Vreeswijk Maaike P G, van der Klift Heleen M
Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Methods Mol Biol. 2012;867:49-63. doi: 10.1007/978-1-61779-767-5_4.
Germ line mutations in genes involved in hereditary cancer syndromes, such as BRCA1 and BRCA2 in breast cancer and MSH2, MSH6, MLH1, and PSM2 in hereditary nonpolyposis colorectal cancer (HNPCC, more recently indicated as Lynch syndrome), confer a high risk to develop cancer. Mutation analysis in these genes has resulted in the identification of a large number of sequence variants, of which mutations causing frame shifts and nonsense codons are considered undoubtedly to be pathogenic. Many variants, however, cannot be classified as either disease-causing mutations or neutral variants and are therefore called unclassified variants (UVs). A subset of these variants may have an effect on RNA splicing. Appropriate RNA analysis will enable the characterization of the exact molecular nature of this effect and hence, is essential to determine the clinical relevance of the genomic variant. This chapter describes the design and implementation of RNA analysis as an indispensible tool in today's clinical diagnostic setting.
参与遗传性癌症综合征的基因中的种系突变，如乳腺癌中的BRCA1和BRCA2，以及遗传性非息肉病性结直肠癌（HNPCC，最近称为林奇综合征）中的MSH2、MSH6、MLH1和PSM2，会增加患癌风险。对这些基因的突变分析已鉴定出大量序列变异，其中导致移码和无义密码子的突变无疑被认为是致病性的。然而，许多变异既不能归类为致病突变，也不能归类为中性变异，因此被称为未分类变异（UVs）。这些变异中的一部分可能会影响RNA剪接。适当的RNA分析将能够确定这种影响的确切分子性质，因此对于确定基因组变异的临床相关性至关重要。本章描述了RNA分析作为当今临床诊断环境中不可或缺的工具的设计和实施。
