Karacan İlker, Uğurlu Serdal, Tolun Aslıhan, Tahir Turanlı Eda, Ozdogan Huri
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.
Division of Rheumatology, Department of Internal Medicine, Cerrahpaşa Faculty of Medicine, Istanbul University, Turkey.
Clin Exp Rheumatol. 2017 Nov-Dec;35 Suppl 108(6):75-81. Epub 2017 Oct 27.
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".
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.
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.
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.
在该疾病高度流行的人群中，约10%临床诊断为家族性地中海热（FMF）的患者未检测到MEFV突变。在两个患有“MEFV阴性临床FMF”的家族中，对其他基因进行致病突变筛查。
A家族的父亲和女儿有发热、腹痛发作及AA型淀粉样变性。B家族的两个兄弟姐妹主诉有发热伴腹痛和关节炎发作。对患者进行临床检查。对A家族的女儿进行外显子组分析，对B家族成员进行连锁分析和候选基因测序。根据基因检测结果对所有患者进行重新评估。
在A家族的女儿中，对25个自身免疫/炎症性疾病相关基因的外显子文件进行变异筛选，发现TNFRSF1A基因中有两个杂合错义变异，新的p.Cys72Phe和常见的p.Arg121Gln。在B家族中，鉴定出MVK基因新的纯合错义变异p.Cys161Arg。对患者进行临床重新评估发现，A家族患者的表型符合FMF而非肿瘤坏死因子受体相关周期性综合征（TRAPS），B家族患者的表型为FMF与高免疫球蛋白D综合征（HIDS）重叠。
在FMF的高危人群中，一部分无MEFV突变的患者可能在其他基因中携带致病突变，且临床发现可能与所鉴定突变预期的表型不完全一致，而更类似于FMF或重叠综合征。
