Estimating the frequency of causal genetic variants in foetuses with congenital heart defects: a Chinese cohort study

(2022) 17:2 Lu et al. Orphanet Journal of Rare Diseases https://doi.org/10.1186/s13023-021-02167-8 Open Access RESEARCH Estimating the frequency of causal genetic variants in foetuses with congenital heart defects: a Chinese cohort study Fengying Lu1†, Peng Xue2†, Bin Zhang1, Jing Wang1, Bin Yu1* and Jianbin Liu1* Abstract Background: The belief that genetics plays a major role in the pathogenesis of congenital heart defects (CHD) has grown popular among clinicians. Although some studies have focused on the genetic testing of foetuses with CHD in China, the genotype–phenotype relationship has not yet been fully established, and hotspot copy number variations (CNVs) related to CHD in the Chinese population are still unclear. This cohort study aimed to assess the prevalence of chromosomal abnormalities in Chinese foetuses with different types of CHD. Results: In a cohort of 200 foetuses, chromosomal abnormalities were detected in 49 (24.5%) after a prenatal chromosome microarray analysis (CMA), including 23 foetuses (11.5%) with aneuploidies and 26 (13.0%) with clinically significant CNVs. The additional diagnostic yield following whole exome sequencing (WES) was 11.5% (6/52). The incidence of total chromosomal abnormality in the non-isolated CHD group (31.8%) was higher than that in the isolated CHD group (20.9%), mainly because the incidence of aneuploidy was significantly increased when CHD was combined with extracardiac structural abnormalities or soft markers. The chromosomal abnormality rate of the complex CHD group was higher than that of the simple CHD group; however, the difference was not statistically significant (31.8% vs. 23.6%, P = 0.398). The most common CNV detected in CHD foetuses was the 22q11.2 deletion, followed by deletions of 5p15.33p15.31, deletions of 15q13.2q13.3, deletions of 11q24.2q25, deletions of 17p13.3p13.2, and duplications of 17q12. Conclusions: CMA is the recommended initial examination for cases of CHD in prenatal settings, for both simple heart defects and isolated heart defects. For cases with negative CMA results, the follow-up application of WES will offer a considerable proportion of additional detection of clinical significance. Keywords: Congenital heart defects, Chromosomal abnormalities, Copy number variations, Chromosome microarray analysis, Whole exome sequencing Background Congenital heart defects (CHD) are the most common congenital defects, occurring in 5–8 in 1,000 live births [1, 2]. The occurrence of CHD is related not only to *Correspondence: ; † Fengying Lu and Peng Xue have contributed equally to this paper 1 Department of Medical Genetics, Changzhou Maternity and Child Health Care Hospital, Nanjing Medical University, Changzhou 213000, China Full list of author information is available at the end of the article genetic factors but also to some maternal factors, such as maternal infection with rubella virus, radiation, drug use, and environmental pollution [3, 4]. Recently, an increasing number of clinicians believe that genetics plays a central role in CHD pathogenesis. Known genetic causes include chromosomal abnormalities, chromosome copy number variations (CNVs), and mutations of heartrelated genes [5]. Chromosomal abnormalities were thought to be the most common causes of CHD [6, 7], © The Author(s) 2021. 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The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lu et al. Orphanet Journal of Rare Diseases (2022) 17:2 of which aneuploidies were the earliest identified and most common [8]. Trisomy 13, trisomy 18, trisomy 21, and Turner syndrome have also been confirmed to be associated with CHD [9]. Clinically significant CNVs have been detected in approximately 10%–15% of patients with CHD [10]. Notably, the deletions at 22q11.2 in DiGeorge syndrome were presented in approximately 2% of CHD patients and 13% of patients with specific cardiac malformations. However, CNVs and aneuploidy may only account for ~ 23% of CHD, overall. With the advances in sequencing technologies, genes associated with CHD have been discovered. It has been confirmed that more than 400 gene variants could cause human CHD. Genes such as, NKX2-5, TBX5, GATA6, CHD7, NOTCH1, etc. affect various aspects of cardiac development and function [11]. Likewise, a chromosome microarray analysis (CMA) can detect both chromosomal aberrations and CNVs at the genome-wide level. Currently, the CMA has been clinically recommended as the preferred cytogenetic diagnostic test for CHD [12]. The rapid development of next-generation sequencing technologies, particularly whole exome sequencing (WES), has uncovered mutations that cannot be defined by traditional genomic approaches, thereby facilitating the understanding of the genetics of complex diseases, such as CHD [13]. Recently, there have been some studies focused on the genetic testing of foetuses with CHD in China. Still, the genotype–phenotype relationship has not yet been fully established, and the hotspot CNVs related to CHD in the Chinese population remain unclear. Here, we present the CMA analysis of 200 CHD foetuses to evaluate the diagnostic effect of CMA for the prenatal diagnosis of CHD and investigate the possible genetic causes of prenatal CHD cases. Further, we aimed to identify new genes associated with CHD through WES and also explore the clinical value of WES in prenatal diagnosis. We also performed a systematic literature search to investigate hotspot pathogenic CNVs associated with CHD in the Chinese population. Our study further aimed to provide the basis for the standard method of gene detection in CHD foetuses. Results Aetiology of CHD Among the 200 foetuses included in the CMA test, 134 presented with isolated CHD and 66 presented with nonisolated CHD, including structural anomalies (n = 28), soft markers (n = 22), and structural anomalies and soft markers (n = 16). Of the 200 foetuses, 178 presented with simple CHD and 22 with complex CHD. Further, according to the anatomical classifi (...truncated)