Abstract：
Familial Mediterranean Fever (FMF) is linked with the MEFV gene and is the commonest among monogenic autoinflammatory diseases, with high prevalence in the Mediterranean basin. Although the clinical presentation of FMF has a major role in diagnosis, genotype/phenotype correlations and the role of \"benign\" gene variants (as R202Q) appear highly variable and incompletely clear, making difficult to select the most effective strategy in the management of patients. Aim of the present study was to investigate the clinical presentation and the genetic background in a homogenous cohort of patients from Apulia (south eastern Italy). We investigated 217 patients with a clinical suspect of autoinflammatory diseases, who were characterized for the occurrence of specific symptoms and with next generation sequencing by a 4-gene panel including MEFV, MVK, NLRP3 and TNFRSF1A. A genetic change was identified in 122 (53.7%) patients, with 161 different MEFV variants recorded in 100 individuals, 10 variants in NLRP3, and 6 each in TNFRSF1A and MVK. The benign variant R202Q was largely prevalent (41.6% of all MEFV variants). When patients were selected according the number of pathogenic MEFV variants (0, 1, or 2 pathogenic variants), results failed to show significant links between the frequency of symptoms and the number of pathogenic variants. Only family history and Pras score (indicative for severity of disease) predicted the presence of pathogenic variants, as compared with carriers of variants considered of uncertain significance or benign. Fever >38 °C and arthralgias appeared more frequently in R202Q-positive patients than in non-R202Q carriers. These two subgroups showed comparable duration of fever, occurrence of myalgia, abdominal and chest pain, Pras, and IFFS scores. In conclusion, results confirm that FMF manifests in mild form in non-middle eastern patients. This possibility partly affects the reliability of clinical criteria/scores. Furthermore, the presence of the R202Q variant might not be completely neutral in selected groups of patients.
摘要：
家族性地中海热（FMF）与MEFV基因有关，是单基因自身炎性疾病中最常见的疾病，在地中海盆地患病率很高。尽管FMF的临床表现在诊断中具有主要作用，基因型/表型相关性和“良性”基因变异的作用（如R202Q）出现高度可变和不完全清楚，使得在患者管理中难以选择最有效的策略。本研究的目的是调查来自普利亚（意大利东南部）的同质患者队列的临床表现和遗传背景。我们调查了217名临床怀疑患有自身炎症性疾病的患者，他们被表征为特定症状的发生，并通过包括MEFV在内的4基因小组进行下一代测序，MVK,NLRP3和TNFRSF1A。在122例（53.7%）患者中发现了基因变化，在100个人中记录了161种不同的MEFV变体，NLRP3中的10个变体,以及TNFRSF1A和MVK中的各6个变体。良性变体R202Q在很大程度上是普遍的(所有MEFV变体的41.6%)。当根据致病性MEFV变异（0、1或2个致病性变异）的数量选择患者时，结果未能显示症状频率和致病变异数量之间的显著联系.只有家族史和Pras评分（指示疾病的严重程度）可以预测致病变异的存在，与被认为意义不确定或良性的变异携带者相比。与非R202Q携带者相比，R202Q阳性患者中发热>38°C和关节痛的出现频率更高。这两个亚组的发热持续时间相当，发生肌痛，腹部和胸部疼痛，Pras,和IFFS分数。总之,结果证实FMF在非中东患者中表现为轻度形式。这种可能性部分影响临床标准/评分的可靠性。此外，在选定的患者组中,R202Q变异体的存在可能不是完全中性的.
