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腾讯登录无创产前诊断在亚染色体异常检测上或会限制临床应用
| 导读 | 近日，来自英国的研究人员通过研究表示，无创产前诊断（NIPT）因亚染色体异常（sub-chromosomal abnormalities）会限制临床应用。随着对胎儿三染色体（21，18，13）检测的无创产前诊断知晓率的增加，如今很多商业供应商都相应扩大了公司的服务范围，包括复发性的微小缺失和微小的重复（recurrent microdeletions and microduplications）。 |
近日，来自英国的研究人员通过研究表示，无创产前诊断（NIPT）因亚染色体异常（sub-chromosomal abnormalities）会限制临床应用。随着对胎儿三染色体（21，18，13）检测的无创产前诊断知晓率的增加，如今很多商业供应商都相应扩大了公司的服务范围，包括复发性的微小缺失和微小的重复（recurrent microdeletions and microduplications）。
来自伦敦大学的研究人员在国际杂志the American Journal of Human Genetics上刊文称，他们开发的用于检测亚染色体重排的流水线技术不仅可以检测染色体的微小缺失或微小重复，还可以帮助揭开大规模的染色体重排现象。随着测序深度的不断改善，未来假阳性率的检出也会随之增加。研究者Chitty表示，为了变得有效，NIPT技术就应当以极低的假阳性率对整个基因组的染色体重排进行检测，由于标准的NIPT技术不仅可以检测大多数的染色体重排，而且其还需要知晓胎儿的各个组成部分及细节，因此研究者认为目前NIPT技术还不足以进行常规的临床应用。
上个月刊登于PNAS上的一项报告中，研究者就报道说，当NIPT技术可以检测亚染色体剔除和重复时，相比常规的非整倍性测试，其可能就会需要更高百分比的胎儿DNA比率或者更加深度的覆盖。这项研究中，研究者对来自孕妇血浆的31份无细胞的DNA样本中的21份样本进行了分析，利用12层重叠测序对这些样本中的染色体重排进行了检测，所有收集的样本中都包含有已知的不平衡的染色体重组现象。对于携带超过600万碱基拷贝数变异的18份样本而言，研究者在其中15份样本中都至少检测到了一处异常性，而敏感性达到了83%。
然而，研究者仅在5份样本低于600万个碱基中检测到了拷贝数变异，其中3份样本都存在复制现象，而且母亲是携带者；在其它10份携带少量拷贝数变异的样本中，仅有两份可以被准确鉴别，敏感性为20%。目前深度测序技术并不能揭示拷贝数变异，而这很有可能取决于胎儿的组分。
这项研究中，研究人员在一系列胎儿组分中评估了不同尺寸的组分中拷贝数变异检测的能力，最终的评估结果对于实验室研究非常重要，而研究者发现，测试的敏感性并不能够通过增加测序的深度来大幅改善（如果胎儿组分跌到5%以下）；同时他们还指出，如果胎儿组分超过20%的话，和100万个碱基一样小的拷贝数变异就可以通过3800万的阅读来检测到。然而增加测序深度的价格或许会随之升高。
最后研究者Chitty说道，毫无疑问，利用NIPT技术进行染色体整倍性筛查带来的明显益处就是安全性提高了，同时也降低了损伤性检测的必要性，将NIPT技术延伸到包括对亚染色体重排的筛查或许就会降低该技术的有益性，因为目前该技术并不能够对于致病性的重排进行综合检测和分析。（转化医学网360zhyx.com）
以上为转化医学网原创翻译整理，转载请注明出处和链接！
转化医学网推荐的原文摘要：
Limited Clinical Utility of Non-invasive Prenatal Testing for Subchromosomal Abnormalities
American Journal of Human Genetics doi：10.1016/j.ajhg.2015.11.016
Kitty K. Lo, Evangelia Karampetsou, Christopher Boustred, Fiona McKay, Sarah Mason, Melissa Hill, Vincent Plagnol, Lyn S. Chitty
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.
American Journal of Human Genetics doi：10.1016/j.ajhg.2015.11.016
Kitty K. Lo, Evangelia Karampetsou, Christopher Boustred, Fiona McKay, Sarah Mason, Melissa Hill, Vincent Plagnol, Lyn S. Chitty
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.
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