İlker Karacan1, Serdal Uğurlu2, Aslıhan Tolun3, Eda Tahir Turanlı4, Huri Ozdogan5. 1. Molecular Biology-Genetics and Biotechnology Department, Dr Orhan Öcalgiray Molecular Biology- Biotechnology and Genetics Research Centre, Graduate School of Science, Engineering and Technology, Istanbul Technical University, Turkey. 2. Division of Rheumatology, Department of Internal Medicine, Cerrahpaşa Faculty of Medicine, Istanbul University, Turkey. 3. Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey. 4. Molecular Biology-Genetics and Biotechnology Dept., Dr Orhan Öcalgiray Molecular Biology-Biotechnology & Genetics Res. Ctre, Graduate School of Science, Engineering and Technology; and Dept. of Molecular Biology & Genetics, Istanbul Technical Univ, Turkey. 5. Division of Rheumatology, Department of Internal Medicine, Cerrahpaşa Faculty of Medicine, Istanbul University, Turkey. huriozdogan@yahoo.com.
Abstract
OBJECTIVES: No MEFV mutations are detected in approximately 10% of the patients with clinical FMF in populations where the disease is highly prevalent. Causative mutations were searched in other genes in two such families with "MEFV negative clinical FMF". METHODS: Father and daughter of family A had attacks of fever, abdominal pain and AA amyloidosis. The two sibs of family B complained of febrile episodes with abdominal pain and arthritis. The patients were clinically investigated. Exome analysis in the daughter in family A and linkage analysis and candidate gene sequencing for the members of family B were performed. All patients were re-evaluated in the light of the genetic findings. RESULTS: In the daughter in family A, filtering of the exome file for variants in 25 autoimmune/inflammatory disease-related genes revealed two heterozygous missense variants in TNFRSF1A, novel p.Cys72Phe and frequent p.Arg121Gln. In family B, novel, homozygous missense p.Cys161Arg in MVK was identified. A clinical re-evaluation of the patients revealed a phenotype consistent with FMF rather than TRAPS in family A and an overlap of FMF with HIDS in family B. CONCLUSIONS: In high risk populations of FMF a proportion of patients without MEFV mutations may carry causative mutations in other genes, and the clinical findings may not be fully consistent with the phenotype expected of the mutation identified but rather resemble FMF or an overlap syndrome.
OBJECTIVES: No MEFV mutations are detected in approximately 10% of the patients with clinical FMF in populations where the disease is highly prevalent. Causative mutations were searched in other genes in two such families with "MEFV negative clinical FMF". METHODS: Father and daughter of family A had attacks of fever, abdominal pain and AA amyloidosis. The two sibs of family B complained of febrile episodes with abdominal pain and arthritis. The patients were clinically investigated. Exome analysis in the daughter in family A and linkage analysis and candidate gene sequencing for the members of family B were performed. All patients were re-evaluated in the light of the genetic findings. RESULTS: In the daughter in family A, filtering of the exome file for variants in 25 autoimmune/inflammatory disease-related genes revealed two heterozygous missense variants in TNFRSF1A, novel p.Cys72Phe and frequent p.Arg121Gln. In family B, novel, homozygous missense p.Cys161Arg in MVK was identified. A clinical re-evaluation of the patients revealed a phenotype consistent with FMF rather than TRAPS in family A and an overlap of FMF with HIDS in family B. CONCLUSIONS: In high risk populations of FMF a proportion of patients without MEFV mutations may carry causative mutations in other genes, and the clinical findings may not be fully consistent with the phenotype expected of the mutation identified but rather resemble FMF or an overlap syndrome.