Medical Genetics Center, Guangdong Women and Children Hospital, Xingnan Road 521, Guangzhou, 510010, Guangdong, China.
Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, China.
J Transl Med. 2024 Jul 9;22(1):644. doi: 10.1186/s12967-024-05468-1.
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.
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.
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.
CES demonstrated high sensitivity and reliability in CNV detection. It emerges as an economical and dependable option for the clinical CNV detection in cases of developmental abnormalities, especially fetal structural abnormalities.
遗传疾病通常表现为胎儿或儿童发育异常。拷贝数变异（CNVs）是此类疾病的重要遗传机制。尽管其重要性不容忽视，但临床外显子组测序（CES）在检测 CNVs，尤其是小型 CNVs 方面的有效性仍不完全清楚。我们旨在评估 CES 在包括亲子三体外和仅先证者分析在内的大量临床队列中检测大、小型 CNVs 的效果。
我们对 2018 年至 2021 年间收集的 2428 个家系的 CES 数据进行了回顾性分析。将检测到的 CNV 分为大或小，并使用染色体微阵列（CMA）、多重连接依赖性探针扩增分析（MLPA）和/或基于 PCR 的方法等各种验证技术进行交叉验证。
我们的 CNV 发现流程在 103 个病例中的 113 个 CNV 中鉴定出 171 个 CNV 事件，总体检出率为 6.3%。对 103 个病例中的 113 个 CNV 进行验证，以评估 CES 的可靠性。CES 与其他验证方法的总体一致性率为 88.49%（100/113）。具体而言，CES 完全一致地检测到大型 CNV。然而，对于小型 CNV，缺失的一致性率为 81.08%（30/37），重复的一致性率为 73.91%（17/23）。
CES 对 CNV 的检测具有较高的灵敏度和可靠性。在发育异常，尤其是胎儿结构异常的情况下，它是一种经济可靠的临床 CNV 检测选择。
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