Theoretical Performance of Comprehensive Non-Invasive Prenatal Screening in Congenital Heart Defects

Comprehensive prenatal screening (CPS) (carrier screening and cfDNA for aneuploidy, 22q11.2 deletion syndrome, CNVs > 7Mb, and single gene disorders) can non-invasively identify genetic conditions in fetuses with congenital heart defects (CHD). We calculated the theoretical performance of CPS for CHDs with underlying genetic diagnoses. Secondarily, we compared theoretical performances across CHD subtypes and by the presence of extracardiac anomalies.

We retrospectively examined cases of fetal cardiac anomalies with known causative genetic diagnoses from January 2020 to October 2024. We calculated theoretical CPS performance by determining which genetic diagnoses were identifiable by CPS modalities.

We extracted 153 fetuses with CHD and a known causative genetic diagnosis. Diagnoses included aneuploidies (37%), single gene disorders (22%), CNVs (18%), 22q11.2 deletion syndrome (17%), multiple diagnoses (6%), and uniparental disomy (1%). Of the 153 cases, 117 were identifiable by CPS, corresponding to a theoretical performance of 76%. Theoretical performances did not differ significantly across CHD categories or by the presence of extracardiac anomalies.

Antenatal diagnostic testing remains the standard of care for fetal anomalies. Among individuals who decline diagnostic testing, our findings suggest that, in cases where a CHD has an underlying genetic cause, an optimal combination of currently available screening tests could theoretically identify up to 76% of genetic causes. However, actual performance will be lower in clinical practice.