Increase in diagnostic yield achieved for 174 whole-exome sequencing cases reanalyzed 1-2 years after initial analysis
Increase in diagnostic yield achieved for 174 whole-exome sequencing cases reanalyzed 1-2 years after initial analysis
复制标题
初次分析 1-2 年后重新分析的 174 个全外显子组测序病例的诊断率有所提高
DOI：
10.1016/j.cca.2021.09.015
复制
发表时间：
2021-09-27
影响因子：
5
通讯作者：
Wu, Lingqian
中科院分区：
文献类型：
--
作者：
Liu, Yingdi;Teng, Yanling;Wu, Lingqian
背景：在全外显子组测序（WES）分析可能存在孟德尔疾病的病例时，出现了一些漏诊。为了评估WES再分析对提高诊断率的贡献有多大，我们回顾了174例未确诊病例的WES数据。方法：利用更新的生物信息学管道进行再分析，包括更好的算法和更新的数据库，以便检测10-50 bp内内含子区域和InDels的CNVs和SNVs。升级的变异解释过程，包括更新软件包、数据库和文献，扩大对基因和疾病的知识，扩展过滤条件和表型重新评估，也被用于再分析。候选变异根据ACMG指南进行分类，并通过Sanger测序、qPCR或MLPA进行认证。结果：再分析新增诊断14例。从以下几个方面对阳性结果进行排序：CNVs检测；内含子区域或10-50 bp内InDels的snv诊断；由于变异或基因疾病关系的新报告而重新分类；导致疾病的基因遗传；由一般人群中频繁变异引起的疾病；准确的表型评估使分子诊断得以建立。结论：本研究通过优化的生物信息学管道和WES变异解释策略，提高了诊断率，为WES再分析提供了分析经验，减少了漏诊。
Background: Some missed diagnoses have been presented in whole-exome sequencing (WES) analysis for cases with possible Mendelian diseases. To assess how much contributions of WES reanalysis might improve diagnostic yield, we reviewed the WES data of 174 undiagnosed cases. Methods: We performed reanalysis with an updated bioinformatics pipeline involving better algorithms and updated databases so that CNVs and SNVs in intron regions and InDels within 10-50 bp can be detected. Upgraded variant interpretation processes, including updated software packages, databases and literature, expanded knowledge of genes and diseases, extended filtering conditions and phenotype reevaluation, were also implemented for reanalysis. Candidate variants were classified by ACMG guidelines and certified by Sanger sequencing, qPCR or MLPA. Results: Fourteen additional cases received new diagnosis in the reanalysis. The results which became positive were sorted according to the following aspects: detection of CNVs; diagnosis by SNVs in intron regions or InDels within 10-50 bp; reclassification due to new reports of variants or gene-disease relationships; digenic inheritance leading to disease; disease caused by frequent variations in the general population; and accurate phenotype assessment enabling the establishment of the molecular diagnosis. Conclusion: Our study improved diagnosis yield through an optimized bioinformatics pipeline and variant interpretation strategy of WES and provided analysis experience learned from the WES reanalysis to reduce missed diagnoses.