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

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-021-02167-8.