Genetic spectrum and clinical outcomes of fetal ventricular septal defect by ultrasound subtype: a prospective single-center cohort study

Ventricular septal defect (VSD) is the most frequently detected congenital heart defect on mid-trimester ultrasounds. We aimed to characterize the chromosomal and monogenic findings of fetal VSD across detailed ultrasound phenotypes and to evaluate associated pregnancy outcomes. This prospective single-center cohort included singleton pregnancies with fetal VSD detected between 2017 and 2024 for which single-nucleotide polymorphism array testing was performed. VSDs were classified as isolated or non-isolated, including additional cardiac anomalies, extracardiac anomalies (ECAs), or soft markers. VSD subtype was additionally classified as muscular, perimembranous, malalignment, or outlet/subarterial when determinable. Trio exome sequencing (ES) was performed in a subset of cases. Pregnancy outcomes were systematically assessed. Among 1,478 fetuses with VSD, clinically significant chromosomal abnormalities were more frequent in non-isolated than isolated cases (12.0% vs. 2.4%). The highest yield of clinically significant chromosomal abnormalities was observed in fetuses with ECAs (33.6%), followed by those with additional cardiac anomalies (12.8%) and soft markers (5.3%), compared with isolated VSD (2.4%). Among muscular, perimembranous, and malalignment VSDs, clinically significant chromosomal findings were least frequent in muscular VSDs (4.3%). Among the subset of cases undergoing trio ES, pathogenic or likely pathogenic single-nucleotide variants were identified in 7.9% (5/63) of isolated and 8.3% (9/109) of non-isolated cases, although most were not considered directly related to the VSD phenotype. Pregnancy outcomes varied substantially across ultrasound phenotypes, with termination rates increasing with phenotypic complexity. Fetal VSD is a heterogeneous condition, with genetic risk varying according to accompanying ultrasound findings. VSD accompanied by ECAs or additional cardiac anomalies showed the highest yields of clinically significant chromosomal abnormalities, while VSD with soft markers also showed a higher overall yield than isolated VSD. These findings may help inform phenotype-based prenatal counseling and support individualized discussions regarding genetic testing options.