# Application of Prenatal Whole Exome Sequencing for Congenital Heart Anomalies

## TL;DR

Prenatal whole exome sequencing improves diagnosis of congenital heart anomalies by identifying genetic causes and guiding precision medicine.

## Contribution

Demonstrates the added diagnostic value of prenatal whole exome sequencing over existing methods for congenital heart disease.

## Key findings

- Prenatal WES detects pathogenic variants in 8.0% to 66.7% of cases not explained by CMA.
- Trio-based WES improves accuracy and reduces variant of uncertain significance compared to proband-only sequencing.
- WES reveals syndromic diagnoses, enabling better prenatal counseling and postnatal care.

## Abstract

Congenital heart disease (CHD) is the most common congenital anomaly worldwide and poses significant diagnostic challenges due to its structural complexity and frequent association with extracardiac anomalies and genetic abnormalities. While conventional tests such as karyotyping, quantitative fluorescent polymerase chain reaction (QF-PCR), and chromosomal microarray analysis (CMA) are standard first-tier investigations, many cases remain genetically unexplained. Prenatal whole exome sequencing (WES) has emerged as a valuable tool to detect pathogenic single gene variants underlying CHD. This narrative review synthesizes findings from 28 studies involving over 2000 WES-tested fetuses and more than 10,000 CHD cases. The additional diagnostic yield of WES over CMA ranged from 8.0% to 66.7%, with higher yields in syndromic or non-isolated CHD (10–50%) compared to isolated cases (7.1–27.8%). Trio-based WES outperformed proband-only sequencing by improving accuracy, reducing turnaround time, and lowering the rate of variant of uncertain significance (VUS). Prenatal WES not only clarifies genetic etiology but also reveals syndromic diagnoses, allowing CHD to be interpreted within broader multisystem contexts. Integration of phenotypic and genomic data enhances prenatal counseling, prognostication, delivery planning, and postnatal care—advancing precision medicine in fetal cardiology.