Prenatal Diagnoses in Fetuses With Simple and Complex Cardiac Malformations through Chromosomal Microarray and Exome Sequencing

Background: This study aimed to explore the differences in the detection rates of chromosomal abnormalities in simple and complex congenital heart disease (CHD) and the association between these rates and genetic factors. Methods: A total of 211 fetuses diagnosed with CHD through prenatal ultrasound at the fetal medicine unit of Zhejiang Jiaxing Maternal and Child Health Care Hospital from July 2017 to December 2023 were retrospectively analyzed. Cases were classified as simple or complex cardiac malformations. Chromosomal microarray analysis (CMA) was used as the primary genetic assessment following invasive sampling in all CHD cases. Clinical exome sequencing (ES) or Trio exome sequencing (Trio-ES) was applied prenatally when the CMA results were nondiagnostic. Results: Of the 211 fetuses, 62.6% and 37.4% presented with simple and complex malformations, respectively. The CMA reported an overall positive rate of 19.0% across all cases: 11.4% for simple cardiac malformations and 31.6% for complex cardiac malformations. The detection rate of chromosomal abnormalities was significantly higher in complex cases (22.8%) than in simple malformations (6.1%; p < 0.001). Among the isolated CHD cases, 8.7% exhibited chromosomal abnormalities, predominantly in complex malformations (20.0% vs. 2.9% for simple malformations; p < 0.001). Meanwhile, the rate was high (23.5%) in non-isolated CHD, but simple and complex malformations did not differ significantly. ES was performed for 32 cases with negative CMA results. One pathogenic (P)/likely pathogenic (LP) variant was identified through Trio-ES in simple malformations, while two P/LP variants were detected in complex malformations. Conclusions: Differentiated genetic assessments could be included in prenatal diagnosis, because complex CHD correlated strongly with chromosomal and genetic anomalies rather than with simple malformations. This finding, although based on a small population, suggests that non-cardiac anomalies may be important indicators for genetic testing regardless of the complexity of heart defects. Therefore, genetic testing could be offered to patients with simple or isolated CHD.