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Recent advances in the understanding of genetic causes of congenital heart defects
1Departments of Pediatrics and Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA. gelb@msvax.mssn.edu
Insights
Genetic research reveals single-gene defects are a more common cause of congenital heart defects (CHD) than previously thought. Understanding these genetic underpinnings is crucial for improving diagnosis and treatment for affected children.
Area of Science:
- Medical Genetics
- Pediatric Cardiology
- Developmental Biology
Background:
- Congenital heart defects (CHD) management has advanced significantly over four decades.
- Understanding the etiology of most CHD has lagged behind clinical advancements.
- Previous studies indicated Mendelian disorders were rare causes of CHD, with polygenic inheritance being dominant.
Purpose of the Study:
- To review molecular genetic studies on specific heart malformations and CHD syndromes.
- To highlight recent insights into the genetic basis of heart malformations.
- To discuss future challenges in applying genomic discoveries to CHD diagnosis and treatment.
Main Methods:
- Review of molecular genetic studies focusing on CHD.
- Analysis of findings from the Human Genome Project related to Mendelian traits with heart defects.
- Synthesis of current knowledge on the genetic causes of congenital heart defects.
Main Results:
- Single-gene or single-locus defects are more prevalent in causing CHD than previously suspected.
- A higher proportion of heart malformations are associated with familial disease.
- Molecular genetic studies have provided new insights into the genetic basis of heart malformations.
Conclusions:
- The identification of genes responsible for Mendelian forms of CHD is accelerating.
- Future efforts will focus on integrating genetic information for improved CHD diagnosis and therapy.
- Genomic approaches are essential for analyzing complex inheritance patterns in isolated heart defects.
Abstract:
The clinical approach to children with congenital heart defects (CHD) has been revolutionized during the past four decades by developments in diagnostics and therapeutics. In contrast, a profound understanding of the causes of the majority of CHD has only begun to emerge within the past few years. Prior epidemiological studies suggested that Mendelian disorders constituted a very small percentage of CHD and that polygenic inheritance was responsible for the majority of cases. Recent discoveries, largely achieved with molecular genetic studies, have provided new insights into the genetic basis of heart malformations. These studies have shown that CHD caused by single gene or single locus defects is more common than had been suspected. In addition, a higher percentage of heart malformations occur in the context of familial disease than was evident previously. In this review, molecular genetic studies of specific heart lesions and syndromes with CHD are reviewed. Progress on the Human Genome Project has accelerated identification of genes for Mendelian traits with heart defects, and it is anticipated that disease genes for most single gene traits will be known within a few years. Future challenges include utilizing this emerging genetic information to improve diagnosis and treatment of children with CHD, and harnessing the power of genomics to analyze isolated heart defects with complex inheritance patterns.