Limited Clinical Utility of Non-invasive Prenatal Testing for Subchromosomal Abnormalities
Limited Clinical Utility of Non-invasive Prenatal Testing for Subchromosomal Abnormalities
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DOI：
10.1016/j.ajhg.2015.11.016
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发表时间：
2016-01-07
影响因子：
9.8
通讯作者：
Chitty, Lyn S.
中科院分区：
文献类型：
--
作者：
Lo, Kitty K.;Karampetsou, Evangelia;Chitty, Lyn S.
将母体cfDNA的大规模平行测序用于非整倍性的非侵入性产前检测（NIPT）是广泛可用的。最近，检测范围已扩大到包括选定的亚染色体异常，但报告的样本数量很少。我们开发了一种基于分割算法的调用管道，用于检测母体血浆中的这些重排。在我们用于非整倍性NIPT的标准流水线中使用的相同读取深度检测到15/18（83%）具有致病性重排> 6 Mb的样品，但仅2/10具有重排< 6 Mb的样品，除非它们是母系遗传的。在534例无已知亚染色体异常的样本中有2例假阳性（特异性99.6%）。使用更高的读取深度，我们检测到29/31的胎儿亚染色体异常，包括三个具有母系遗传微重复的样本。我们得出结论，测试灵敏度是胎儿分数，读取深度和胎儿CNV的大小的函数，并且两个假阴性中至少有一个是由于胎儿分数低。缺乏一个独立的方法来确定胎儿分数，特别是对女性胎儿，导致测试灵敏度的不确定性，这对该技术作为临床诊断测试的未来有影响。此外，为了有效，NIPT必须能够检测整个基因组中的染色体重排，以获得非常低的假阳性率。由于标准NIPT只能检测大多数较大（>6 Mb）的染色体重排，并需要了解胎儿分数，我们认为它还没有准备好进行常规临床实施。
The use of massively parallel sequencing of maternal cfDNA for non-invasive prenatal testing (NIPT) of aneuploidy is widely available. Recently, the scope of testing has increased to include selected subchromosomal abnormalities, but the number of samples reported has been small. We developed a calling pipeline based on a segmentation algorithm for the detection of these rearrangements in maternal plasma. The same read depth used in our standard pipeline for aneuploidy NIPT detected 15/18 (83%) samples with pathogenic rearrangements > 6 Mb but only 2/10 samples with rearrangements < 6 Mb, unless they were maternally inherited. There were two false-positive calls in 534 samples with no known subchromosomal abnormalities (specificity 99.6%). Using higher read depths, we detected 29/31 fetal subchromosomal abnormalities, including the three samples with maternally inherited microduplications. We conclude that test sensitivity is a function of the fetal fraction, read depth, and size of the fetal CNV and that at least one of the two false negatives is due to a low fetal fraction. The lack of an independent method for determining fetal fraction, especially for female fetuses, leads to uncertainty in test sensitivity, which currently has implications for this technique's future as a clinical diagnostic test. Furthermore, to be effective, NIPT must be able to detect chromosomal rearrangements across the whole genome for a very low false-positive rate. Because standard NIPT can only detect the majority of larger (>6 Mb) chromosomal rearrangements and requires knowledge of fetal fraction, we consider that it is not yet ready for routine clinical implementation.