Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA; AstraZeneca Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA; Laboratory of Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
Lancet. 2019 Feb 23;393(10173):758-767. doi: 10.1016/S0140-6736(18)32042-7. Epub 2019 Jan 31.
Identification of chromosomal aneuploidies and copy number variants that are associated with fetal structural anomalies has substantial value. Although whole-exome sequencing (WES) has been applied to case series of a few selected prenatal cases, its value in routine clinical settings has not been prospectively assessed in a large unselected cohort of fetuses with structural anomalies. We therefore aimed to determine the incremental diagnostic yield (ie, the added value) of WES following uninformative results of standard investigations with karyotype testing and chromosomal microarray in an unselected cohort of sequential pregnancies showing fetal structural anomalies.
In this prospective cohort study, the parents of fetuses who were found to have a structural anomaly in a prenatal ultrasound were screened for possible participation in the study. These participants were predominantly identified in or were referred to the Columbia University Carmen and John Thain Center for Prenatal Pediatrics (New York, NY, USA). Fetuses with confirmed aneuploidy or a causal pathogenic copy number variant were excluded from WES analyses. By use of WES of the fetuses and parents (parent-fetus trios), we identified genetic variants that indicated an underlying cause (diagnostic genetic variants) and genetic variants that met the criteria of bioinformatic signatures that had previously been described to be significantly enriched among diagnostic genetic variants.
Between April 24, 2015, and April 19, 2017, 517 sequentially identified pregnant women found to have fetuses with a structural anomaly were screened for their eligibility for inclusion in our study. 71 (14%) couples declined testing, 87 (17%) trios were missing at least one DNA sample (from either parent or the fetus), 69 (13%) trios had a clinically relevant abnormal karyotype or chromosomal microarray finding, 51 (10%) couples did not consent to WES or withdrew consent, and five (1%) samples were not of good enough quality for analysis. DNA samples from 234 (45%) eligible trios were therefore used for analysis of the primary outcome. By use of trio sequence data, we identified diagnostic genetic variants in 24 (10%) families. Mutations with bioinformatic signatures that were indicative of pathogenicity but with insufficient evidence to be considered diagnostic were also evaluated; 46 (20%) of the 234 fetuses assessed were found to have such signatures.
Our analysis of WES data in a prospective cohort of unselected fetuses with structural anomalies shows the value added by WES following the use of routine genetic tests. Our findings suggest that, in cases of fetal anomalies in which assessment with karyotype testing and chromosomal microarray fail to determine the underlying cause of a structural anomaly, WES can add clinically relevant information that could assist current management of a pregnancy. The unique challenges of WES-based prenatal diagnostics require analysis by a multidisciplinary team of perinatal practitioners and laboratory specialists.
Institute for Genomic Medicine (Columbia University Irving Medical Center).
鉴定与胎儿结构异常相关的染色体非整倍体和拷贝数变异具有重要价值。虽然全外显子组测序（WES）已应用于少数选定的产前病例系列，但它在大规模未选择的具有结构异常的胎儿队列中的常规临床环境中的价值尚未前瞻性评估。因此，我们旨在确定在未选择的连续出现胎儿结构异常的队列中，在进行标准核型检测和染色体微阵列检查后，WES 的增量诊断收益（即附加价值）。
在这项前瞻性队列研究中，对在产前超声检查中发现结构异常的胎儿的父母进行了可能参与研究的筛查。这些参与者主要是在哥伦比亚大学 Carmen 和 John Thain 产前儿科中心（纽约，NY，美国）发现的或转介到该中心的。排除了经确认存在非整倍体或因果致病性拷贝数变异的胎儿进行 WES 分析。通过对胎儿及其父母（父母-胎儿三联体）进行 WES 分析，我们确定了表明潜在病因的遗传变异（诊断性遗传变异）和符合先前描述的生物信息学特征标准的遗传变异，这些变异在诊断性遗传变异中显著富集。
2015 年 4 月 24 日至 2017 年 4 月 19 日，对 517 名连续发现胎儿结构异常的孕妇进行了筛查，以确定其是否符合纳入我们研究的条件。71 对（14%）夫妇拒绝检测，87 对（17%）三联体缺少至少一份来自父母或胎儿的 DNA 样本，69 对（13%）三联体有临床相关的异常核型或染色体微阵列发现，51 对（10%）夫妇不同意 WES 或撤回同意，5 个（1%）样本的质量不足以进行分析。因此，来自 234 对（45%）合格三联体的 DNA 样本用于分析主要结局。通过使用三联体序列数据，我们在 24 个（10%）家庭中确定了诊断性遗传变异。还评估了具有生物信息学特征但证据不足不足以被认为是致病性的突变；评估的 234 名胎儿中有 46 名（20%）具有这种特征。
我们对未选择的具有结构异常的胎儿的 WES 数据进行的分析表明，在常规基因检测无法确定结构异常的潜在病因的情况下，WES 增加了价值。我们的研究结果表明，在核型检测和染色体微阵列评估未能确定胎儿异常的潜在病因的情况下，WES 可以提供具有临床意义的信息，有助于当前妊娠的管理。基于 WES 的产前诊断所面临的独特挑战需要由围产期从业者和实验室专家组成的多学科团队进行分析。
基因组医学研究所（哥伦比亚大学欧文医学中心）。
