Integrative prenatal imaging and genomic testing in fetal congenital heart defects: Insights from a 30-year retrospective study

To assess the combined role of prenatal imaging and stepwise genetic testing in diagnosing fetal congenital heart defects (CHDs) over a 30-year period, focusing on CHD subtypes, extracardiac anomalies, and diagnostic yield.

This retrospective cohort study included 423 fetuses diagnosed with CHDs at Taichung Veterans General Hospital between 1995 and 2024. All underwent detailed fetal echocardiography. Genetic testing was conducted using a tiered approach: most cases underwent karyotyping, with chromosomal microarray analysis (CMA), targeted gene panels, or whole-exome sequencing (WES) added based on clinical indications. Diagnostic yields were assessed by testing modality, with subgroup analyses based on CHD type and extracardiac features.

Septal defects were the most common diagnosis (18.7 %), increasing to 26.5 % when coexisting intracardiac anomalies were included. Cyanotic CHDs predominated (39.5 %), followed by miscellaneous anomalies (22.9 %), left-to-right shunts (18.9 %), obstructive lesions (11.6 %), and arrhythmias (7.1 %). Extracardiac structural problems and fetal hydrops were present in 22.2 % and 5.0 %, respectively. Chromosomal abnormalities were detected in 12.3 % (40/326), predominantly trisomies, and were significantly associated with left-to-right shunts (55 %, P < 0.001) and extracardiac problems (62.5 %, P < 0.001). Among the 181 cases with normal karyotypes, CMA identified pathogenic or likely pathogenic copy number variants in 7.7 %, including deletions at 22q11.21 (involving TBX1), 7q11.23 (involving ELN), and 16q24.2-q24.3 (involving ZFPM1), among others. With the addition of WES or targeted sequencing, the overall diagnostic yield rose to 14.1 % (27/191), with pathogenic or likely pathogenic variants detected including ANKRD11, ACVRL1, EFTUD2, TSC2, and FBN1. The diagnostic yield P was significantly higher in fetuses with extracardiac problems (51.9 %, P < 0.001).

Combining prenatal imaging with tiered genetic testing enhances the diagnostic precision in fetal CHDs, particularly in cases with extracardiac anomalies and left-to-right shunts. These findings support a clinically driven, resource-sensitive approach to prenatal genetic evaluation.