Genetic aetiology distribution of 398 foetuses with congenital heart disease in the prenatal setting

Abstract

Aims 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. Methods and results 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 . Conclusions 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.

Efficiency of copy number variation sequencing combined with karyotyping in fetuses with congenital heart disease and the following outcomes

“…In our present paper, 28 cases (16.77%) of chromosomal aberrations were detected by karyotyping in 167 fetuses with CHD. The DR of aneuploidies accounted for 12.57% (21/167) in our study, among which trisomy 21 and 18 presented with the largest proportion (76.19%, 16/21), similar results to those in the literature [ 11 – 13 ]. The above information indicates that the dose alterations of genetic materials might increases the risk of malformations of fetuses [ 12 ].…”

“…Moreover, 3% to 25% of fetuses with CHD have been reported to be associated with PCNVs [ 9 , 14 , 15 ]. As shown in Table 3 , the pathogenic DR of CNV-seq was 23.17% (19/82) similar to that observed in the previous study [ 13 ], containing severe syndromes, such as SGBS1, 22q11.2 microdeletion. Relative to traditional karyotyping, an additional 7.32% PCNVs (6/82) by CNV-seq in our study was similar to previous research 7.70 ~ 7.95% by chromosome microarray analysis (CMA) [ 12 , 16 ].…”

Diagnostic yield after next-generation sequencing in pediatric cardiovascular disease

“… 19 One study attributed higher diagnostic yield in fetuses with non-isolated CHD (52/133, 39.10%) compared to fetuses with isolated CHD (77/265, 29.06%; p < 0.05) to differences in the frequency of chromosome aneuploidy. 22 In our study, it is of interest that patients with isolated cardiac defects had a higher median number of cardiac phenotypes compared to patients with syndromic cardiac defects ( Figure S1 A), but there was no significant association of the number of cardiac phenotypes with numbers of negative or positive diagnoses ( Figure S1 B). Participants with isolated vs. syndromic cardiac defects also varied with respect to their underlying cardiac diagnoses, with CHD having the highest rate of extracardiac findings ( p = 0.0048).…”

Editors' highlight picks from 2023 in ESC heart failure

“…Importantly, CNV-seq and ES revealed genetic abnormalities in almost 1/3 of foetal CHD cases suggesting that these methods can significantly advance diagnostic efforts, and thus, they will probably provide clinically relevant information for pregnancy management in the future. 55 Besides genetic predispositions, epigenetic factors are considered to be detrimental during the course of HF specific myocardial remodelling via cardiomyocyte loss, interstitial fibrosis, vascular remodelling, 56 and for both the left and the right ventricles. 57 Short non-coding RNA molecules, called microRNAs (miRNAs) have the potential to regulate gene expression at the post-transcriptional level and thereby to contribute to the HF specific phenotype.…”

“…Yi et al conducted a translational investigation on a cohort of 398 foetuses with CHD using high level genetic analyses: copy number variant‐sequencing (CNV‐seq) and exome sequencing (ES). Importantly, CNV‐seq and ES revealed genetic abnormalities in almost 1/3 of foetal CHD cases suggesting that these methods can significantly advance diagnostic efforts, and thus, they will probably provide clinically relevant information for pregnancy management in the future 55 …”