Estimate the Frequency of Causal Genetic Variants in Fetuses With Congenital Heart Defects: a Chinese Cohort Study

Abstract Purpose: This cohort study was designed to assess the prevalence of chromosomal abnormalities in fetuses with different types of congenital heart defects (CHD).Methods: In a cohort of 200 fetuses with CHD, we performed prenatal chromosome microarray analysis (CMA) firstly, and then WES analysis was carried out on some fetuses with negative CMA results. Meanwhile, we conducted a systematic literature search on hot spot pathogenic copy number variations (CNVs) related to CHD in the Chinese population.Results: Chromosomal abnormalities were detected in 49 (24.5%) fetuses after prenatal CMA detection, including 23(11.5%) with aneuploidies and 26 (13.0%) with significant clinical CNVs. The additional diagnostic yield diagnosed by followed 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 combined with extracardial structural abnormalities or soft markers. The chromosome abnormal rate of complex CHD group was higher than that of the simple CHD group, but the difference was not statistically significant (31.8% vs. 23.6%, P = 0.398). The most common CNVs detected in CHD fetuses was the 22q11.2 deletions, followed by deletions of 5p15.33p15.31, deletions of 15q13.2q13.3, deletions of 11q24.2q25, deletions of 17p13.3p13.2, duplications of 17q12.Conclusion: CMA is the recommended initial examination for cases of CHD in the prenatal setting, whether it is simple heart defects or isolated heart defect. For cases with negative CMA results, the follow-up application of WES will offer a considerable proportion of additional detection of clinical significance.