Abstract：
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.
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.
摘要：
目的：拷贝数变异测序（CNV-seq）和外显子组测序（ES）已被用作了解遗传变异在先天性心脏病（CHD）中的作用的有力工具。先前的一些大型队列研究已经利用CNV-seq和ES来调查产前诊断的CHD。这里,我们试图确定CNV-seq和ES在胎儿CHD遗传评估中的价值。
结果：我们招募了398名在2017年1月8日至2020年11月30日期间诊断为冠心病的孕妇。对胎儿和母体样品进行CNV-seq和ES。根据《国际儿科和先天性心脏病法典》以及《国际疾病分类》第十次和第十一次修订的指南对CHD病例进行分类。非整倍体数据（AUP），致病性CNVs（pCNVs），收集并比较单核苷酸变体（SNV），遵循适当的程序。我们在129个（32.41％）胎儿中发现了遗传异常。这些异常包括AUP（10.80％），pCNVs（13.32%），和SNV（8.04%）。ES分析在没有AUP或pCNV的情况下产生更高的SNV。非孤立性CHD比孤立性CHD与更高的遗传异常相关，主要是由于两组之间的AUP差异。在房室间隔缺损（AVSD）的胎儿中，遗传缺陷的患病率最高。左心室流出道梗阻(LVOTO),和截尾缺损（CTD）。AVSD和房室连接处和瓣膜异常与AUP异常有关。CTD,心外动脉干的异常,和心室流出道异常是使用CNV诊断的最常见的CHD类别。与单心室（SV）异常相关的最常见的CHD是异位性（Hex）（14.89％），LVOTO（14.58%），室间隔缺损（VSD）（26.67％，4/15）。尽管ES产率高于VSD的CNV-seq(44.4%，4/9),LVOTO(20%，7/35），十六进制（14.89%，7/47),和CTD（9.1%，11/121),SV的诊断率没有增加(6.7%，1/15),AVSD（3.8%，1/26),或右心室梗阻缺陷（2.6%，1/38).在KMT2D中观察到最常见的突变，CHD7和NOTCH1。
结论：据我们所知，这是调查胎儿CHD中使用ES的SNV发生率的最大队列研究.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。
结果：我们招募了398名在2017年1月8日至2020年11月30日期间诊断为冠心病的孕妇。对胎儿和母体样品进行CNV-seq和ES。根据《国际儿科和先天性心脏病法典》以及《国际疾病分类》第十次和第十一次修订的指南对CHD病例进行分类。非整倍体数据（AUP），致病性CNVs（pCNVs），收集并比较单核苷酸变体（SNV），遵循适当的程序。我们在129个（32.41％）胎儿中发现了遗传异常。这些异常包括AUP（10.80％），pCNVs（13.32%），和SNV（8.04%）。ES分析在没有AUP或pCNV的情况下产生更高的SNV。非孤立性CHD比孤立性CHD与更高的遗传异常相关，主要是由于两组之间的AUP差异。在房室间隔缺损（AVSD）的胎儿中，遗传缺陷的患病率最高。左心室流出道梗阻(LVOTO),和截尾缺损（CTD）。AVSD和房室连接处和瓣膜异常与AUP异常有关。CTD,心外动脉干的异常,和心室流出道异常是使用CNV诊断的最常见的CHD类别。与单心室（SV）异常相关的最常见的CHD是异位性（Hex）（14.89％），LVOTO（14.58%），室间隔缺损（VSD）（26.67％，4/15）。尽管ES产率高于VSD的CNV-seq(44.4%，4/9),LVOTO(20%，7/35），十六进制（14.89%，7/47),和CTD（9.1%，11/121),SV的诊断率没有增加(6.7%，1/15),AVSD（3.8%，1/26),或右心室梗阻缺陷（2.6%，1/38).在KMT2D中观察到最常见的突变，CHD7和NOTCH1。
结论：据我们所知，这是调查胎儿CHD中使用ES的SNV发生率的最大队列研究.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。
