Effectiveness of integrated interpretation of exome and corresponding transcriptome data for detecting splicing variants of genes associated with autosomal recessive disorders
Effectiveness of integrated interpretation of exome and corresponding transcriptome data for detecting splicing variants of genes associated with autosomal recessive disorders
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DOI：
10.1016/j.ymgmr.2019.100531
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发表时间：
2019-12-01
影响因子：
1.9
通讯作者：
Kosaki, Kenjiro
中科院分区：
文献类型：
--
作者：
Yamada, Mamiko;Suzuki, Hisato;Kosaki, Kenjiro
目的：外显子组分析的部分弱点在于无法检测异常剪接。对剪接后 mRNA 序列与基因组变异同时进行评估可以提高诊断率。我们的目的是调查公开的外显子组测序数据及其匹配的表型正常个体的转录组学数据，以在某些受试者可能是此类疾病携带者的前提下，从与常染色体隐性遗传疾病相关的已知基因中识别可变剪接变异。方法：借助最初为癌症基因组学开发的贝叶斯网络方法“SAVNet”检测异常剪接事件及其触发基因组变异。结果：包括外显子在内的 40 个异常剪接事件在千人基因组计划的 179 名受试者中，有 31 名受试者的 1916 个基因中检测到跳跃、新剪接位点的创建以及使用隐秘剪接位点来应对真实位点的破坏。预测对蛋白质的影响要么是移码突变 (30)，要么是大的框内插入或缺失 (10)。五个错义突变和两个沉默突变被重新解释为触发转录序列的重大变化。与传统的外显子组分析相比，临时截断的致病性变异的检出率提高了19%。结论：外显子组和转录组数据的耦合解释通过正确解释GT/AG剪接共有序列之外的内含子变异，增强了传统外显子组分析的性能，并且还允许重新解释确实对剪接产生巨大影响的“错义”或“沉默”替换。
Purpose: Part of the weakness of exome analysis lies in the inability to detect aberrant splicing. An evaluation of the post-splicing mRNA sequence concurrently with genomic variants could improve the diagnostic rate. We aimed to investigate publicly available exome sequencing data and its matching transcriptomics data of phenotypically normal individuals to identify alternatively spliced variants from known genes associated with autosomal recessive disorders under the premise that some of the subjects could be carriers of such disorders.Methods: Aberrant splicing events and their triggering genomic variants were detected with the aid of Bayesian network method "SAVNet" which was originally developed for cancer genomics.Results: Forty aberrant splicing events including exon skipping, the creation of a new splice site, and the use of a cryptic splice site in response to the disruption of the authentic site were detected in 1916 genes among 31 of the 179 subjects from the 1000 Genomes Project. The predicted effects on proteins were either frameshift mutations (30) or large in-frame insertions or deletions (10). Five missense mutations and 2 silent mutations were reinterpreted as triggering major changes in transcript sequences. The detection rate of provisionally truncating pathogenic variants increased by 19%, compared with a conventional exome analysis.Conclusion: The coupling interpretation of exome and transcriptome data enhances the performance of conventional exome analyses through the proper interpretation of intronic variants that are outside of the GT/AG splicing consensus sequences and also allows the reinterpretation of "missense" or "silent" substitutions that can indeed have drastic effects on splicing.