Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
Guanzghou Umbilical Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
Ultrasound Obstet Gynecol. 2018 Apr;51(4):493-502. doi: 10.1002/uog.18915.
To evaluate the diagnostic yield of prenatal whole exome sequencing (WES) for monogenic disorders in fetuses with structural malformations and normal results on cytogenetic testing, and to describe information on pathogenic variants that is provided by WES.
Karyotyping, chromosomal microarray analysis (CMA) and WES were performed sequentially on stored samples from a cohort of 3949 pregnancies with fetal structural abnormalities detected on ultrasound and/or magnetic resonance imaging, referred between January 2011 and December 2015. Diagnostic rates of the three techniques were investigated overall, for phenotypic subgroups and for proband-only vs fetus-mother-father samples. Information on pathogenic variants was identified by WES.
Overall, 18.2% (720/3949) of fetuses had an abnormal karyotype. Pathogenic copy number variants were detected on CMA in 8.2% (138/1680) of fetuses that had a normal karyotype result. WES performed on a subgroup of 196 fetuses with normal CMA and karyotype results revealed the putative genetic variants responsible for the abnormal phenotypes in 47 cases (24%). The molecular diagnosis rates for fetus-mother-father and proband-only samples were 26.5% (13/49) and 23.1% (34/147), respectively. Variants of uncertain significance were detected in 12.8% (25/196) of fetuses, of which 22 were identified in the fetal proband-only group (15%; 22/147) and three in the fetus-mother-father group (6.1%; 3/49). The incidental finding rate was 6.1% (12/196).
WES is a promising method for the identification of genetic variants that cause structural abnormalities in fetuses with normal results on karyotyping and CMA. This enhanced diagnostic yield has the potential to improve the clinical management of pregnancies and to inform better the reproductive decisions of affected families. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
评估产前全外显子组测序（WES）在结构畸形且核型分析和染色体微阵列分析（CMA）结果正常的胎儿中用于单基因疾病诊断的效能，并描述 WES 提供的致病性变异信息。
对 2011 年 1 月至 2015 年 12 月期间因超声和/或磁共振成像检测到胎儿结构异常而转诊的 3949 例妊娠患者的存储样本，依次进行核型分析、CMA 和 WES。总体上以及在表型亚组中，以及在仅胎儿-母亲-父亲样本和胎儿样本中，分别研究了这三种技术的诊断率。通过 WES 确定致病性变异信息。
总体而言，3949 例胎儿中有 18.2%（720/3949）的胎儿核型异常。在核型正常的 1680 例胎儿中，有 8.2%（138/1680）的胎儿 CMA 检测到致病性拷贝数变异。对核型和 CMA 结果正常的 196 例胎儿进行 WES 检测，发现其中 47 例（24%）的异常表型与潜在的遗传变异有关。仅胎儿-母亲-父亲和胎儿样本的分子诊断率分别为 26.5%（13/49）和 23.1%（34/147）。在 196 例胎儿中检测到意义不明的变异 12.8%（25/196），其中仅胎儿样本组中检测到 22 例（15%；22/147），仅母亲-父亲样本组中检测到 3 例（6.1%；3/49）。偶然发现率为 6.1%（12/196）。
WES 是一种很有前途的方法，可用于鉴定核型和 CMA 结果正常的胎儿结构异常的遗传变异。这种提高的诊断效能有可能改善妊娠的临床管理，并为受影响的家庭提供更好的生殖决策信息。版权所有 © 2017 ISUOG。由 John Wiley & Sons Ltd 出版。
