Assessment of functional effects of unclassified genetic variants.
Assessment of functional effects of unclassified genetic variants.
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DOI：
10.1002/humu.20899
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发表时间：
2008-11
期刊：
影响因子：
3.9
通讯作者：
de Wind, Niels
中科院分区：
文献类型：
--
作者：
Couch, Fergus J.;Rasmussen, Lene Juel;Hofstra, Robert;Monteiro, Alvaro N. A.;Greenblatt, Marc S.;de Wind, Niels
遗传性的疾病倾向通常与疾病相关基因产物的活性降低有关。因此，遗传变异对基因功能影响的定量可潜在地用于预测这些变异的疾病相关性。虽然许多疾病基因已在功能水平上得到广泛表征，但很少建立基于编码蛋白质功能特性的分析方法来预测罕见遗传变异对疾病的影响。建立预测功能测定的大部分困难源于测定的技术复杂性。然而，用于临床测试目的的功能测定开发最具挑战性的方面也许是验证测定的敏感性和特异性以及确定测定相对于疾病易感性的“金标准”测量的阳性预测值和阴性预测值的绝对要求。在这篇评论中，我们提供了一些正在开发的针对几种癌症易感基因 [BRCA1、BRCA2、CDKN2A 和错配修复 (MMR) 基因 MLH1、MSH2、MSH6 和 PMS2] 的功能测定的示例，并详细回顾了与功能测定开发相关的问题。我们的结论是，验证对于用于任何基因的遗传变异的临床解释的所有检测至关重要，但请注意，在某些情况下，从不完全验证的检测中获得的信息在用于补充从其他来源获得的数据时，对于临床目的的变异分类可能是有价值的。
Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been extensively characterized at the functional level, few assays based on functional properties of the encoded proteins have been established for the purpose of predicting the contribution of rare inherited variants to disease. Much of the difficulty in establishing predictive functional assays stems from the technical complexity of the assays. However, perhaps the most challenging aspect of functional assay development for clinical testing purposes is the absolute requirement for validation of the sensitivity and specificity of the assays and the determination of positive predictive and negative predictive values of the assays relative to a “gold standard” measure of disease predisposition. In this commentary we provide examples of some of the functional assays under development for several cancer predisposition genes [BRCA1, BRCA2, CDKN2A, and mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2] and present a detailed review of the issues associated with functional assay development. We conclude that validation is paramount for all assays that will be used for clinical interpretation of inherited variants of any gene, but note that in certain circumstances information derived from incompletely validated assays may be valuable for classification of variants for clinical purposes when used to supplement data derived from other sources.
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