Beijing Key Laboratory of Maternal-Fetal Medicine and Fetal Heart Disease, Capital Medical University Affiliated Anzhen Hospital, Beijing, China.
ESC Heart Fail. 2023 Apr;10(2):917-930. doi: 10.1002/ehf2.14209. Epub 2022 Dec 7.
Copy number variant-sequencing (CNV-seq) and exome sequencing (ES) have been used as powerful tools in understanding the role of genetic variants in congenital heart diseases (CHDs). A few previous large cohort studies have utilized CNV-seq and ES to investigate prenatally diagnosed CHD. Here, we sought to determine the value of CNV-seq and ES for genetic evaluation of foetal CHDs.
We recruited 398 pregnant women diagnosed with CHDs between 8 January 2017 and 30 November 2020. CNV-seq and ES were performed on foetal and parent samples. CHD cases were classified following the guidelines of the International Paediatric and Congenital Cardiac Code and the Tenth and Eleventh Revisions of the International Classification of Diseases. Data on aneuploids (AUP), pathogenic CNVs (pCNVs), and single nucleotide variants (SNVs) were collected and compared, following appropriate procedures. We identified genetic abnormalities in 129 (32.41%) foetuses. These abnormalities included AUP (10.80%), pCNVs (13.32%), and SNVs (8.04%). ES analysis yielded higher SNVs in cases without AUP or pCNVs. Non-isolated CHDs were associated with higher genetic abnormalities than isolated CHDs, mainly due to AUP differences between the two groups. The prevalence of genetic defects was the highest in foetuses with atrioventricular septal defects (AVSD), left ventricular outflow tract obstruction (LVOTO), and conotruncal defects (CTD). AVSD and anomalies of atrioventricular junctions and valves were associated with AUP abnormalities. CTD, anomalies of extrapericardial arterial trunks, and anomalies of the ventricular outflow tracts were the most common CHD categories diagnosed using CNVs. The most common CHDs associated with single ventricle (SV) abnormalities were heterotaxy (Hex) (14.89%), LVOTO (14.58%), and ventricular septal defect (VSD) (26.67%, 4/15). Although the ES yields were higher than CNV-seq for VSD (44.4%, 4/9), LVOTO (20%, 7/35), Hex (14.89%, 7/47), and CTD (9.1%, 11/121), its diagnostic yield did not increase for SV (6.7%, 1/15), AVSD (3.8%, 1/26), or right ventricular obstruction defects (2.6%, 1/38). The most common mutations were observed in KMT2D, CHD7, and NOTCH1.
To our knowledge, this is the largest cohort study to investigate the incidence of SNVs using ES in foetal CHD. CNV-seq and ES identified genetic abnormalities in nearly 1/3 of foetal CHD cases. Thus, CNV-seq and ES can provide clinically relevant information for pregnancy management.
拷贝数变异-测序（CNV-seq）和外显子组测序（ES）已被用于理解遗传变异在先天性心脏病（CHD）中的作用的有力工具。一些先前的大型队列研究已经利用 CNV-seq 和 ES 来研究产前诊断的 CHD。在这里，我们旨在确定 CNV-seq 和 ES 对胎儿 CHD 遗传评估的价值。
我们招募了 398 名在 2017 年 1 月 8 日至 2020 年 11 月 30 日期间被诊断为 CHD 的孕妇。对胎儿和父母样本进行了 CNV-seq 和 ES 分析。CHD 病例按照国际儿科和先天性心脏病分类以及国际疾病分类第十和第十一次修订的指南进行分类。收集并比较了非整倍体（AUP）、致病性 CNV（pCNV）和单核苷酸变异（SNV）的数据，并按照适当的程序进行了比较。我们在 129 名（32.41%）胎儿中发现了遗传异常。这些异常包括 AUP（10.80%）、pCNV（13.32%）和 SNV（8.04%）。ES 分析在没有 AUP 或 pCNV 的情况下产生了更高的 SNVs。非孤立性 CHD 与更高的遗传异常有关，主要是由于两组之间 AUP 的差异。在患有房室间隔缺损（AVSD）、左心室流出道梗阻（LVOTO）和圆锥动脉干畸形（CTD）的胎儿中，遗传缺陷的发生率最高。AVSD 和房室结及瓣膜异常与 AUP 异常有关。CTD、心包外动脉干异常和流出道心室异常是使用 CNVs 诊断最常见的 CHD 类别。与单心室（SV）异常相关的最常见 CHD 是异构症（Hex）（14.89%，14/99）、LVOTO（14.58%，14/99）和室间隔缺损（VSD）（26.67%，4/15）。尽管 ES 对 VSD（44.4%，4/9）、LVOTO（20%，7/35）、Hex（14.89%，7/47）和 CTD（9.1%，11/121）的检出率高于 CNV-seq，但对 SV（6.7%，1/15）、AVSD（3.8%，1/26）或右心室梗阻性缺损（2.6%，1/38）的诊断率并未增加。最常见的突变发生在 KMT2D、CHD7 和 NOTCH1 中。
据我们所知，这是最大的队列研究，使用 ES 研究胎儿 CHD 中的 SNV 发生率。CNV-seq 和 ES 在近 1/3 的胎儿 CHD 病例中发现了遗传异常。因此，CNV-seq 和 ES 可以为妊娠管理提供临床相关信息。
