of one allele over the other due to extensive polymorphism within the genomic sequence that would account for the lack of detection of the second pathogenic mutation. Alternatively, the effects of modifier genes or other loci that influence the clinical picture of FMF in Arabic populations can not be excluded. The comprehensive identification of MEFV mutant alleles among FMF patients is essential for the efficient examination of specific genotype - phenotype correlation patterns and for development of molecular tools to support the clinical diagnosis.