Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA
Ilse Meerschaut1,2, Wouter Steyaert1,3, Thierry Bové4
1Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
Insights
This study investigated the genetic causes of isolated congenital heart defects (CHD) using exome sequencing on cardiac tissue. Results suggest rare inherited and de novo variants contribute to ICHD, not somatic mutations.
Area of Science:
- Genetics
- Developmental Biology
- Cardiology
Background:
- Congenital heart defects (CHD) are common birth anomalies.
- The genetic basis of isolated CHD (ICHD) is complex and poorly understood.
- Both Mendelian conditions and multifactorial genetic architectures are implicated in ICHD.
Purpose of the Study:
- To investigate the genetic underpinnings of isolated congenital heart defects (ICHD).
- To explore the roles of germline de novo variants, inherited variants, and somatic mosaicism in ICHD.
- To assess the diagnostic utility of exome sequencing on cardiac tissue for ICHD.
Main Methods:
- Exome sequencing (ES) was performed on DNA from cardiac tissue of 73 parent-offspring ICHD trios.
- Analysis included identification of germline de novo and inherited variants.
- Transmission disequilibrium testing (TDT) and association testing (AT) were employed.
Main Results:
- No CHD-relevant somatic variants were detected.
- Six germline de novo variants and 625 rare inherited variants with predicted damaging effects were identified in cardiac-relevant genes.
- Association testing showed a potential link between missense variants in cilia genes and ICHD.
Conclusions:
- Somatic mutations are unlikely to be a common cause of ICHD.
- Rare de novo and inherited protein-damaging variants may contribute to ICHD, potentially within oligogenic or polygenic models.
- Exome sequencing on cardiac tissue has limited diagnostic value for individual ICHD cases, though TDT and AT provide a foundation for larger studies.
Abstract:
Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian conditions, somatic mosaicism or a complex multifactorial genetic architecture are assumed for most ICHD. We performed exome sequencing (ES) in 73 parent-offspring ICHD trios using proband DNA extracted from cardiac tissue. We identified six germline de novo variants and 625 germline rare inherited variants with 'damaging' in silico predictions in cardiac-relevant genes expressed in the developing human heart. There were no CHD-relevant somatic variants. Transmission disequilibrium testing (TDT) and association testing (AT) yielded no statistically significant results, except for the AT of missense variants in cilia genes. Somatic mutations are not a common cause of ICHD. Rare de novo and inherited protein-damaging variants may contribute to ICHD, possibly as part of an oligogenic or polygenic disease model. TDT and AT failed to provide informative results, likely due to the lack of power, but provided a framework for future studies in larger cohorts. Overall, the diagnostic value of ES on cardiac tissue is limited in individual ICHD cases.
