United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen, China.
Department of Medical Ultrasonics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.
Cytogenet Genome Res. 2022;162(7):354-364. doi: 10.1159/000528600. Epub 2023 Mar 10.
Fetal cystic hygroma (CH) is associated with poor prognosis and chromosomal anomalies. Recent studies have suggested that the genetic background of affected fetuses is essential for predicting pregnancy outcomes. However, the detection performance of different genetic approaches for the etiological diagnosis of fetal CH remains unclear. In this study, we aimed to compare the diagnostic efficiency of karyotyping and chromosomal microarray analysis (CMA) in a local fetal CH cohort, and tried to propose an optimized testing strategy that may help improve the cost-effectiveness of disease management. We reviewed all pregnancies that underwent invasive prenatal diagnosis between January 2017 and September 2021 at one of the largest prenatal diagnostic centers in Southeast China. We collected cases identified by the presence of fetal CH. Prenatal phenotypes and laboratory records of these patients were audited, collated, and analyzed. The detection rates of karyotyping and CMA were compared, and the concordance rate of these two methods was calculated. A total of 157 fetal CH cases were screened from 6,059 patients who underwent prenatal diagnosis. Diagnostic genetic variants were identified in 44.6% (70/157) of the cases. Karyotyping, CMA, and whole-exome sequencing (WES) identified pathogenic genetic variants in 63, 68, and 1 case, respectively. The Cohen's κ coefficient between karyotyping and CMA was 0.96, with a concordance of 98.0%. Of the 18 cases in which cryptic copy number variants <5 Mb were detected by CMA, 17 were interpreted as variants of uncertain significance, and the remaining cases were interpreted as pathogenic. Trio exome sequencing revealed a pathogenic homozygous splice site mutation in the PIGN gene in a case undiagnosed by CMA and karyotyping. Our study demonstrated that chromosomal aneuploidy abnormalities are the main genetic cause of fetal CH. Based on this, we recommend karyotyping combined with rapid aneuploidy detection as a first-tier approach for the genetic diagnosis of fetal CH. WES and CMA could improve the diagnostic yield when routine genetic tests fail to determine the cause of fetal CH.
胎儿囊状水瘤（CH）与不良预后和染色体异常有关。最近的研究表明，受影响胎儿的遗传背景对于预测妊娠结局至关重要。然而，不同遗传方法在胎儿 CH 的病因诊断中的检测性能仍不清楚。在这项研究中，我们旨在比较核型分析和染色体微阵列分析（CMA）在当地胎儿 CH 队列中的诊断效率，并尝试提出一种优化的检测策略，以帮助提高疾病管理的成本效益。我们回顾了 2017 年 1 月至 2021 年 9 月期间在中国东南部最大的产前诊断中心之一进行的所有侵袭性产前诊断的妊娠。我们收集了通过胎儿 CH 存在确定的病例。审核了这些患者的产前表型和实验室记录，并进行了整理和分析。比较了核型分析和 CMA 的检测率，并计算了这两种方法的一致性率。从 6059 名接受产前诊断的患者中筛选出 157 例胎儿 CH 病例。在 70/157 例（44.6%）病例中发现了诊断性遗传变异。核型分析、CMA 和全外显子组测序（WES）分别鉴定出致病性遗传变异 63、68 和 1 例。核型分析和 CMA 之间的 Cohen's κ 系数为 0.96，一致性为 98.0%。在 CMA 检测到的 18 例<5 Mb 的隐匿性拷贝数变异中，17 例被解释为意义不明的变异，其余病例被解释为致病性。对 CMA 和核型分析均未诊断的 1 例病例进行三体外显子测序，发现 PIGN 基因的致病性纯合剪接位点突变。我们的研究表明，染色体非整倍体异常是胎儿 CH 的主要遗传原因。在此基础上，我们建议核型分析结合快速非整倍体检测作为胎儿 CH 遗传诊断的一线方法。当常规遗传检测无法确定胎儿 CH 的病因时，WES 和 CMA 可以提高诊断率。
