High positive predictive value of CNVs detected by clinical exome sequencing in suspected genetic diseases

作者：Yimo Zeng, Hongke Ding, Xingwang Wang, Yanlin Huang, Ling Liu, Li Du, Jian Lü, Jing Wu, Yukun Zeng, Mingqin Mai, Juan Zhu, Lihua Yu, Wei He, Fangfang Guo, Haishan Peng, Cuize Yao, Yiming Qi, Yuan Liu, Fake Li, Jiexia Yang, Rong Hu, Jie Liang, Jicheng Wang, Wei Wang, Yan Zhang, Aihua Yin · 发表于：Journal of Translational Medicine · 年份：2024 · DOI：10.1186/s12967-024-05468-1 · 被引用次数：9 · 研究领域：Genomic variations and chromosomal abnormalities、Genomics and Rare Diseases、Prenatal Screening and Diagnostics

BACKGROUND: Genetic disorders often manifest as abnormal fetal or childhood development. Copy number variations (CNVs) represent a significant genetic mechanism underlying such disorders. Despite their importance, the effectiveness of clinical exome sequencing (CES) in detecting CNVs, particularly small ones, remains incompletely understood. We aimed to evaluate the detection of both large and small CNVs using CES in a substantial clinical cohort, including parent-offspring trios and proband only analysis. METHODS: We conducted a retrospective analysis of CES data from 2428 families, collected from 2018 to 2021. Detected CNV were categorized as large or small, and various validation techniques including chromosome microarray (CMA), Multiplex ligation-dependent probe amplification assay (MLPA), and/or PCR-based methods, were employed for cross-validation. RESULTS: Our CNV discovery pipeline identified 171 CNV events in 154 cases, resulting in an overall detection rate of 6.3%. Validation was performed on 113 CNVs from 103 cases to assess CES reliability. The overall concordance rate between CES and other validation methods was 88.49% (100/113). Specifically, CES demonstrated complete consistency in detecting large CNV. However, for small CNVs, consistency rates were 81.08% (30/37) for deletions and 73.91% (17/23) for duplications. CONCLUSION: CES demonstrated high sensitivity and reliability in CNV detection. It emerges as an economical and dependable option for the clinical C...