Background Maternal cell contamination (MCC) in prenatal samples poses a risk for misdiagnosis, and therefore, testing for contamination is necessary during genetic analysis of prenatal specimens. MCC testing is currently performed as a method separate from the diagnostic method. With the increasing application of whole exome sequencing (WES) in prenatal diagnosis, we sought to develop a method to estimate the level of contamination from WES data, aiming to eliminate the need for a separate MCC test. Methods To investigate the impact of MCC on the distribution of the variant allele fraction in WES data, contamination was both simulated in silico and artificially induced. Subsequently, a bioinformatic WES contamination method was developed and validated by comparing its performance to that of the gold standard (short tandem repeat [STR]) MCC test, validated for detecting ≥5% contamination. Finally, post-implementation performance was monitored for a 15-month period. Results During validation, 270 prenatal samples underwent analysis with both WES and the gold standard test. In 259 samples, the results were concordant (248 not contaminated, 11 contaminated with both tests). In 11 samples, contamination was only detected in WES data (2 of which contained ≥5% contamination with WES, which is above the detection limit of the gold standard test). The data of the post-implementation evaluation on 361 samples, of which 68 were contaminated, were in line with the validation data. Conclusions Contamination can reliably be detected in WES data, rendering a separate contamination test unnecessary for the majority of samples.

中文翻译：

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从全外显子组测序数据中检测产前样本中的 DNA 污染


背景 产前样本中的母体细胞污染 （MCC） 存在误诊风险，因此，在产前标本的基因分析过程中，必须进行污染检测。MCC 检测目前作为一种独立于诊断方法的方法进行。随着全外显子组测序 （WES） 在产前诊断中的应用越来越多，我们试图开发一种方法来估计 WES 数据中的污染水平，旨在消除对单独 MCC 测试的需要。方法 为了研究 MCC 对 WES 数据中变异等位基因分数分布的影响，污染既在计算机模拟中进行模拟，也进行人工诱导。随后，开发了一种生物信息学 WES 污染方法，并通过将其性能与金标准（短串联重复 [STR]）MCC 测试的性能进行比较进行验证，经验证可检测 ≥5% 污染。最后，对实施后的性能进行了 15 个月的监测。结果 在验证过程中，对 270 份产前样本进行了 WES 和金标准检测分析。在 259 个样本中，结果是一致的（248 个样本未受污染，11 个样本受两项检测污染）。在 11 个样品中，仅在 WES 数据中检测到污染（其中 2 个样品含有 ≥5% 的 WES 污染，高于金标准测试的检测限）。对 361 个样品（其中 68 个受到污染）的实施后评估数据与验证数据一致。结论 WES 数据中可以可靠地检测到污染，因此大多数样品无需进行单独的污染检测。