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Application of Prenatal Whole Exome Sequencing for Congenital Heart Anomalies
Threebhorn Kamlungkuea1,2, Fuanglada Tongprasert1,2, Duangrurdee Wattanasirichaigoon3
1Fetal Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Insights
Prenatal whole exome sequencing (WES) significantly improves genetic diagnosis for congenital heart disease (CHD) beyond conventional methods. Trio-based WES offers higher accuracy and faster results, aiding in better prenatal care and understanding of complex genetic conditions.
Area of Science:
- Medical Genetics
- Fetal Cardiology
- Genomic Medicine
Background:
- Congenital heart disease (CHD) is the most common birth defect, presenting complex diagnostic challenges.
- Standard genetic tests like CMA often fail to identify the underlying cause in many CHD cases.
- Prenatal diagnosis of CHD requires advanced genetic tools for accurate etiological identification.
Purpose of the Study:
- To review the diagnostic utility of prenatal whole exome sequencing (WES) for congenital heart disease (CHD).
- To compare the effectiveness of WES against conventional genetic testing methods for CHD.
- To highlight the benefits of WES in syndromic and isolated CHD cases and its impact on prenatal care.
Main Methods:
- Narrative review of 28 studies.
- Analysis of over 2000 fetuses tested with WES and more than 10,000 CHD cases.
- Synthesis of data on diagnostic yield, comparison of WES vs. CMA, and trio-based vs. proband-only WES.
Main Results:
- Prenatal WES demonstrated a significant additional diagnostic yield over chromosomal microarray analysis (CMA), ranging from 8.0% to 66.7%.
- Higher yields were observed in syndromic/non-isolated CHD (10-50%) compared to isolated CHD (7.1-27.8%).
- Trio-based WES improved accuracy, reduced turnaround time, and lowered variant of uncertain significance (VUS) rates compared to proband-only sequencing.
Conclusions:
- Prenatal WES is a powerful tool for clarifying the genetic etiology of CHD, including syndromic diagnoses.
- WES facilitates a comprehensive understanding of CHD within multisystem contexts.
- Integrating genomic data with phenotypic information enhances prenatal counseling, planning, and postnatal care, advancing precision medicine in fetal cardiology.
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.
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