Improvement of MEFV gene variants classification to aid treatment decision making in familial Mediterranean fever
Improvement of MEFV gene variants classification to aid treatment decision making in familial Mediterranean fever
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DOI：
10.1093/rheumatology/kez332
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发表时间：
2020-04-01
期刊：
影响因子：
5.5
通讯作者：
Stella, Alessandro
中科院分区：
文献类型：
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作者：
Accetturo, Matteo;D'Uggento, Angela Maria;Stella, Alessandro
目的：FMF是一种由MEFV基因突变引起的遗传性自身炎症综合征。MEFV变异体仍然在很大程度上被分类为意义不确定的非变异体，或者分类尚未解决，这对FMF诊断构成了重大挑战。REVEL（Rare Exome Variant Encoder Learner）是一种新开发的变异元预测工具。为了减少MEFV变异的数量与模糊的分类，我们提取REVEL分数的所有错义变异存在于INFEVERS数据库，并分析其相关性与专家为基础的分类和本地化的MEFV编码的pyrin functional domains.Methods：216 MEFV错义变异的数据集被分为四类（可能良性，变异的不确定的意义，可能致病和未解决）。变体绘制到pyrin蛋白，在每个类别中的REVEL分数的分布进行计算，并计算平均值，置信区间，和接收器操作曲线下面积were calculated.Results：我们观察到致病性变体的非随机分布沿着pyrin功能域。REVEL评分与系统性自身炎性疾病国际研究组的共识分类具有良好的相关性。针对REVEL评分的不同截止值计算灵敏度、特异性和准确性，并计算出具有置信边界限制的基因特异性阈值0.298。结论：将现有的专家信息与敏感的预测工具相结合，可以更准确地解释MEFV基因变异的临床后果，从而更好地进行遗传咨询和患者管理。
Objective: FMF is an inherited autoinflammatory syndrome caused by mutations in the MEFV gene. MEFV variants are still largely classified as acvariant of uncertain significance, or with unresolved classification, posing significant challenges in FMF diagnosis. Rare Exome Variant Ensemble Learner (REVEL) is a recently developed variant metapredictor tool. To reduce the number of MEFV variants with ambiguous classification, we extracted REVEL scores for all missense variants present in the INFEVERS database, and analysed its correlation with expert-based classification and localization in the MEFV-encoded pyrin functional domains.Methods: The data set of 216 MEFV missense variants was divided into four categories (likely benign, variant of uncertain significance, likely pathogenic and unresolved). Variants were plotted onto the pyrin protein, the distribution of REVEL scores in each category was computed and means, confidence intervals, and area under the receiver operating curve were calculated.Results: We observed a non-random distribution of pathogenic variants along the pyrin functional domains. The REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Autoinflammatory Diseases. Sensitivity, specificity and accuracy were calculated for different cut-off values of REVEL scores and a gene-specific-threshold of 0.298 was computed with confidence boundary limits. This cut-off value allowed us to propose a reclassification of 96 MEFV gene variants, thus reducing the variant of uncertain significance proportion from 61.6% to 17.6%.Conclusion: The combination of available expert information with sensitive predictor tools could result in a more accurate interpretation of clinical consequences of MEFV gene variants, and to a better genetic counselling and patient management.