Accuracy and clinical value of maternal incidental findings during noninvasive prenatal testing for fetal aneuploidies
Accuracy and clinical value of maternal incidental findings during noninvasive prenatal testing for fetal aneuploidies
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DOI：
10.1038/gim.2016.113
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发表时间：
2017-03-01
影响因子：
8.8
通讯作者：
Vermeesch, Joris R.
中科院分区：
文献类型：
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作者：
Brison, Nathalie;Van Den Bogaert, Kris;Vermeesch, Joris R.
对孕妇血清中的无细胞（cf）DNA进行全基因组鸟枪测序可以识别未出生胎儿的染色体失衡。虽然最初开发用于筛查胎儿21、18和13三体，但一些研究现在已经证明全基因组分析也可以检测其他胎儿非整倍性、节段不平衡，甚至亚显微拷贝数变异（CNVs）。因为全基因组cfDNA测序询问母体以及胎儿DNA，所以也可以检测母体遗传变异。然而，目前的分析不包括母体拷贝数变异的解释。在这项研究中，分析了9882名接受cfDNA筛查的妇女的结果，以解释不同类型CNV的发生率。正如先前基于人群的研究所预期的那样，确定了10%的非复发性（独特）和0.4%的易感性CNV（基因组疾病）。其中5例的结果被返回给妇女，因为它们被认为代表了可采取行动的条件，包括RUNX1基因的缺失，以及4例对后代具有潜在意义的染色体重排。在进行产前cfDNA筛查时，分析来自母体cfDNA的测序数据有助于整体妊娠管理。如果具有临床意义，应报告母体血清中存在此类变异。这种CNVs的识别和报告，但是，提高潜在的咨询困境，值得consideration.Purpose：全基因组测序的无细胞（cf）DNA的孕妇的目的是检测胎儿染色体不平衡。由于cfDNA的最大部分由母体而不是胎儿DNA片段组成，因此还测量了母体来源的拷贝数变体（CNV）。尽管它们具有潜在的临床相关性，但目前的分析不能解释母体CNV。在这里，我们探讨孕妇CNV分析的准确性和临床价值。方法：无创性产前检测全基因组鸟枪测序血浆样本。在测序读数作图后，使用SeqCBS分析绘制了9，882名女性的母体CNV景观。通过将其发生率与已发表的报告进行比较，回顾性验证复发性CNV。非复发性CNVs的前瞻性确认阵列比较基因组杂交或荧光原位杂交分析母体lymphocyte.Results：一致的人口估计，10%的非复发性和0.4%的易感性CNVs低渗透基因组疾病被确定。五个临床上可操作的变体报告给孕妇，包括单倍不足的RUNX1，嵌合体的节段性染色体13缺失，不平衡易位，和两个间质染色体X deletions.Conclusion：霰弹枪测序的cfDNA不仅可以检测胎儿非整倍体，但也揭示了母亲CNVs的存在。其中一些变异在临床上是可行的，或者可能对胎儿有害。询问母体CNV景观可以改善整体妊娠管理，如果临床相关，我们建议报告这些变异。这种CNVs的识别和报告带来了新的咨询困境，需要进一步讨论和制定社会指南。
Genome-wide shotgun sequencing of cell-free (cf) DNA from the serum of pregnant women can identify chromosomal imbalances in an unborn fetus. Although initially developed to screen for fetal trisomies 21, 18, and 13, several studies have now demonstrated that genome-wide analysis can also detect other fetal aneuploidies, segmental imbalances, and even submicroscopic copy-number variations (CNVs). Because genome-wide cfDNA sequencing interrogates maternal as well as fetal DNA, maternal genetic variation can be detected as well. However, current analyses do not include an interpretation of maternal copy number variants.In this study, results from 9882 women undergoing cfDNA screening were analyzed to interpret the incidence of different types of CNVs. As expected based on prior population-based studies, 10% of nonrecurrent (unique) and 0.4% of susceptibility CNVs (for genomic disorders) were identified. Results from 5 of these were returned to the women, as they were felt to represent actionable conditions, including a deletion in the RUNX1 gene, and 4 cases of chromosomal rearrangements of potential significance to offspring.Analyzing sequencing data from the maternal cfDNA when performing prenatal cfDNA screening can be helpful to overall pregnancy management. The presence of such variants in maternal serum should be reported if clinically relevant. The identification and reporting of such CNVs, however, raise potential counseling dilemmas that warrant consideration.Purpose: Genome-wide sequencing of cell-free (cf) DNA of pregnant women aims to detect fetal chromosomal imbalances. Because the largest fraction of cfDNA consists of maternal rather than fetal DNA fragments, maternally derived copy-number variants (CNVs) are also measured. Despite their potential clinical relevance, current analyses do not interpret maternal CNVs. Here, we explore the accuracy and clinical value of maternal CNV analysis.Methods: Noninvasive prenatal testing was performed by wholegenome shotgun sequencing on plasma samples. Following mapping of the sequencing reads, the landscape of maternal CNVs was charted for 9,882 women using SeqCBS analysis. Recurrent CNVs were validated retrospectively by comparing their incidence with published reports. Nonrecurrent CNVs were prospectively confirmed by array comparative genomic hybridization or fluorescent in situ hybridization analysis on maternal lymphocytes.Results: Consistent with population estimates, 10% nonrecurrent and 0.4% susceptibility CNVs for low-penetrant genomic disorders were identified. Five clinically actionable variants were reported to the pregnant women, including haploinsufficiency of RUNX1, a mosaicism for segmental chromosome 13 deletion, an unbalanced translocation, and two interstitial chromosome X deletions.Conclusion: Shotgun sequencing of cfDNA not only enables the detection of fetal aneuploidies but also reveals the presence of maternal CNVs. Some of those variants are clinically actionable or could potentially be harmful for the fetus. Interrogating the maternal CNV landscape can improve overall pregnancy management, and we propose reporting those variants if clinically relevant. The identification and reporting of such CNVs pose novel counseling dilemmas that warrant further discussions and development of societal guidelines.