Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study
Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study
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DOI：
10.1016/s0140-6736(18)32042-7
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发表时间：
2019-02-23
期刊：
影响因子：
168.9
通讯作者：
Wapner, Ronald J.
中科院分区：
文献类型：
--
作者：
Petrovski, Slave;Aggarwal, Vimla;Wapner, Ronald J.
背景：染色体非整倍体和拷贝数变异与胎儿结构异常的鉴别具有重要价值。虽然全外显子组测序（WES）已被应用于一些选定的产前病例的病例系列，其在常规临床设置的价值尚未进行前瞻性评估，在一个大的胎儿结构异常的队列。因此，我们的目标是确定增量诊断率（即，附加值）WES以下的标准调查结果与核型检测和染色体微阵列在一个队列的连续怀孕显示胎儿结构异常。方法在这个前瞻性队列研究，在产前超声检查中发现胎儿结构异常的父母被筛选出可能参与研究。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，USA）确定或转诊的。从WES分析中排除确认为非整倍体或致病性拷贝数变异的胎仔。通过使用胎儿和父母的WES（父母-胎儿三人组），我们确定了遗传变异，表明潜在的原因（诊断性遗传变异）和符合生物信息学特征标准的遗传变异，这些生物信息学特征以前被描述为在诊断性遗传变异中显著富集。筛选了517名发现胎儿结构异常的连续鉴定孕妇，以确定其是否有资格纳入我们的研究。71对（14%）夫妇拒绝检测，87对（17%）三人组缺少至少一个DNA样本（来自父母或胎儿），69对（13%）三人组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对（1%）样本质量不足以进行分析。因此，来自234（45%）个合格三人组的DNA样本用于分析主要结局。通过使用三重序列数据，我们在24个（10%）家庭中确定了诊断性遗传变异。突变的生物信息学签名，指示致病性，但没有足够的证据被认为是诊断也进行了评估; 46（20%）的234个胎儿评估被发现有这样的signature.Interpretation我们的分析WES数据在一个前瞻性队列的胎儿结构异常显示的价值增加WES后使用常规基因检测。我们的研究结果表明，在胎儿异常的情况下，核型检测和染色体微阵列评估未能确定结构异常的根本原因，WES可以添加临床相关信息，可以帮助目前的妊娠管理。基于WES的产前诊断的独特挑战需要由围产期从业人员和实验室专家组成的多学科团队进行分析。资助基因组医学研究所（哥伦比亚大学欧文医学中心）。版权所有（c）2019 Elsevier Ltd.保留所有权利。
Background 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.Methods 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.Findings 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.Interpretation 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 multi-disciplinary team of perinatal practitioners and laboratory specialists.Funding Institute for Genomic Medicine (Columbia University Irving Medical Center). Copyright (c) 2019 Elsevier Ltd. All rights reserved.