Estimate the Frequency of Causal Genetic Variants in Fetuses with Congenital Heart Defect: A Chinese Cohort Study

Purpose: This cohort study aims to estimate the prevalence of chromosomal abnormalities in fetuses with different types of congenital heart defect (CHD). Methods: In a cohort of 200 fetuses with CHD, we performed prenatal chromosome microarray analysis (CMA) firstly, and WES analysis was carried out on some selected fetuses with negative CMA results. Then, the relationship between chromosomal abnormalities and CHD types was discussed comprehensively.  Meanwhile, a systematic literature search to investigate hot spot pathogenic copy number variations (CNVs) associated with CHD in Chinese population.   Results: After prenatal CMA testing, 49 (24.5%)  CHD fetuses with chromosomal abnormalities were detected, including 11.5% of aneuploidies and 13.0% of clinical significant CNVs. The additional diagnostic yield by followed WES was 28.8% (15/52). The chromosomal abnormalities rate of the non-isolated CHD group and isolated CHD group were 31.8% and 20.9% (p<0.05) respectively. Importantly, the increase of chromosome abnormalities in non-isolated CHD was mainly due to the increase of aneuploidies (13.4% vs. 7.5%, p=0.110). There was no significant difference in chromosome abnormality rate between the simple CHD group and the complex CHD group (23.6% vs. 31.8%, p=0.398). Atrioventricular septal defect (AVSD) (54.5%) and complex CHD (31.8%) were revealed to have higher incidence of pathogenic chromosomal abnormalities. After summarized and analyzed our data and five literature reports, 22q11.2 was the most common region of clinical significant CNVs in Chinese population, and followed by 17p13.3p13.2, 11q24.2q25, 3q29 and 5p15.33p15.31. Conclusion: Almost half of CHD is associated with chromosomal abnormalities. CMA is the recommended initial examination for cases of CHD in the prenatal setting, including simple heart disease and isolated heart disease. The follow-up application of WES will offer a considerable proportion of additional detection of clinical significance. 22q11.2 was the most common pathogenic region of Chinese population. Funding Statement: This study was funded by the Changzhou Key Laboratory of High-tech Research (grant number CM20193009), Changzhou Social Development Science and Technology Support Project (grant number CE20205035), Jiangsu Maternal and Children Healthcare Key Discipline (FXK201754). Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethics Approval Statement: The study design and protocol were reviewed and approved by the Ethics Committee of the Changzhou Maternity and Child Health Care Hospital, Nanjing Medical University.